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Webster EM, Ahsan MD, Chandler IR, Primiano M, Mcdougale A, Howard D, Fishman D, Rosenberg SM, Chapman-Davis E, Levi S, Grant B, Bull LE, Christos P, Sharaf RN, Frey MK. Digital tool for genetic cancer risk assessment in a historically underserved population: a randomized controlled trial. Am J Obstet Gynecol 2025:S0002-9378(25)00172-3. [PMID: 40157522 DOI: 10.1016/j.ajog.2025.03.026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2024] [Revised: 03/15/2025] [Accepted: 03/18/2025] [Indexed: 04/01/2025]
Abstract
BACKGROUND Up to 95% of individuals with cancer-predisposing germline pathogenic variants in the U.S. remain unidentified, particularly among historically underserved populations. OBJECTIVE In this 2-arm randomized controlled trial, we compared the proportion of high-risk patients identified and recommended for hereditary cancer syndrome genetic testing when risk assessment was performed by a digital tool vs usual clinician interview. STUDY DESIGN New gynecology patients at an urban academic clinic were randomized 1:1 to either a digital risk stratification tool or usual clinician-driven interview for genetic risk assessment. Eligibility for genetic testing was determined by criteria set forth by the National Comprehensive Cancer Network. The primary outcome was the proportion of high-risk patients identified and recommended for hereditary cancer syndrome genetic testing. The secondary outcomes were completion of genetic testing and exploration of patient factors including social determinants of health. RESULTS From January to December 2023, 100 patients enrolled in the study; 51 were randomized to genetic cancer risk assessment via digital tool and 49 via usual clinician interview. Thirty-nine (39%) patients self-identified as Hispanic, 23 (23%) as non-Hispanic White, 20 (20%) as non-Hispanic Black, 11 (11%) as Asian, 2 (2%) as mixed race, and 5 (5%) preferred not to answer. Most patients had Medicaid insurance (68; 68%), and 32 (32%) reported having a household income of less than $40,000. In the intervention arm, 44 (86%) completed the digital tool. Twenty-one (21%) patients were identified by study personnel as high-risk and met criteria for genetic testing (intervention: 8; control: 13). Use of the genetic cancer risk assessment tool was associated with a higher likelihood of high-risk patients being identified and recommended for genetic testing (7 [88%] vs 2 [15%]; P=.002). Among high-risk patients, 4 (50%) in the intervention arm and 2 (15%) in the control arm proceeded with genetic testing for hereditary cancers (P=.146). Within the intervention arm, social determinants of health did not impact use of the digital tool. CONCLUSION In a historically underserved population, the use of a digital genetic cancer risk stratification tool led to increased identification and counseling high-risk patients identified and recommended for genetic testing. The integration of a digital risk stratification tool may work toward mitigating disparities in utilization of genetic services.
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Affiliation(s)
- Emily M Webster
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA; Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine, New York, NY, USA.
| | - Muhammad Danyal Ahsan
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA; Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine, New York, NY, USA
| | - Isabelle R Chandler
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA; Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine, New York, NY, USA
| | - Michelle Primiano
- Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine, New York, NY, USA
| | - Auja Mcdougale
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Denise Howard
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - David Fishman
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Shoshana M Rosenberg
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Eloise Chapman-Davis
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Sarah Levi
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Benjamin Grant
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Leslie E Bull
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA
| | - Paul Christos
- Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | - Ravi N Sharaf
- Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine, New York, NY, USA; Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA; Department of Medicine, Weill Cornell Medicine, New York, NY, USA
| | - Melissa K Frey
- Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY, USA; Genetics and Personalized Cancer Prevention Program, Weill Cornell Medicine, New York, NY, USA
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Holtzman S, Cox M, Blank SV. The Current State-or Lack Thereof-of Screening and Prevention for Gynecologic Malignancies for Patients With Lynch Syndrome. Clin Obstet Gynecol 2024; 67:687-695. [PMID: 39431490 DOI: 10.1097/grf.0000000000000892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2024]
Abstract
Lynch syndrome (LS) is an autosomal dominant genetic disorder that results in an increased risk of ovarian and endometrial cancers. The aim of this paper was to explore the management of this risk through screening and prevention. Published materials and evidence were explored and summarized. This paper demonstrated that while there has been increased awareness and advances in the identification and diagnosis of patients with LS, recommendations for screening and prevention remain less evidence-based. In decisions of management of patients with LS, a shared decision-making model should be used considering individual patient goals.
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Affiliation(s)
- Sharonne Holtzman
- Department of Obstetrics, Gynecology and Reproductive Sciences, Icahn School of Medicine at Mount Sinai, New York, New York
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Chen YP, Hsiao TH, Lin WT, Liao YJ, Liao SC, Tsai HJ, Chen YJ, Jhan PP, Kao PY, Lin YC, Chuang HN. Characteristics of Cancer in Subjects Carrying Lynch Syndrome-Associated Gene Variants in Taiwanese Population: A Hospital-Based Study in Taiwan. Cancers (Basel) 2024; 16:3682. [PMID: 39518119 PMCID: PMC11544957 DOI: 10.3390/cancers16213682] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/26/2024] [Accepted: 10/29/2024] [Indexed: 11/16/2024] Open
Abstract
Lynch syndrome (LS) is an autosomal dominant disorder characterized by increased risks of colorectal and endometrial cancers. LS is defined by pathogenic variants in mismatch repair (MMR) genes, including MLH1, MSH2, and MSH6. Data on the prevalence and associated cancer risks of LS in the Han Chinese population remain limited. In this study, using a broad biobank approach through the Taiwan Precision Medicine Initiative (TPMI), we identified LS-associated MMR gene variants within a cohort of 42,828 participants from a Taiwanese medical center. A total of 89 individuals were found to carry pathogenic MMR variants: MLH1 (n = 22, 25%), MSH2 (n = 47, 53%), and MSH6 (n = 20, 22%). The overall prevalence of MMR variants was calculated, and cancer incidence rates among carriers were determined. The prevalence of MMR variants in the study population was 1 in 481. The distribution of MLH1, MSH2, and MSH6 variants were 24.7%, 52.8%, and 22.5%, respectively. Cumulative cancer incidence rates of carriers were 40.9% for MLH1 carriers, 29.8% for MSH2, and 40% for MSH6. Among the 19 individuals who underwent colonoscopy screening, the prevalence of polyps was similar to that of the control group (adenoma detection rate: 32% vs 26%, p = 0.585). A meticulous analysis of the detected polyps in seven participants, considering factors such as location, size, morphology, and pathological features, showed no significant differences from controls. A significant cancer risk is associated with LS-related MMR variants in the Taiwanese population. The apparent under diagnosis of LS highlights the urgent need for enhanced surveillance and genetic counseling in this demographic. Our findings suggest that adjustments in the current screening protocols may be warranted to better identify and manage at-risk individuals.
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Affiliation(s)
- Yi-Peng Chen
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-P.C.); (W.-T.L.); (Y.-J.L.); (S.-C.L.); (H.-J.T.)
| | - Tzu-Hung Hsiao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (T.-H.H.); (Y.-J.C.); (P.-P.J.); (P.-Y.K.)
- Department of Public Health, Fu Jen Catholic University, New Taipei City 24205, Taiwan
- Institute of Genomics and Bioinformatics, National Chung Hsing University, Taichung 40227, Taiwan
| | - Wan-Tzu Lin
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-P.C.); (W.-T.L.); (Y.-J.L.); (S.-C.L.); (H.-J.T.)
| | - Yi-Jun Liao
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-P.C.); (W.-T.L.); (Y.-J.L.); (S.-C.L.); (H.-J.T.)
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
| | - Szu-Chia Liao
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-P.C.); (W.-T.L.); (Y.-J.L.); (S.-C.L.); (H.-J.T.)
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
| | - Hsin-Ju Tsai
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-P.C.); (W.-T.L.); (Y.-J.L.); (S.-C.L.); (H.-J.T.)
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
| | - Yen-Ju Chen
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (T.-H.H.); (Y.-J.C.); (P.-P.J.); (P.-Y.K.)
- Division of Allergy, Immunology and Rheumatology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan
- School of Medicine, National Yang Ming Chiao Tung University, Taipei 112304, Taiwan
| | - Pei-Pei Jhan
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (T.-H.H.); (Y.-J.C.); (P.-P.J.); (P.-Y.K.)
| | - Pei-Ying Kao
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (T.-H.H.); (Y.-J.C.); (P.-P.J.); (P.-Y.K.)
| | - Ying-Cheng Lin
- Division of Gastroenterology, Department of Internal Medicine, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (Y.-P.C.); (W.-T.L.); (Y.-J.L.); (S.-C.L.); (H.-J.T.)
- Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung 40227, Taiwan
| | - Han-Ni Chuang
- Department of Medical Research, Taichung Veterans General Hospital, Taichung 40705, Taiwan; (T.-H.H.); (Y.-J.C.); (P.-P.J.); (P.-Y.K.)
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Noah N, Gilani M, Kumar R. Asymptomatic endometrial cancer with Lynch syndrome; in a woman with primary infertility-A case report and literature review. Int J Gynaecol Obstet 2024; 167:58-61. [PMID: 38695128 DOI: 10.1002/ijgo.15578] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 04/08/2024] [Accepted: 04/21/2024] [Indexed: 09/25/2024]
Abstract
Lynch syndrome, also called hereditary non-polyposis colorectal cancer, is an autosomal dominant disorder characterized by germline pathogenic mutations in DNA mismatch repair genes-resulting in increased susceptibility to colorectal, endometrial, and other tumors. This case report presents an incidental finding of endometrial cancer with Lynch syndrome during investigation for primary infertility. A 34-year-old woman presented to the fertility clinic with unexplained primary infertility. Investigations showed possible endometrial polyp, 13 × 11 mm in size. Hysteroscopic polypectomy and endometrial biopsy revealed complex endometrial hyperplasia amounting to endometroid adenocarcinoma. The case was discussed at the West of Scotland Gynecology-Oncology MDT meeting-management options including fertility-sparing treatment or radical surgery were presented to the patient and she opted for the latter. A total laparoscopic hysterectomy with bilateral salpingo-oophorectomy was performed with pathology results consistent with well-differentiated endometroid adenocarcinoma Stage 1A. Peritoneal washings showed no malignant cells. Genetic testing confirmed a diagnosis of Lynch syndrome. On further questioning, it was revealed that the patient had a strong family history of colon cancer but had not previously met the criteria for genetic testing. She was referred to colorectal surgeons and underwent colonoscopy. This showed no abnormality; she was therefore scheduled for 2-yearly colonoscopic surveillance.
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Affiliation(s)
- Nancy Noah
- Department of Obstetrics and Gynaecology, University Hospital Wishaw, NHS Lanarkshire, Wishaw, UK
| | - Misha Gilani
- Department of Obstetrics and Gynaecology, University Hospital Wishaw, NHS Lanarkshire, Wishaw, UK
| | - Ranitha Kumar
- Department of Obstetrics and Gynaecology, University Hospital Wishaw, NHS Lanarkshire, Wishaw, UK
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Cragun D, Salvati ZM, Schneider JL, Burnett-Hartman AN, Epstein MM, Hunter JE, Liang SY, Lowery J, Lu CY, Pawloski PA, Schlieder V, Sharaf RN, Williams MS, Rahm AK. Identifying factors and causal chains associated with optimal implementation of Lynch syndrome tumor screening: An application of coincidence analysis. Genet Med 2024; 26:101201. [PMID: 38953292 DOI: 10.1016/j.gim.2024.101201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2023] [Revised: 06/24/2024] [Accepted: 06/25/2024] [Indexed: 07/03/2024] Open
Abstract
PURPOSE This study compared Lynch syndrome universal tumor screening (UTS) across multiple health systems (some of which had 2 or more distinct UTS programs) to understand multilevel factors that may affect the successful implementation of complex programs. METHODS Data from 66 stakeholder interviews were used to conduct multivalue coincidence analysis and identify key factors that consistently make a difference in whether UTS programs were implemented and optimized at the system level. RESULTS The selected coincidence analysis model revealed combinations of conditions that distinguish 4 optimized UTS programs, 10 nonoptimized programs, and 4 systems with no program. Fully optimized UTS programs had both a maintenance champion and a positive inner setting. Two independent paths were unique to nonoptimized programs: (1) positive attitudes and a mixed inner setting or (2) limited planning and engaging among stakeholders. Negative views about UTS evidence or lack of knowledge about UTS led to a lack of planning and engaging, which subsequently prevented program implementation. CONCLUSION The model improved our understanding of program implementation in health care systems and informed the creation of a toolkit to guide UTS implementation, optimization, and changes. Our findings and toolkit may serve as a use case to increase the successful implementation of other complex precision health programs.
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Affiliation(s)
- Deborah Cragun
- College of Public Health, University of South Florida, Tampa, FL
| | | | | | | | - Mara M Epstein
- Division of Health Systems Science, University of Massachusetts Chan Medical School, Worcester, MA
| | - Jessica Ezzell Hunter
- Genomics, Ethics, and Translational Research Program, RTI International, Research Triangle Park, NC
| | - Su-Ying Liang
- Palo Alto Medical Research Foundation, Sutter Health, Palo Alto, CA
| | - Jan Lowery
- University of Colorado Cancer Center, University of Colorado, Aurora, CO
| | - Christine Y Lu
- Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA
| | | | | | - Ravi N Sharaf
- Population Health Sciences, Weill Cornell Medicine, New York, NY
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Kulchak Rahm A, Wolfinger T, Salvati ZM, Schneider JL, Cragun D. Development, Evaluation, and User Testing of a Decision-Making Toolkit to Promote Organizations to Implement Universal Tumor Screening for Lynch Syndrome. Public Health Genomics 2024; 27:136-149. [PMID: 39159623 DOI: 10.1159/000540943] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Accepted: 08/13/2024] [Indexed: 08/21/2024] Open
Abstract
INTRODUCTION The Implementing Universal Lynch Syndrome Screening (IMPULSS) study explained institutional variation in universal tumor screening (UTS) with the goal of identifying ways to aid organizational decision-makers in implementing and optimizing Lynch syndrome UTS programs. METHODS After applying the Consolidated Framework for Implementation Research (CFIR 1.0) to analyze interviews with 66 stakeholders across 9 healthcare systems to develop a toolkit for implementation, we adapted the International Patient Decision Aid Standards (IPDAS) to assess toolkit potential to aid decision-making consistent with organizational values. We then conducted user testing with two experienced and four non-experienced implementers of UTS to improve the content and functionality of the toolkit and assess its acceptability and appropriateness. RESULTS Toolkit components were organized to address findings related to CFIR 1.0 constructs of evidence strength and quality, relative advantage, cost, engaging, planning, executing, and reflecting and evaluating. A home page was added to direct users to different sections based on whether they are deciding to implement UTS, planning for implementation, improving an existing UTS program, or considering a different approach to identify patients with Lynch syndrome. Upon initial evaluation, 31 of 64 IPDAS criteria were met by the original toolkit. All users rated the toolkit as acceptable and appropriate for assisting organizational decision-making and identified multiple areas for improvement. Numerous iterative changes were made to the toolkit, resulting in meeting 17 of the previously unmet IPDAS criteria. CONCLUSION We demonstrate the rigorous development of a toolkit guided by the CFIR and show how user testing helped improve the toolkit to ensure it is acceptable, appropriate, and meets most IPDAS criteria relevant to organizational values-based decision-making.
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Affiliation(s)
| | | | - Zachary M Salvati
- Department of Genomic Health, Geisinger, Danville, Pennsylvania, USA
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Maoz A, Yurgelun MB. Leveraging Electronic Health Record Data to Understand Gaps Underlying the Underdiagnosis of Lynch Syndrome. JCO Clin Cancer Inform 2024; 8:e2400032. [PMID: 38838279 DOI: 10.1200/cci.24.00032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2024] [Accepted: 04/09/2024] [Indexed: 06/07/2024] Open
Abstract
Using the electronic health record to address the underdiagnosis of Lynch syndrome.
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Affiliation(s)
- Asaf Maoz
- Dana-Farber Cancer Institute, Boston, MA
- Brigham & Women's Hospital, Boston, MA
- Harvard Medical School, Boston, MA
| | - Matthew B Yurgelun
- Dana-Farber Cancer Institute, Boston, MA
- Brigham & Women's Hospital, Boston, MA
- Harvard Medical School, Boston, MA
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Passero LE, Roberts MC. Challenges and opportunities for Lynch syndrome cascade testing in the United States. Fam Cancer 2024; 23:147-154. [PMID: 38548925 DOI: 10.1007/s10689-024-00374-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2023] [Accepted: 03/09/2024] [Indexed: 06/06/2024]
Abstract
Lynch syndrome is an underdiagnosed genetic condition that increases lifetime colorectal, endometrial, and other cancer risk. Cascade testing in relatives is recommended to increase diagnoses and enable access to cancer prevention services, yet uptake is limited due to documented multi-level barriers. Individual barriers such as feelings of fear, guilt, and anxiety and limited knowledge about Lynch syndrome as well as interpersonal barriers including complex family dynamics and language barriers limit family communication about Lynch syndrome and prevent uptake of genetic screening for relatives. Organizational and environmental barriers including a shortage of genetics professionals, high costs, and fears of discrimination also reduce cascade testing. These multi-level barriers may disproportionately impact underserved populations in the United States, such as individuals with lower incomes, limited English-speaking proficiency, lower educational attainment, and inadequate access to health systems. Multi-level facilitators of cascade testing include interpersonal support from family members, peers, and healthcare providers, educational resources, and motivation to improve family health. Taken together, these barriers and facilitators demonstrate a need for interventions and strategies that address multi-level factors to increase cascade testing in families with Lynch syndrome and other hereditary cancer conditions. We provide an example of a cascade testing intervention that has been developed for use in individuals diagnosed with Lynch syndrome and discuss the variety of current approaches to addressing these multi-level barriers.
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Affiliation(s)
- Lauren E Passero
- Division of Pharmaceutical Outcomes and Policy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Megan C Roberts
- Division of Pharmaceutical Outcomes and Policy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.
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Fazelpour S, Deverapalli SC, Nguyen B. Skin cancer-associated genodermatoses in skin of color patients: a review. Arch Dermatol Res 2024; 316:282. [PMID: 38796611 DOI: 10.1007/s00403-024-03087-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2023] [Revised: 10/22/2023] [Accepted: 04/26/2024] [Indexed: 05/28/2024]
Abstract
Skin cancers are associated with a large number of genodermatoses. Existing knowledge and guidelines on the presentations of these genodermatoses focus disproportionately on White patients. Our goal is to identify notable characteristics in location, frequency, and severity of cutaneous findings along with the median age of skin cancers in skin-of-color (SOC) patients with skin-cancer-associated genodermatoses to improve diagnosis rates. We searched for genodermatoses on six databases. Each case report or case series was reviewed, including reports, published in English, containing adult patient descriptions. Duplicate manuscripts were removed using EndNote. The following case-level data were collected from the manuscripts: age, gender, patient country or region of origin, author country/continent of residence, skin cancer-related, and other key dermatologic features. 381 published articles, with a total of 578 SOC patients, met criteria for inclusion. SOC patients can present with fewer classic findings, such as a lower incidence of basal cell carcinomas (44%) in SOC Gorlin syndrome patients than palmar pits (66%) and mandibular cysts (66%). Differences between SOC populations were also noted, such as leukoplakia being more common in Asian dyskeratosis congenita patients (80%) in comparison to African dyskeratosis congenita patients (44%). SOC patients also have varying onset of skin cancer depending on the genodermatosis, from a median of 25 years of age in Rothmund-Thomson syndrome to 53 in Muir-Torre syndrome. In this review, SOC patients with genodermatoses can have varying presentations. Being cognizant of these characteristics may lead to earlier diagnosis and interventions to mitigate skin-cancer-related morbidity in SOC patients.
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Affiliation(s)
- Sherwin Fazelpour
- Boston University School of Medicine, 72 E Concord St, Boston, MA, 02118, USA.
| | | | - Bichchau Nguyen
- Tufts Medical Center, 800 Washington St, Boston, MA, 02111, USA
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Dal Buono A, Puccini A, Franchellucci G, Airoldi M, Bartolini M, Bianchi P, Santoro A, Repici A, Hassan C. Lynch Syndrome: From Multidisciplinary Management to Precision Prevention. Cancers (Basel) 2024; 16:849. [PMID: 38473212 DOI: 10.3390/cancers16050849] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/10/2024] [Accepted: 02/19/2024] [Indexed: 03/14/2024] Open
Abstract
BACKGROUND AND AIMS Lynch syndrome (LS) is currently one of the most prevalent hereditary cancer conditions, accounting for 3% of all colorectal cancers and for up to 15% of those with DNA mismatch repair (MMR) deficiency, and it was one of the first historically identified. The understanding of the molecular carcinogenesis of LS tumors has progressed significantly in recent years. We aim to review the most recent advances in LS research and explore genotype-based approaches in surveillance, personalized cancer prevention, and treatment strategies. METHODS PubMed was searched to identify relevant studies, conducted up to December 2023, investigating molecular carcinogenesis in LS, surveillance strategies, cancer prevention, and treatment in LS tumors. RESULTS Multigene panel sequencing is becoming the benchmark in the diagnosis of LS, allowing for the detection of a pathogenic constitutional variant in one of the MMR genes. Emerging data from randomized controlled trials suggest possible preventive roles of resistant starch and/or aspirin in LS. Vaccination with immunogenic frameshift peptides appears to be a promising approach for both the treatment and prevention of LS-associated cancers, as evidenced by pre-clinical and preliminary phase 1/2a studies. CONCLUSIONS Although robust diagnostic algorithms, including prompt testing of tumor tissue for MMR defects and referral for genetic counselling, currently exist for suspected LS in CRC patients, the indications for LS screening in cancer-free individuals still need to be refined and standardized. Investigation into additional genetic and non-genetic factors that may explain residual rates of interval cancers, even in properly screened populations, would allow for more tailored preventive strategies.
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Affiliation(s)
- Arianna Dal Buono
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Alberto Puccini
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
| | - Gianluca Franchellucci
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Marco Airoldi
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Michela Bartolini
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Paolo Bianchi
- Clinical Analysis Laboratory, Oncological Molecular Genetics Section, IRCCS Humanitas Research Hospital, 20089 Rozzano, Milan, Italy
| | - Armando Santoro
- Medical Oncology and Haematology Unit, Humanitas Cancer Center, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Alessandro Repici
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
| | - Cesare Hassan
- Department of Gastroenterology, IRCCS Humanitas Research Hospital, Via Manzoni 56, 20089 Rozzano, Milan, Italy
- Department of Biomedical Sciences, Humanitas University, 20072 Pieve Emanuele, Milan, Italy
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Joder C, Gmür A, Solass W, Christe L, Rabaglio M, Fluri M, Rau TT, Saner FAM, Knabben L, Imboden S, Mueller MD, Siegenthaler F. Real-World Data on Institutional Implementation of Screening for Mismatch Repair Deficiency and Lynch Syndrome in Endometrial Cancer Patients. Cancers (Basel) 2024; 16:671. [PMID: 38339422 PMCID: PMC10854690 DOI: 10.3390/cancers16030671] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2023] [Revised: 01/25/2024] [Accepted: 02/02/2024] [Indexed: 02/12/2024] Open
Abstract
Lynch syndrome is an inherited tumor syndrome caused by a pathogenic germline variant in DNA mismatch repair genes. As the leading cause of hereditary endometrial cancer, international guidelines recommend universal screening in women with endometrial cancer. However, testing for Lynch syndrome is not yet well established in clinical practice. The aim of this study was to evaluate adherence to our Lynch syndrome screening algorithm. A retrospective, single-center cohort study was conducted of all endometrial cancer patients undergoing surgical treatment at the Bern University Hospital, Switzerland, between 2017 and 2022. Adherence to immunohistochemical analysis of mismatch repair status, and, if indicated, to MLH1 promoter hypermethylation and to genetic counseling and testing was assessed. Of all 331 endometrial cancer patients, 102 (30.8%) were mismatch repair-deficient and 3 (0.9%) patients were diagnosed with Lynch syndrome. Overall screening adherence was 78.2%, with a notable improvement over the six years from 61.4% to 90.6%. A major reason for non-adherence was lack of provider recommendation for testing, with advanced patient age as a potential patient risk factor. Simplification of the algorithm through standardized reflex screening was recommended to provide optimal medical care for those affected and to allow for cascading testing of at-risk relatives.
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Affiliation(s)
- Carmen Joder
- Faculty of Medicine, University of Bern, 3010 Bern, Switzerland;
| | - Andrea Gmür
- Department of Obstetrics and Gynecology, Bern University Hospital, 3010 Bern, Switzerland
| | - Wiebke Solass
- Institute of Tissue Medicine and Pathology, University of Bern, 3010 Bern, Switzerland
| | - Lucine Christe
- Institute of Tissue Medicine and Pathology, University of Bern, 3010 Bern, Switzerland
| | - Manuela Rabaglio
- Department of Medical Oncology, Bern University Hospital, 3010 Bern, Switzerland
| | - Muriel Fluri
- Department of Medical Oncology, Bern University Hospital, 3010 Bern, Switzerland
| | - Tilman T. Rau
- Institute of Pathology, Universitätsklinikum Düsseldorf, 40225 Düsseldorf, Germany
| | - Flurina A. M. Saner
- Department of Obstetrics and Gynecology, Bern University Hospital, 3010 Bern, Switzerland
| | - Laura Knabben
- Department of Obstetrics and Gynecology, Bern University Hospital, 3010 Bern, Switzerland
| | - Sara Imboden
- Department of Obstetrics and Gynecology, Bern University Hospital, 3010 Bern, Switzerland
| | - Michael D. Mueller
- Department of Obstetrics and Gynecology, Bern University Hospital, 3010 Bern, Switzerland
| | - Franziska Siegenthaler
- Department of Obstetrics and Gynecology, Bern University Hospital, 3010 Bern, Switzerland
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Trembath HE, Yeh JJ, Lopez NE. Gastrointestinal Malignancy: Genetic Implications to Clinical Applications. Cancer Treat Res 2024; 192:305-418. [PMID: 39212927 DOI: 10.1007/978-3-031-61238-1_15] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/04/2024]
Abstract
Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.
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Affiliation(s)
- Hannah E Trembath
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Jen Jen Yeh
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA
| | - Nicole E Lopez
- Division of Colon and Rectal Surgery, Department of Surgery, University of California San Diego, 4303 La Jolla Village Drive Suite 2110, San Diego, CA, 92122, USA.
- Division of Surgical Oncology, Department of Surgery, University of North Carolina, 170 Manning Drive, CB#7213, 1150 Physician's Office Building, Chapel Hill, NC, 27599-7213, USA.
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Schneider JL, Firemark AJ, Gille S, Davis J, Pawloski PA, Liang SY, Epstein MM, Lowery J, Lu CY, Sharaf RN, Burnett-Hartman AN, Schlieder V, Salvati ZM, Cragun D, Rahm AK, Hunter JE. "Go ahead and screen" - advice to healthcare systems for routine lynch syndrome screening from interviews with newly diagnosed colorectal cancer patients. Hered Cancer Clin Pract 2023; 21:24. [PMID: 37978552 PMCID: PMC10657118 DOI: 10.1186/s13053-023-00270-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2023] [Accepted: 11/13/2023] [Indexed: 11/19/2023] Open
Abstract
BACKGROUND Lynch syndrome (LS) is the most common cause of inherited colorectal cancer (CRC). Universal tumor screening (UTS) of newly diagnosed CRC cases is recommended to aid in diagnosis of LS and reduce cancer-related morbidity and mortality. However, not all health systems have adopted UTS processes and implementation may be inconsistent due to system and patient-level complexities. METHODS To identify barriers, facilitators, and suggestions for improvements of the UTS process from the patient perspective, we conducted in-depth, semi-structured interviews with patients recently diagnosed with CRC, but not screened for or aware of LS. Patients were recruited from eight regionally diverse US health systems. Interviews were conducted by telephone, 60-minutes, audio-recorded, and transcribed. An inductive, constant comparative analysis approach was employed. RESULTS: We completed 75 interviews across the eight systems. Most participants were white (79%), about half (52%) were men, and the mean age was 60 years. Most self-reported either no (60%) or minimal (40%) prior awareness of LS. Overall, 96% of patients stated UTS should be a routine standard of care for CRC tumors, consistently citing four primary motivations for wanting to know their LS status and engage in the process for LS identification: "knowledge is power"; "family knowledge"; "prevention and detection"; and "treatment and surveillance." Common concerns pertaining to the process of screening for and identifying LS included: creating anticipatory worry for patients, the potential cost and the accuracy of the genetic test, and possibly having one's health insurance coverage impacted by the LS diagnosis. Patients suggested health systems communicate LS results in-person or by phone from a trained expert in LS; offer proactive verbal and written education about LS, the screening steps, and any follow-up surveillance recommendations; and support patients in communicating their LS screening to any of their blood relatives. CONCLUSION Our qualitative findings demonstrate patients with CRC have a strong desire for healthcare systems to regularly implement and offer UTS. Patients offer key insights for health systems to guide future implementation and optimization of UTS and other LS screening programs and maximize diagnosis of individuals with LS and improve cancer-related surveillance and outcomes. TRIAL REGISTRATION Not available: not a clinical trial.
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Affiliation(s)
- Jennifer L Schneider
- Kaiser Permanente Center for Health Research, 3800 N Interstate Ave, 97227, Portland, OR, USA.
| | - Alison J Firemark
- Kaiser Permanente Center for Health Research, 3800 N Interstate Ave, 97227, Portland, OR, USA
| | - Sara Gille
- Kaiser Permanente Center for Health Research, 3800 N Interstate Ave, 97227, Portland, OR, USA
| | - James Davis
- Kaiser Permanente Center for Health Research, 3800 N Interstate Ave, 97227, Portland, OR, USA
| | | | - Su-Ying Liang
- Palo Alto Medical Foundation Research Institute, Palo Alto, CA, USA
| | - Mara M Epstein
- Division of Health Systems Science, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
| | - Jan Lowery
- University of Colorado Cancer Center, Aurora, CO, USA
| | - Christine Y Lu
- Department of Population Medicine, Harvard Medical School, Harvard Pilgrim Health Care Institute, Boston, MA, USA
| | - Ravi N Sharaf
- Division of Gastroenterology, Department of Medicine, Division of Epidemiology, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
| | | | | | | | - Deborah Cragun
- University of South Florida, 3720 Spectrum Blvd, Suite 304, Tampa, Fl, USA
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Trujillo-Rojas MA, Ayala-Madrigal MDLL, Gutiérrez-Angulo M, González-Mercado A, Moreno-Ortiz JM. Diagnosis of patients with Lynch syndrome lacking the Amsterdam II or Bethesda criteria. Hered Cancer Clin Pract 2023; 21:21. [PMID: 37864171 PMCID: PMC10589993 DOI: 10.1186/s13053-023-00266-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 10/06/2023] [Indexed: 10/22/2023] Open
Abstract
BACKGROUND Lynch Syndrome (LS) is an autosomal dominant inheritance disorder characterized by genetic predisposition to develop cancer, caused by pathogenic variants in the genes of the mismatch repair system. Cases are detected by implementing the Amsterdam II and the revised Bethesda criteria, which are based on family history. MAIN BODY Patients who meet the criteria undergo posterior tests, such as germline DNA sequencing, to confirm the diagnosis. However, these criteria have poor sensitivity, as more than one-quarter of patients with LS do not meet the criteria. It is very likely that the lack of sensitivity of the criteria is due to the incomplete penetrance of this syndrome. The penetrance and risk of developing a particular type of cancer are highly dependent on the affected gene and probably of the variant. Patients with variants in low-penetrance genes have a lower risk of developing a cancer associated with LS, leading to families with unaffected generations and showing fewer clear patterns. This study focuses on describing genetic aspects of LS cases that underlie the lack of sensitivity of the clinical criteria used for its diagnosis. CONCLUSION Universal screening could be an option to address the problem of underdiagnosis.
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Affiliation(s)
- Miguel Angel Trujillo-Rojas
- Doctorado en Genética Humana e Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México
| | - María de la Luz Ayala-Madrigal
- Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México
| | - Melva Gutiérrez-Angulo
- Departamento de Ciencias de la Salud, Centro Universitario de los Altos, Universidad de Guadalajara, Av. Rafael Casillas Aceves #1200. Tepatitlán de Morelos, C.P. 47620, Jalisco, México
| | - Anahí González-Mercado
- Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México
| | - José Miguel Moreno-Ortiz
- Instituto de Genética Humana "Dr. Enrique Corona Rivera", Departamento de Biología Molecular y Genómica, Centro Universitario de Ciencias de la Salud, Sierra Mojada #950, Col. Independencia, Guadalajara, C.P. 44340, Jalisco, México.
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15
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Emons G, Steiner E, Vordermark D, Uleer C, Paradies K, Tempfer C, Aretz S, Cremer W, Hanf V, Mallmann P, Ortmann O, Römer T, Schmutzler RK, Horn LC, Kommoss S, Lax S, Schmoeckel E, Mokry T, Grab D, Reinhardt M, Steinke-Lange V, Brucker SY, Kiesel L, Witteler R, Fleisch MC, Heinrich Prömpeler † 25, Friedrich M, Höcht S, Lichtenegger W, Mueller M, Runnebaum I, Feyer P, Hagen V, Juhasz-Böss I, Letsch A, Niehoff P, Zeimet AG, Battista MJ, Petru E, Widhalm S, van Oorschot B, Panke JE, Weis J, Dauelsberg T, Haase H, Beckmann MW, Jud S, Wight E, Prott FJ, Micke O, Bader W, Reents N, Henscher U, Reina Tholen † 52, Schallenberg M, Rahner N, Mayr D, Kreißl M, Lindel K, Mustea A, Strnad V, Goerling U, Bauerschmitz GJ, Langrehr J, Neulen J, Ulrich UA, Nothacker MJ, Blödt S, Follmann M, Langer T, Wenzel G, Weber S, Erdogan S. Endometrial Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry Number 032/034-OL, September 2022). Part 1 with Recommendations on the Epidemiology, Screening, Diagnosis and Hereditary Factors of Endometrial Cancer, Geriatric Assessment and Supply Structures. Geburtshilfe Frauenheilkd 2023; 83:919-962. [PMID: 37588260 PMCID: PMC10427205 DOI: 10.1055/a-2066-2051] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Accepted: 06/22/2023] [Indexed: 08/18/2023] Open
Abstract
Summary The S3-guideline on endometrial cancer, first published in April 2018, was reviewed in its entirety between April 2020 and January 2022 and updated. The review was carried out at the request of German Cancer Aid as part of the Oncology Guidelines Program and the lead coordinators were the German Society for Gynecology and Obstetrics (DGGG), the Gynecology Oncology Working Group (AGO) of the German Cancer Society (DKG) and the German Cancer Aid (DKH). The guideline update was based on a systematic search and assessment of the literature published between 2016 and 2020. All statements, recommendations and background texts were reviewed and either confirmed or amended. New statements and recommendations were included where necessary. Aim The use of evidence-based risk-adapted therapies to treat women with endometrial cancer of low risk prevents unnecessarily radical surgery and avoids non-beneficial adjuvant radiation therapy and/or chemotherapy. For women with endometrial cancer and a high risk of recurrence, the guideline defines the optimum level of radical surgery and indicates whether chemotherapy and/or adjuvant radiation therapy is necessary. This should improve the survival rates and quality of life of these patients. The S3-guideline on endometrial cancer and the quality indicators based on the guideline aim to provide the basis for the work of certified gynecological cancer centers. Methods The guideline was first compiled in 2018 in accordance with the requirements for S3-level guidelines and was updated in 2022. The update included an adaptation of the source guidelines identified using the German Instrument for Methodological Guideline Appraisal (DELBI). The update also used evidence reviews which were created based on selected literature obtained from systematic searches in selected literature databases using the PICO process. The Clinical Guidelines Service Group was tasked with carrying out a systematic search and assessment of the literature. Their results were used by interdisciplinary working groups as a basis for developing suggestions for recommendations and statements which were then modified during structured online consensus conferences and/or additionally amended online using the DELPHI process to achieve a consensus. Recommendations Part 1 of this short version of the guideline provides recommendations on epidemiology, screening, diagnosis, and hereditary factors. The epidemiology of endometrial cancer and the risk factors for developing endometrial cancer are presented. The options for screening and the methods used to diagnose endometrial cancer are outlined. Recommendations are given for the prevention, diagnosis, and therapy of hereditary forms of endometrial cancer. The use of geriatric assessment is considered and existing structures of care are presented.
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Affiliation(s)
- Günter Emons
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Eric Steiner
- Frauenklinik GPR Klinikum Rüsselsheim am Main, Rüsselsheim, Germany
| | - Dirk Vordermark
- Universität Halle (Saale), Radiotherapie, Halle (Saale), Germany
| | - Christoph Uleer
- Facharzt für Frauenheilkunde und Geburtshilfe, Hildesheim, Germany
| | - Kerstin Paradies
- Konferenz onkologischer Kranken- und Kinderkrankenpfleger (KOK), Hamburg, Germany
| | - Clemens Tempfer
- Frauenklinik der Ruhr-Universität Bochum, Bochum/Herne, Germany
| | - Stefan Aretz
- Institut für Humangenetik, Universität Bonn, Zentrum für erbliche Tumorerkrankungen, Bonn, Germany
| | | | - Volker Hanf
- Frauenklinik Nathanstift – Klinikum Fürth, Fürth, Germany
| | | | - Olaf Ortmann
- Universität Regensburg, Fakultät für Medizin, Klinik für Frauenheilkunde und Geburtshilfe, Regensburg, Germany
| | - Thomas Römer
- Evangelisches Klinikum Köln Weyertal, Gynäkologie Köln, Köln, Germany
| | - Rita K. Schmutzler
- Universitätsklinikum Köln, Zentrum Familiärer Brust- und Eierstockkrebs, Köln, Germany
| | | | - Stefan Kommoss
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Sigurd Lax
- Institut für Pathologie, LKH Graz Süd-West, Graz, Austria
| | | | - Theresa Mokry
- Universitätsklinikum Heidelberg, Diagnostische und Interventionelle Radiologie, Heidelberg, Germany
| | - Dieter Grab
- Universitätsklinikum Ulm, Frauenheilkunde und Geburtshilfe, Ulm, Germany
| | - Michael Reinhardt
- Klinik für Nuklearmedizin, Pius Hospital Oldenburg, Oldenburg, Germany
| | - Verena Steinke-Lange
- MGZ – Medizinisch Genetisches Zentrum München, München, Germany
- Medizinische Klinik und Poliklinik IV, LMU München, München, Germany
| | - Sara Y. Brucker
- Universitätsklinikum Tübingen, Universitätsfrauenklinik Tübingen, Tübingen, Germany
| | - Ludwig Kiesel
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Ralf Witteler
- Universitätsklinikum Münster, Frauenklinik A Schweitzer Campus 1, Münster, Germany
| | - Markus C. Fleisch
- Helios, Universitätsklinikum Wuppertal, Landesfrauenklinik, Wuppertal, Germany
| | | | - Michael Friedrich
- Helios Klinikum Krefeld, Klinik für Frauenheilkunde und Geburtshilfe, Krefeld, Germany
| | - Stefan Höcht
- XCare, Praxis für Strahlentherapie Saarlouis, Saarlouis, Germany
| | - Werner Lichtenegger
- Universitätsmedizin Berlin, Frauenklinik Charité, Campus Virchow-Klinikum, Berlin, Germany
| | - Michael Mueller
- Universitätsklinik für Frauenheilkunde, Inselspital Bern, Bern, Switzerland
| | | | - Petra Feyer
- Vivantes Klinikum Neukölln, Klinik für Strahlentherapie und Radioonkologie, Berlin, Germany
| | - Volker Hagen
- Klinik für Innere Medizin II, St.-Johannes-Hospital Dortmund, Dortmund, Germany
| | | | - Anne Letsch
- Universitätsklinikum Schleswig Holstein, Campus Kiel, Innere Medizin, Kiel, Germany
| | - Peter Niehoff
- Strahlenklinik, Sana Klinikum Offenbach, Offenbach, Germany
| | - Alain Gustave Zeimet
- Medizinische Universität Innsbruck, Universitätsklinik für Gynäkologie und Geburtshilfe, Innsbruck, Austria
| | | | - Edgar Petru
- Med. Univ. Graz, Frauenheilkunde, Graz, Austria
| | | | - Birgitt van Oorschot
- Universitätsklinikum Würzburg, Interdisziplinäres Zentrum Palliativmedizin, Würzburg, Germany
| | - Joan Elisabeth Panke
- Medizinischer Dienst des Spitzenverbandes Bund der Krankenkassen e. V. Essen, Essen, Germany
| | - Joachim Weis
- Albert-Ludwigs-Universität Freiburg, Medizinische Fakultät, Tumorzentrum Freiburg – CCCF, Freiburg, Germany
| | - Timm Dauelsberg
- Universitätsklinikum Freiburg, Klinik für Onkologische Rehabilitation, Freiburg, Germany
| | | | | | | | - Edward Wight
- Frauenklinik des Universitätsspitals Basel, Basel, Switzerland
| | - Franz-Josef Prott
- Facharzt für Radiologie und Strahlentherapie, Wiesbaden, Wiesbaden, Germany
| | - Oliver Micke
- Franziskus Hospital Bielefeld, Klinik für Strahlentherapie und Radioonkologie, Bielefeld, Germany
| | - Werner Bader
- Klinikum Bielefeld Mitte, Zentrum für Frauenheilkunde, Bielefeld, Germany
| | | | | | | | | | | | - Doris Mayr
- LMU München, Pathologisches Institut, München, Germany
| | - Michael Kreißl
- Universität Magdeburg, Medizinische Fakultät, Universitätsklinik für Radiologie und Nuklearmedizin, Germany
| | - Katja Lindel
- Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - Alexander Mustea
- Universitätsklinikum Bonn, Zentrum Gynäkologie und gynäkologische Onkologie, Bonn, Germany
| | - Vratislav Strnad
- Universitätsklinikum Erlangen, Brustzentrum Franken, Erlangen, Germany
| | - Ute Goerling
- Universitätsmedizin Berlin, Campus Charité Mitte, Charité Comprehensive Cancer Center, Berlin, Germany
| | - Gerd J. Bauerschmitz
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Jan Langrehr
- Martin-Luther-Krankenhaus, Klinik für Allgemein-, Gefäß- und Viszeralchirurgie, Berlin, Germany
| | - Joseph Neulen
- Uniklinik RWTH Aachen, Klinik für Gynäkologische Endokrinologie und Reproduktionsmedizin, Aachen, Germany
| | - Uwe Andreas Ulrich
- Martin-Luther-Krankenhaus, Johannesstift Diakonie, Gynäkologie, Berlin, Germany
| | | | | | - Markus Follmann
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Thomas Langer
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Gregor Wenzel
- Deutsche Krebsgesellschaft, Office des Leitlinienprogramms Onkologie, Berlin, Germany
| | - Sylvia Weber
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
| | - Saskia Erdogan
- Universitätsmedizin Göttingen, Klinik für Gynäkologie und Geburtshilfe, Göttingen, Germany
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Frey MK, Ahsan MD, Webster E, Levi SR, Brewer JT, Lin J, Blank SV, Krinsky H, Nchako C, Wolfe I, Thomas C, Christos P, Cantillo E, Chapman-Davis E, Holcomb K, Sharaf RN. Web-based tool for cancer family history collection: A prospective randomized controlled trial. Gynecol Oncol 2023; 173:22-30. [PMID: 37062188 PMCID: PMC10310435 DOI: 10.1016/j.ygyno.2023.04.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Revised: 03/31/2023] [Accepted: 04/01/2023] [Indexed: 04/18/2023]
Abstract
OBJECTIVES Approximately 1% of individuals have a hereditary cancer predisposition syndrome, however, the majority are not aware. Collecting a cancer family history (CFH) can triage patients to receive genetic testing. To rigorously assess different methods of CFH collection, we compared a web-based tool (WBT) to usual care (clinician collects CFH) in a randomized controlled trial. METHODS New gynecologic oncology patients (seen 9/2019-9/2021) were randomized to one of three arms in a 2:2:1 allocation ratio: 1) usual care clinician CFH collection, 2) WBT completed at home, or 3) WBT completed in office. The WBT generated a cancer-focused pedigree and scores on eight validated cancer risk models. The primary outcome was collection of an adequate CFH (based on established guidelines) with usual care versus the WBT. RESULTS We enrolled 250 participants (usual care - 110; WBT home - 105; WBT office - 35 [closed early due to COVID-19]). Within WBT arms, 109 (78%) participants completed the tool, with higher completion for office versus home (33 [94%] vs. 76 [72%], P = 0.008). Among participants completing the WBT, 63 (58%) had an adequate CFH versus 5 (5%) for usual care (P < 0.001). Participants completing the WBT were significantly more likely to complete genetic counseling (34 [31%] vs. 15 [14%], P = 0.002) and genetic testing (20 [18%] vs. 9 [8%], P = 0.029). Participant and provider WBT experience was favorable. CONCLUSIONS WBTs for CFH collection are a promising application of health information technology, resulting in more comprehensive CFH and a significantly greater percentage of participants completing genetic counseling and testing.
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Affiliation(s)
- Melissa K Frey
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America.
| | - Muhammad Danyal Ahsan
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Emily Webster
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Sarah R Levi
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Jesse T Brewer
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Jenny Lin
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Stephanie V Blank
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Icahn School of Medicine at Mount Sinai, United States of America
| | - Hannah Krinsky
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Corbyn Nchako
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Isabel Wolfe
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Charlene Thomas
- Population Health Sciences, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, United States of America
| | - Paul Christos
- Population Health Sciences, Division of Biostatistics and Epidemiology, Weill Cornell Medicine, New York, NY, United States of America
| | - Evelyn Cantillo
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Eloise Chapman-Davis
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Kevin Holcomb
- Department of Obstetrics and Gynecology, Division of Gynecology Oncology, Weill Cornell Medicine, New York, NY, United States of America
| | - Ravi N Sharaf
- Division of Gastroenterology, Department of Medicine, Weill Cornell Medicine, New York, NY, United States of America; Division of Epidemiology, Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, United States of America
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17
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Perez L, Webster E, Bull L, Brewer JT, Ahsan MD, Lin J, Levi SR, Cantillo E, Chapman-Davis E, Holcomb K, Rosenberg SM, Frey MK. Patient perspectives on risk-reducing salpingectomy with delayed oophorectomy for ovarian cancer risk-reduction: A systematic review of the literature. Gynecol Oncol 2023; 173:106-113. [PMID: 37116391 PMCID: PMC10650971 DOI: 10.1016/j.ygyno.2023.04.006] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2023] [Revised: 04/10/2023] [Accepted: 04/11/2023] [Indexed: 04/30/2023]
Abstract
OBJECTIVE Increasing evidence suggests the fallopian tube as the site of origin of BRCA1/2-associated high-grade ovarian cancers. Several ongoing trials are evaluating salpingectomy with delayed oophorectomy (RRSDO) for ovarian cancer risk reduction and patients are beginning to ask their clinicians about this surgical option. This study sought to systematically review the available literature examining patient preferences regarding RRSDO and risk-reducing salpingo-oophorectomy (RRSO) to provide clinicians with an understanding of patient values, concerns, and priorities surrounding ovarian cancer risk-reducing surgery. METHODS We conducted a systematic review in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines (PROSPERO No.: CRD42023400690). We searched key electronic databases to identify studies evaluating acceptance and surgical decision-making regarding RRSO and RRSDO among patients with an increased risk of ovarian cancer. RESULTS The search yielded 239 results, among which six publications met the systematic review inclusion criteria. Acceptance of RRSDO was evaluated in all studies and ranged from 34% to 71%. Factors positively impacting patients' acceptance of RRSDO included: avoidance of surgical menopause, preservation of fertility, concerns about sexual dysfunction, family history of breast cancer, and avoidance of hormone replacement therapy. Factors limiting this acceptance reported by patients included concerns regarding oncologic safety, surgical timing, and surgical complications. CONCLUSION To date, few studies have explored patient perspectives surrounding RRSDO. Collectively, the limited data available indicate a high level of acceptance among BRCA1/2 carriers, and provides insight regarding both facilitating and limiting factors associated with patient preferences to better equip clinicians in the counseling and support of their patients.
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Affiliation(s)
- Luiza Perez
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Emily Webster
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Leslie Bull
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Jesse T Brewer
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | | | - Jenny Lin
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Sarah R Levi
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Evelyn Cantillo
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Eloise Chapman-Davis
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Kevin Holcomb
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Shoshana M Rosenberg
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA
| | - Melissa K Frey
- Weill Cornell Medicine, 525 East 68th Street, Suite J-130, New York, NY 10065, USA.
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18
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Kotnik U, Maver A, Peterlin B, Lovrecic L. Assessment of pathogenic variation in gynecologic cancer genes in a national cohort. Sci Rep 2023; 13:5307. [PMID: 37002323 PMCID: PMC10066348 DOI: 10.1038/s41598-023-32397-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Accepted: 03/27/2023] [Indexed: 04/03/2023] Open
Abstract
Population-based estimates of pathogenic variation burden in gynecologic cancer predisposition genes are a prerequisite for the development of effective precision public health strategies. This study aims to reveal the burden of pathogenic variants in a comprehensive set of clinically relevant breast, ovarian, and endometrial cancer genes in a large population-based study. We performed a rigorous manual classification procedure to identify pathogenic variants in a panel of 17 gynecologic cancer predisposition genes in a cohort of 7091 individuals, representing 0.35% of the general population. The population burden of pathogenic variants in hereditary gynecologic cancer-related genes in our study was 2.14%. Pathogenic variants in genes ATM, BRCA1, and CDH1 are significantly enriched and the burden of pathogenic variants in CHEK2 is decreased in our population compared to the control population. We have identified a high burden of pathogenic variants in several gynecologic cancer-related genes in the Slovenian population, most importantly in the BRCA1 gene.
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Affiliation(s)
- Urška Kotnik
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia.
- Biotechnical Faculty, University of Ljubljana, Ljubljana, Slovenia.
| | - Aleš Maver
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Borut Peterlin
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Luca Lovrecic
- Clinical Institute of Genomic Medicine, University Medical Centre Ljubljana, Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
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19
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Underkofler KA, Ring KL. Updates in gynecologic care for individuals with lynch syndrome. Front Oncol 2023; 13:1127683. [PMID: 36937421 PMCID: PMC10014618 DOI: 10.3389/fonc.2023.1127683] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Accepted: 02/16/2023] [Indexed: 03/05/2023] Open
Abstract
Lynch syndrome is an autosomal dominant hereditary cancer syndrome caused by germline pathogenic variants (PVs) in DNA mismatch repair genes (MLH1, MSH2, PMS2, MSH6) or the EPCAM gene. It is estimated to affect 1 in 300 individuals and confers a lifetime risk of cancer of 10-90%, depending on the specific variant and type of cancer. Lynch syndrome is the most common cause of inherited colorectal cancer, but for women, endometrial cancer is more likely to be the sentinel cancer. There is also evidence that certain PVs causing Lynch syndrome confer an increased risk of ovarian cancer, while the risk of ovarian cancer in others is not well defined. Given this, it is essential for the practicing gynecologist and gynecologic oncologist to remain up to date on the latest techniques in identification and diagnosis of individuals with Lynch syndrome as well as evidence-based screening and risk reduction recommendations for those impacted. Furthermore, as the landscape of gynecologic cancer treatment shifts towards treatment based on molecular classification of tumors, knowledge of targeted therapies well-suited for mismatch repair deficient Lynch tumors will be crucial. The objective of this review is to highlight recent updates in the literature regarding identification and management of individuals with Lynch syndrome as it pertains to endometrial and ovarian cancers to allow gynecologic providers the opportunity to both prevent and identify Lynch-associated cancers earlier, thereby reducing the morbidity and mortality of the syndrome.
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Affiliation(s)
| | - Kari L. Ring
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Virginia, Charlottesville, VA, United States
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20
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Georgiou D, Monje-Garcia L, Miles T, Monahan K, Ryan NAJ. A Focused Clinical Review of Lynch Syndrome. Cancer Manag Res 2023; 15:67-85. [PMID: 36699114 PMCID: PMC9868283 DOI: 10.2147/cmar.s283668] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2022] [Accepted: 12/23/2022] [Indexed: 01/19/2023] Open
Abstract
Lynch syndrome (LS) is an autosomal dominant condition that increases an individual's risk of a constellation of cancers. LS is defined when an individual has inherited pathogenic variants in the mismatch repair genes. Currently, most people with LS are undiagnosed. Early detection of LS is vital as those with LS can be enrolled in cancer reduction strategies through chemoprophylaxis, risk reducing surgery and cancer surveillance. However, these interventions are often invasive and require refinement. Furthermore, not all LS associated cancers are currently amenable to surveillance. Historically only those with a strong family history suggestive of LS were offered testing; this has proved far too restrictive. New criteria for testing have recently been introduced including the universal screening for LS in associated cancers. This has increased the number of people being diagnosed with LS but has also brought about unique challenges such as when to consent for germline testing and questions over how and who should carry out the consent. The results of germline testing for LS can be complicated and the diagnostic pathway is not always clear. Furthermore, by testing only those with cancer for LS we fail to identify these individuals before they develop potentially fatal pathology. This review will outline these challenges and explore solutions. Furthermore, we consider the potential future of LS care and the related treatments and interventions which are the current focus of research.
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Affiliation(s)
- Demetra Georgiou
- Genomics and Personalised Medicine Service, Charing Cross Hospital, London, UK
| | - Laura Monje-Garcia
- The St Mark's Centre for Familial Intestinal Cancer Polyposis, St Mark's Hospital, London, UK.,School of Public Health, Imperial College, London, UK
| | - Tracie Miles
- South West Genomics Medicine Service Alliance, Bristol, UK
| | - Kevin Monahan
- The St Mark's Centre for Familial Intestinal Cancer Polyposis, St Mark's Hospital, London, UK.,Department of Gastroenterology, Imperial College, London, UK
| | - Neil A J Ryan
- Department of Gynaecological Oncology, Royal Infirmary of Edinburgh, Edinburgh, UK.,The College of Medicine and Veterinary Medicine, The University of Edinburgh, Edinburgh, UK
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21
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Onishi S, Yamasaki F, Kuraoka K, Taguchi A, Takayasu T, Akagi K, Hinoi T. Diagnostic and therapeutic challenges of glioblastoma as an initial malignancy of constitutional mismatch repair deficiency (CMMRD): two case reports and a literature review. BMC Med Genomics 2023; 16:6. [PMID: 36647049 PMCID: PMC9843912 DOI: 10.1186/s12920-022-01403-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Accepted: 11/25/2022] [Indexed: 01/18/2023] Open
Abstract
BACKGROUND Constitutional mismatch repair deficiency (CMMRD) results from a biallelic germline pathogenic variant in a mismatch repair (MMR) gene. The most common CMMRD-associated malignancies are brain tumors; an accurate diagnosis is challenging when a malignant brain tumor is the only tumor at presentation. We describe two cases of glioblastoma as the initial CMMRD malignancy and discuss current diagnostic and therapeutic challenges. CASE PRESENTATION Two children with brain tumors without remarkable family history had biallelic pathogenic germline variants in PMS2. Patient 1: A 6-year-old girl presented biallelic PMS2 germline pathogenic variants. Glioblastomas at the left frontal lobe and right temporal lobe were resistant to immune-checkpoint inhibitor, temozolomide, and bevacizumab. Patient 2: A 10-year-old boy presented biallelic PMS2 germline variants. His glioblastoma with primitive neuroectodermal tumor-like features responded to chemoradiotherapy, but he developed advanced colon cancer and acute lymphocytic leukemia. In both patients, only a monoallelic PMS2 germline variant was detected by conventional gene tests. PMS2 immunohistochemistry showed lack of staining at both the tumors and normal tissue as vascular endothelial cells. Further gene tests revealed large genomic deletion including the entire PMS2 gene, confirming biallelic PMS2 germline variants. CONCLUSION Conventional multi-gene panel tests are insufficient for detecting large deletions of MMR genes, resulting in misdiagnoses of CMMRD as Lynch syndrome. PMS2 variants have low cancer penetrance; family histories may thus be absent. Long-range gene analyses or immunohistochemical staining of MMR proteins in normal tissue should be considered for pediatric brain tumors with a single allele MMR variant when CMMRD is suspected.
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Affiliation(s)
- Shumpei Onishi
- grid.257022.00000 0000 8711 3200Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan ,grid.416698.4Department of Neurosurgery, Kure Medical Center and Chugoku Cancer Center, National Hospital Organization, Hiroshima, Japan
| | - Fumiyuki Yamasaki
- grid.257022.00000 0000 8711 3200Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kazuya Kuraoka
- grid.440118.80000 0004 0569 3483Department of Diagnostic Pathology, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima, Japan
| | - Akira Taguchi
- grid.257022.00000 0000 8711 3200Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Takeshi Takayasu
- grid.257022.00000 0000 8711 3200Department of Neurosurgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Kiwamu Akagi
- grid.416695.90000 0000 8855 274XDepartment of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Saitama, Japan
| | - Takao Hinoi
- grid.470097.d0000 0004 0618 7953Department of Clinical and Molecular Genetics, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-Ku, Hiroshima, 734-8551 Japan
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22
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Lahiri S, Pirzadeh-Miller S, Moriarty K, Kubiliun N. Implementation of a Population-Based Cancer Family History Screening Program for Lynch Syndrome. Cancer Control 2023; 30:10732748231175011. [PMID: 37161761 DOI: 10.1177/10732748231175011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/11/2023] Open
Abstract
OBJECTIVES Lynch syndrome increases risks for colorectal and other cancers. Though published Lynch syndrome cancer risk-management guidelines are effective for risk-reduction, the condition remains under-recognized. The Cancer Genetics Program at an academic medical center implemented a population-based cancer family history screening program, Detecting Unaffected Individuals with Lynch syndrome, to aid in identification of individuals with Lynch syndrome. METHODS In this retrospective cohort study, simple cancer family history screening questionnaires were used to identify those at risk for Lynch syndrome. Program navigators triaged and educated those who screened positive about hereditary cancer, and genetic counseling and testing services, offering genetic counseling if eligible. Genetic counseling was provided primarily via telephone. Genetic counselors performed hereditary cancer risk assessment and offered genetic testing via hereditary cancer panels to those eligible. Remote service delivery models via telephone genetic counseling and at-home saliva testing were used to increase access to medical genetics services. RESULTS This program screened 212,827 individuals, over half of whom were considered underserved, and identified 133 clinically actionable genetic variants associated with hereditary cancer. Of these, 47 (35%) were associated with Lynch syndrome while notably, 70 (53%) were not associated with hereditary colorectal cancer. Of 3,344 patients offered genetic counseling after initial triage, 2,441 (73%) elected to schedule the appointment and 1,775 individuals (73%) completed genetic counseling. Among underserved patients, telephone genetic counseling completion rates were significantly higher than in-person appointment completion rates (P < .05). While remote service delivery improved appointment completion rates, challenges with genetic test completion using at-home saliva sample collection kits were observed, with 242 of 1592 individuals (15%) not completing testing. CONCLUSION Population-based cancer family history screening and navigation can help identify individuals with hereditary cancer syndromes across diverse patient populations, but logistics of certain downstream service delivery models can impact outcomes.
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Affiliation(s)
- Sayoni Lahiri
- Department of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, USA
| | | | - Kelsey Moriarty
- Department of Cancer Genetics, UT Southwestern Medical Center, Dallas, TX, USA
| | - Nisa Kubiliun
- Division of Digestive and Liver Diseases, UT Southwestern Medical Center, Dallas, TX, USA
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23
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Scott A, Hernandez F, Chamberlin A, Smith C, Karam R, Kitzman JO. Saturation-scale functional evidence supports clinical variant interpretation in Lynch syndrome. Genome Biol 2022; 23:266. [PMID: 36550560 PMCID: PMC9773515 DOI: 10.1186/s13059-022-02839-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 12/13/2022] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Lynch syndrome (LS) is a cancer predisposition syndrome affecting more than 1 in every 300 individuals worldwide. Clinical genetic testing for LS can be life-saving but is complicated by the heavy burden of variants of uncertain significance (VUS), especially missense changes. RESULT To address this challenge, we leverage a multiplexed analysis of variant effect (MAVE) map covering >94% of the 17,746 possible missense variants in the key LS gene MSH2. To establish this map's utility in large-scale variant reclassification, we overlay it on clinical databases of >15,000 individuals with LS gene variants uncovered during clinical genetic testing. We validate these functional measurements in a cohort of individuals with paired tumor-normal test results and find that MAVE-based function scores agree with the clinical interpretation for every one of the MSH2 missense variants with an available classification. We use these scores to attempt reclassification for 682 unique missense VUS, among which 34 scored as deleterious by our function map, in line with previously published rates for other cancer predisposition genes. Combining functional data and other evidence, ten missense VUS are reclassified as pathogenic/likely pathogenic, and another 497 could be moved to benign/likely benign. Finally, we apply these functional scores to paired tumor-normal genetic tests and identify a subset of patients with biallelic somatic loss of function, reflecting a sporadic Lynch-like Syndrome with distinct implications for treatment and relatives' risk. CONCLUSION This study demonstrates how high-throughput functional assays can empower scalable VUS resolution and prospectively generate strong evidence for variant classification.
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Affiliation(s)
- Anthony Scott
- grid.214458.e0000000086837370Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109 USA ,grid.214458.e0000000086837370Division of Genetic Medicine, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109 USA
| | - Felicia Hernandez
- grid.465138.d0000 0004 0455 211XAmbry Genetics, Aliso Viejo, CA 92656 USA
| | - Adam Chamberlin
- grid.465138.d0000 0004 0455 211XAmbry Genetics, Aliso Viejo, CA 92656 USA
| | - Cathy Smith
- grid.214458.e0000000086837370Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109 USA ,grid.214458.e0000000086837370Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109 USA
| | - Rachid Karam
- grid.465138.d0000 0004 0455 211XAmbry Genetics, Aliso Viejo, CA 92656 USA ,grid.214458.e0000000086837370Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109 USA
| | - Jacob O. Kitzman
- grid.214458.e0000000086837370Department of Human Genetics, University of Michigan Medical School, Ann Arbor, MI 48109 USA ,grid.214458.e0000000086837370Department of Computational Medicine and Bioinformatics, University of Michigan Medical School, Ann Arbor, MI 48109 USA
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24
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Passero L, Srinivasan S, Grewe ME, Leeman J, Berg J, Reuland D, Roberts MC. Development and initial testing of a multi-stakeholder intervention for Lynch syndrome cascade screening: an intervention mapping approach. BMC Health Serv Res 2022; 22:1411. [PMID: 36434579 PMCID: PMC9694070 DOI: 10.1186/s12913-022-08732-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2022] [Accepted: 10/25/2022] [Indexed: 11/26/2022] Open
Abstract
BACKGROUND Lynch syndrome is an underdiagnosed hereditary condition carrying an increased lifetime risk for colorectal and endometrial cancer and affecting nearly 1 million people in the United States. Cascade screening, systematic screening through family members of affected patients, could improve identification of Lynch syndrome, but this strategy is underused due to multi-level barriers including low knowledge about Lynch syndrome, low access to genetics services, and challenging family dynamics. METHODS We used intervention mapping, a 6-step methodology to create stakeholder-driven interventions that meet the needs of a target population, to develop an intervention to improve cascade screening for Lynch syndrome. The intervention development process was guided by input from key stakeholders in Lynch syndrome care and patients. We conducted usability testing on the intervention with Lynch syndrome patients using qualitative semi-structured interviewing and rapid qualitative analysis. RESULTS We developed a workbook intervention named Let's Talk that addresses gaps in knowledge, skills, self-efficacy, outcome expectancy and other perceived barriers to cascade screening for Lynch syndrome. Let's Talk contained educational content, goal setting activities, communication planning prompts and supplemental resources for patients to plan family communication. Evidence-based methods used in the workbook included information chunking, guided practice, goal setting and gain-framing. We conducted usability testing focused on the complexity and relative advantage of the intervention through 45-min virtual interviews with 10 adult patients with Lynch syndrome recruited from a national advocacy organization in the United States. Usability testing results suggested the intervention was acceptable in terms of complexity and relative advantage to other available resources, but additional information for communication with young or distant family members and a web-based platform could enhance the intervention's usability. CONCLUSIONS Intervention mapping provided a framework for intervention development that addressed the unique needs of Lynch syndrome patients in overcoming barriers to cascade screening. Future work is needed to transform Let's Talk into a web-based tool and evaluate the effectiveness of the intervention in clinical practice with patients and genetic counselors. Intervention mapping can be useful to researchers as an evidence-based technique to develop stakeholder-centered interventions for addressing the needs of other unique populations.
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Affiliation(s)
- Lauren Passero
- Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, Chapel Hill, US
| | - Swetha Srinivasan
- Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, Chapel Hill, US
| | - Mary E Grewe
- North Carolina Translational and Clinical Sciences Institute, University of North Carolina at Chapel Hill, NC, Chapel Hill, US
| | - Jennifer Leeman
- School of Nursing, University of North Carolina at Chapel Hill, NC, Chapel Hill, US
| | - Jonathan Berg
- School of Medicine, University of North Carolina at Chapel Hill, NC, Chapel Hill, US
| | - Daniel Reuland
- School of Medicine, University of North Carolina at Chapel Hill, NC, Chapel Hill, US
| | - Megan C Roberts
- Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, NC, Chapel Hill, US.
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25
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Coughlin SE, Heald B, Clark DF, Nielsen SM, Hatchell KE, Esplin ED, Katona BW. Multigene Panel Testing Yields High Rates of Clinically Actionable Variants Among Patients With Colorectal Cancer. JCO Precis Oncol 2022; 6:e2200517. [PMID: 36370464 PMCID: PMC9812641 DOI: 10.1200/po.22.00517] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2022] [Revised: 09/30/2022] [Accepted: 10/10/2022] [Indexed: 11/15/2022] Open
Abstract
PURPOSE Whether germline multigene panel testing (MGPT) should be performed in all individuals with colorectal cancer (CRC) remains uncertain. Therefore, we aimed to determine the yield and potential clinical impact of MGPT across a large, diverse CRC cohort. METHODS This was a retrospective cohort study of adults with CRC who underwent MGPT of > 10 genes at a commercial laboratory between March 2015 and May 2021. All data were prospectively collected through a single commercial laboratory and retrospectively analyzed. RESULTS A total of 34,244 individuals with a history of CRC underwent germline MPGT and were included in the analysis. This cohort was predominantly female (60.7%), White (70.6%), and age 50 years or older (68.9%), with 35.5% also reporting a noncolorectal malignancy. At least one pathogenic/likely pathogenic germline variant (PGV) was found in 4,864 (14.2%), with 3,111 (9.1%) having a PGV associated with increased CRC/polyposis risk and 1,048 (3.1%) having an otherwise clinically actionable PGV. Larger gene panels were not clearly associated with higher yield of clinically actionable PGVs. PGVs were more prevalent in individuals of Ashkenazi Jewish descent (P < .001) and Hispanic ethnicity (P < .001). Across all ages, panel sizes, and races/ethnicities, the rate of clinically actionable PGVs on MGPT was 7.9% or greater. A variant of uncertain significance was identified in 13,094 individuals (38.2%). Identification of a variant of uncertain significance associated with panel size (P < .001) and was lower in individuals of Ashkenazi Jewish descent (P < .001), but higher in Black, Asian, and Hispanic individuals (P < .001). CONCLUSION To our knowledge, this is the largest study to date examining MGPT in CRC, demonstrating high rates of clinically actionable variants detected across all age groups, panel sizes, and racial/ethnic groups. This work supports consideration of broadening germline genetic testing criteria for individuals with CRC.
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Affiliation(s)
- Sarah E. Coughlin
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | - Dana Farengo Clark
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
| | | | | | | | - Bryson W. Katona
- University of Pennsylvania Perelman School of Medicine, Philadelphia, PA
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26
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Heald B, Mokhtary S, Nielsen SM, Rojahn S, Yang S, Michalski ST, Esplin ED. Unexpected actionable genetic variants revealed by multigene panel testing of patients with uterine cancer. Gynecol Oncol 2022; 166:344-350. [PMID: 35691755 DOI: 10.1016/j.ygyno.2022.05.023] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Revised: 05/09/2022] [Accepted: 05/28/2022] [Indexed: 01/17/2023]
Abstract
OBJECTIVE Hereditary uterine cancer (UC) is traditionally associated with pathogenic/likely pathogenic germline variants (PGVs) in Lynch syndrome genes or PTEN; however, growing evidence supports a role for other genes that may reveal new clinical management options. In this study we assessed the prevalence and potential clinical impact of PGVs identified in UC patients referred for comprehensive germline genetic testing that combined testing for Lynch syndrome, PTEN, and other cancer predisposition genes. METHODS Prevalence of PGVs in patients referred to a single clinical lab for germline genetic testing with an indication of uterine or endometrial cancer were retrospectively assessed and compared by syndrome type, patient age at testing, and self-reported ancestry. Potential clinical actionability of PGVs was based on established guidelines for clinical management, targeted therapies, and clinical trial eligibility. RESULTS PGVs were detected in 13.6% of the cohort (880/6490). PGVs were most frequently observed in Lynch syndrome genes (60.4%) and PTEN (1.5%), with 38.1% in another cancer predisposition gene (i.e., CHEK2, BRCA1/BRCA2). PGV prevalence was similar for patients <50 years and those ≥50 years (15.1% vs 13.2%). Nearly all PGVs (97.2%) were associated with guideline-recommended management, including cascade testing; 60.5% were associated with FDA-approved therapies; and 35.2% were associated with clinical trials. CONCLUSIONS Focusing germline testing on Lynch syndrome genes and PTEN and limiting testing to patients <50 years of age at diagnosis may overlook a substantial proportion of UC patients who harbor actionable PGVs. Universal comprehensive genetic testing of UC patients could benefit many patients and at-risk family members.
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Affiliation(s)
- Brandie Heald
- Invitae, 1400 16th Street, San Francisco, CA 94103, USA
| | - Sara Mokhtary
- Invitae, 1400 16th Street, San Francisco, CA 94103, USA
| | | | - Susan Rojahn
- Invitae, 1400 16th Street, San Francisco, CA 94103, USA
| | - Shan Yang
- Invitae, 1400 16th Street, San Francisco, CA 94103, USA
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27
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Zorn KK, Simonson ME, Faulkner JL, Carr CL, Acuna J, Hall TL, Jenkins JF, Drummond KL, Curran GM. Can Automated Alerts in the Electronic Health Record Encourage Referrals for Genetic Counseling and Testing Among Patients at High Risk for Hereditary Cancer Syndromes? JCO Oncol Pract 2022; 18:e1219-e1224. [PMID: 35316088 PMCID: PMC9287297 DOI: 10.1200/op.21.00641] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2021] [Revised: 01/26/2022] [Accepted: 02/15/2022] [Indexed: 11/20/2022] Open
Abstract
PURPOSE Up to 10% of cancers may be associated with an inherited mutation that increases cancer risk. National guidelines emphasize referral for genetic counseling and testing for patients whose personal and/or family history increases their risk of having a hereditary cancer syndrome. METHODS To increase appropriate referrals for cancer genetic counseling and testing, we piloted an automated alert known as a Best Practice Advisory (BPA) in the electronic health record, Epic, to notify oncology providers when a patient had a personal and/or family history that merited referral to cancer genetics. Epic could not gather the complex clinical data needed for the referral decision automatically, necessitating staff completion of a questionnaire. After educating providers, the BPA was implemented with resources to support its use. RESULTS Initial interaction with the alert was high but rapidly dwindled, resulting in questionnaire completion in 7.2% of more than 32,000 encounters and 14.9% of patients over 9 months. However, cancer genetics referrals increased 95.9% during the pilot (P < .0001), with 18.5% placed through the BPA and the rest from a non-BPA mechanism. Semistructured interviews with key stakeholders revealed not only general acceptance of the BPA concept but also barriers to completion, such as pressure to room patients quickly in the face of competing BPAs and lack of buy-in from some providers. CONCLUSION These results suggest that provider engagement and BPA fatigue are significant obstacles to acceptance of a new automated alert. Despite interest in a tool for cancer genetics, the demand on clinical time for this complex BPA was poorly tolerated.
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Affiliation(s)
- Kristin K. Zorn
- University of Arkansas for Medical Sciences, Little Rock, AR
| | | | | | - Cyndee L. Carr
- University of Arkansas for Medical Sciences, Little Rock, AR
| | - Joshua Acuna
- University of Arkansas for Medical Sciences, Little Rock, AR
| | - Tiffany L. Hall
- University of Arkansas for Medical Sciences, Little Rock, AR
| | - John F. Jenkins
- University of Arkansas for Medical Sciences, Little Rock, AR
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Crain PR, Zepp JM, Gille S, Jenkins L, Kauffman TL, Shuster E, Goddard KAB, Wilfond BS, Hunter JE. Identifying patients with Lynch syndrome using a universal tumor screening program in an integrated healthcare system. Hered Cancer Clin Pract 2022; 20:17. [PMID: 35436948 PMCID: PMC9014602 DOI: 10.1186/s13053-022-00217-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Accepted: 03/01/2022] [Indexed: 11/15/2022] Open
Abstract
INTRODUCTION Lynch syndrome (LS) is associated with an increased risk of colorectal (CRC) and endometrial (EC) cancers. Universal tumor screening (UTS) of all individuals diagnosed with CRC and EC is recommended to increase identification of LS. Kaiser Permanente Northwest (KPNW) implemented a UTS program for LS among individuals newly diagnosed with CRC in January 2016 and EC in November 2016. UTS at KPNW begins with immunohistochemistry (IHC) of tumor tissue to determine loss of mismatch repair proteins associated with LS (MLH1, MSH2, MSH6, and PMS2)., IHC showing loss of MLH1 is followed by reflex testing (automatic testing) to detect the presence of the BRAF V600E variant (in cases of CRC) and MLH1 promoter hypermethylation to rule out likely sporadic cases. MATERIALS AND METHODS Individuals newly diagnosed with CRC and EC were identified between the initiation of the respective UTS programs and July 2018. Electronic medical records were reviewed to extract patient data related to UTS, including IHC and reflex testing results, date of referrals to the genetics department, and results of germline genetic testing for LS. RESULTS 313 out of 362 individuals diagnosed with CRC and 61 out of 64 individuals diagnosed with EC who were eligible were screened by IHC for LS. Most (47/52 or 90%, including 46/49 CRC and 1/3 EC) individuals that were not screened by IHC only had a biopsy sample available. Fourteen individuals (3.7% overall, including 13/313 CRC and 1/61 EC) received an abnormal result after reflex testing and were referred for genetic counseling. Of these, 10 individuals (71% overall, including 9/13 CRC and 1/1 EC) underwent germline genetic testing for LS. Five individuals diagnosed with CRC were found to have pathogenic variants. in PMS2 (n = 3), MLH1 (n = 1), and MSH6 (n = 1). No pathogenic variants were identified in individuals diagnosed with EC. CONCLUSIONS UTS identified individuals at risk for LS. Most individuals who screened positive for LS had follow-up germline genetic testing for LS. The consistent use of biopsy samples is an opportunity to improve UTS.
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Affiliation(s)
- Philip R Crain
- Department of Biostatistics, School of Public Health, University of Washington, Seattle, WA, USA
| | - Jamilyn M Zepp
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Sara Gille
- Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Lindsay Jenkins
- Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Tia L Kauffman
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Elizabeth Shuster
- Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Katrina A B Goddard
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA
| | - Benjamin S Wilfond
- Treuman Katz Center for Pediatric Bioethics, Department of Pediatrics, Seattle Children's Research Institute and Hospital, University of Washington School of Medicine, Seattle, WA, USA
| | - Jessica Ezzell Hunter
- Department of Translational and Applied Genomics, Center for Health Research, Kaiser Permanente Northwest, Portland, OR, USA.
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Liquid Biopsy as a Source of Nucleic Acid Biomarkers in the Diagnosis and Management of Lynch Syndrome. Int J Mol Sci 2022; 23:ijms23084284. [PMID: 35457101 PMCID: PMC9029375 DOI: 10.3390/ijms23084284] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Revised: 04/07/2022] [Accepted: 04/12/2022] [Indexed: 02/06/2023] Open
Abstract
Lynch syndrome (LS) is an autosomal dominant inherited cancer predisposition disorder, which may manifest as colorectal cancer (CRC), endometrial cancer (EC) or other malignancies of the gastrointestinal and genitourinary tract as well as the skin and brain. Its genetic cause is a defect in one of the four key DNA mismatch repair (MMR) loci. Testing of patients at risk is currently based on the absence of MMR protein staining and detection of mutations in cancer tissue and the germline, microsatellite instability (MSI) and the hypermethylated state of the MLH1 promoter. If LS is shown to have caused CRC, lifetime follow-up with regular screening (most importantly, colonoscopy) is required. In recent years, DNA and RNA markers extracted from liquid biopsies have found some use in the clinical diagnosis of LS. They have the potential to greatly enhance the efficiency of the follow-up process by making it minimally invasive, reproducible, and time effective. Here, we review markers reported in the literature and their current clinical applications, and we comment on possible future directions.
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Curtius K, Gupta S, Boland CR. Review article: Lynch Syndrome-a mechanistic and clinical management update. Aliment Pharmacol Ther 2022; 55:960-977. [PMID: 35315099 DOI: 10.1111/apt.16826] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/02/2021] [Accepted: 02/02/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND Lynch syndrome (LS) is an autosomal dominant familial condition caused by a pathogenic variant (PV) in a DNA mismatch repair gene, which then predisposes carriers to various cancers. AIM To review the pathogenesis, clinical presentation, differential diagnosis and clinical strategies for detection and management of LS. METHODS A narrative review synthesising knowledge from published literature, as well as current National Comprehensive Cancer Network guidelines for management of LS was conducted. RESULTS LS tumours are characterised by unique pathogenesis, ultimately resulting in hypermutation, microsatellite instability and high immunogenicity that has significant implications for cancer risk, clinical presentation, treatment and surveillance. LS is one of the most common hereditary causes of cancer, and about 1 in 279 individuals carry a PV in an LS gene that predisposes to associated cancers. Individuals with LS have increased risks for colorectal, endometrial and other cancers, with significant variation in lifetime risk by LS-associated gene. CONCLUSIONS As genetic testing becomes more widespread, the number of individuals identified with LS is expected to increase in the population. Understanding the pathogenesis of LS informs current strategies for detection and clinical management, and also guides future areas for clinical innovation. Unravelling the mechanisms by which these tumours evolve may help to more precisely tailor management by the gene involved.
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Affiliation(s)
- Kit Curtius
- Division of Biomedical Informatics, Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Samir Gupta
- Section of Gastroenterology, San Diego Veterans Affairs Healthcare System, San Diego, CA, USA.,Division of Gastroenterology, School of Medicine, University of California San Diego, La Jolla, CA, USA
| | - C Richard Boland
- Division of Gastroenterology, School of Medicine, University of California San Diego, La Jolla, CA, USA
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31
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Shi WK, Li YH, Bai XS, Lin GL. The Cell Cycle-Associated Protein CDKN2A May Promotes Colorectal Cancer Cell Metastasis by Inducing Epithelial-Mesenchymal Transition. Front Oncol 2022; 12:834235. [PMID: 35311137 PMCID: PMC8929760 DOI: 10.3389/fonc.2022.834235] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2021] [Accepted: 01/31/2022] [Indexed: 01/04/2023] Open
Abstract
Colorectal cancer (CRC) is a common gastrointestinal malignancy, and recurrence and metastasis contribute considerably to its high mortality. It is well known that the epithelial-mesenchymal transition (EMT) accelerates the rate of cancer cell dissemination and migration, thus promoting cancer metastasis. Targeted therapy is a common modality for cancer treatment, and it can play a role in inhibiting cancer progression. In this study, bioinformatics was used to search for genes associated with the prognosis of CRC. First, differential analysis was performed on colon and rectal cancer samples to obtain 2,840 and 3,177 differentially expressed genes (DEGs), respectively. A Venn diagram was then used to identify 262 overlapping genes from the two groups of DEGs and EMT-related genes. The overlapping genes were subjected to batch survival analysis and batch expression analysis successively, and nine genes were obtained whose high expression in CRC led to a poor prognosis. The least absolute shrinkage and selection operator (LASSO) prognostic model was then constructed to obtain the risk score formula. A nomogram was constructed to seek prognostic independent factors to obtain CDKN2A. Finally, CCK-8 assay, flow cytometry and western blotting assays were performed to analyze the cellular biological function of CDKN2A. The results showed that knockdown of CDKN2A expression inhibited HT-29 cell proliferation, promoted apoptosis and cell cycle progression, and affected the EMT process in CRC.
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Affiliation(s)
- Wei-Kun Shi
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Yun-Hao Li
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
| | - Xue-Shan Bai
- Plastic Surgery Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Guo-Le Lin
- Department of General Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing, China
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32
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Patient navigation for hereditary colorectal cancer: Design of a randomized controlled trial to determine the effectiveness of pathways to genetic counseling. Contemp Clin Trials 2022; 116:106735. [PMID: 35331945 DOI: 10.1016/j.cct.2022.106735] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2021] [Revised: 01/28/2022] [Accepted: 03/17/2022] [Indexed: 11/20/2022]
Abstract
BACKGROUND Diagnosis of Lynch and other hereditary colorectal cancer (CRC) syndromes through germline genetic testing has important implications for treatment and risk-management, yet guideline-recommended genetic counseling referral and attendance is suboptimal. METHODS Our team developed an adapted patient navigation program-Pathways to Genetic Counseling-to address multilevel barriers to genetic counseling referral and receipt. This paper describes the methods of a randomized controlled trial (RCT) testing Pathways to Genetic Counseling's effectiveness at increasing genetic counseling attendance in the University of Washington Medicine health system. We will identify CRC patients eligible for genetic counseling (diagnosed before age 50 or at any age with evidence of inherited mismatch repair deficiency) through a combination of structured electronic health record queries and manual chart review. Patients will be randomized 1:1 prior to consent and receive either care as usual (no contact) or be invited to participate in patient navigation. We will use chart review to compare rates of genetic counseling referral and attendance within six months of randomization, regardless of patients' engagement with navigation. We plan to identify and randomize 161 eligible CRC patients over a nine-month period beginning in late 2021. DISCUSSION Our pragmatic RCT design will provide real-world data on the potential for patient navigation to address longstanding care gaps in preventive genomic medicine. If effective, we hope to pilot Pathways to Genetic Counseling in additional settings with a long-term goal of improving appropriate diagnosis of hereditary CRC syndromes and subsequent cascade screening of eligible family members.
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33
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Morrison J, Balega J, Buckley L, Clamp A, Crosbie E, Drew Y, Durrant L, Forrest J, Fotopoulou C, Gajjar K, Ganesan R, Gupta J, Hughes J, Miles T, Moss E, Nanthakumar M, Newton C, Ryan N, Walther A, Taylor A. British Gynaecological Cancer Society (BGCS) uterine cancer guidelines: Recommendations for practice. Eur J Obstet Gynecol Reprod Biol 2022; 270:50-89. [DOI: 10.1016/j.ejogrb.2021.11.423] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2021] [Accepted: 11/19/2021] [Indexed: 12/24/2022]
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34
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Patel SG, Karlitz JJ, Yen T, Lieu CH, Boland CR. The rising tide of early-onset colorectal cancer: a comprehensive review of epidemiology, clinical features, biology, risk factors, prevention, and early detection. Lancet Gastroenterol Hepatol 2022; 7:262-274. [DOI: 10.1016/s2468-1253(21)00426-x] [Citation(s) in RCA: 360] [Impact Index Per Article: 120.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 10/27/2021] [Accepted: 11/01/2021] [Indexed: 02/07/2023]
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35
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Kurpiel B, Thomas MS, Mubeen M, Ring KL, Modesitt SC, Moskaluk CA, Mills AM. MLH1/PMS2-deficient Endometrial Carcinomas in a Universally Screened Population: MLH1 Hypermethylation and Germline Mutation Status. Int J Gynecol Pathol 2022; 41:1-11. [PMID: 33577226 DOI: 10.1097/pgp.0000000000000767] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
MLH1/PMS2 loss due to epigenetic hypermethylation of the MLH1 promoter is the most common cause of mismatch repair deficiency in endometrial carcinoma, and typically provides reassurance against an associated germline mutation. To further characterize the genetic features of MLH1/PMS2-deficient endometrial cancers, the departmental database was searched for cases with dual MLH1/PMS2 loss and retained MSH2/6 expression which underwent MLH1 hypermethylation testing. Genetic testing results were obtained when available. One hundred seventeen endometrial cancers met inclusion criteria: 100 (85%) were MLH1-hypermethylated, 3 (3%) were low-level/borderline, 7 (6%) were nonmethylated, and 7 (6%) were insufficient for testing. Sixteen cases (12 MLH1-hypermethylated, 3 nonmethylated, and 1 insufficient for testing) underwent germline testing, 6 of which (37.5%) demonstrated germline variants of unknown significance (VUS) (MSH6, PMS2, POLD1, BRIP1, RAD51D, CHEK2) but no known deleterious mutations. Notably, however, the patients harboring the MSH6 and PMS2 germline VUS had clinical features concerning for Lynch syndrome. One nonmethylated, germline-normal case underwent somatic tumor testing, and demonstrated a somatic MLH1 mutation. In summary, MLH1-hypermethylation accounts for the vast majority of MLH1/PMS2-deficient cancers in a universally screened population, although MLH1 somatic and germline mutations can occur. Occasionally, patients with MLH1-hypermethlated tumors also bear germline VUS in other mismatch repair genes as well as genes implicated in other hereditary cancer syndromes, but their clinical relevance is unclear. Family and personal cancer histories must always be evaluated to determine the need for germline testing in women with loss of MLH1/PMS2, even in the setting of hypermethylation.
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36
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Shen EC, Srinivasan S, Passero LE, Allen CG, Dixon M, Foss K, Halliburton B, Milko LV, Smit AK, Carlson R, Roberts MC. Barriers and Facilitators for Population Genetic Screening in Healthy Populations: A Systematic Review. Front Genet 2022; 13:865384. [PMID: 35860476 PMCID: PMC9289280 DOI: 10.3389/fgene.2022.865384] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 06/02/2022] [Indexed: 11/25/2022] Open
Abstract
Studies suggest that 1-3% of the general population in the United States unknowingly carry a genetic risk factor for a common hereditary disease. Population genetic screening is the process of offering otherwise healthy patients in the general population testing for genomic variants that predispose them to diseases that are clinically actionable, meaning that they can be prevented or mitigated if they are detected early. Population genetic screening may significantly reduce morbidity and mortality from these diseases by informing risk-specific prevention or treatment strategies and facilitating appropriate participation in early detection. To better understand current barriers, facilitators, perceptions, and outcomes related to the implementation of population genetic screening, we conducted a systematic review and searched PubMed, Embase, and Scopus for articles published from date of database inception to May 2020. We included articles that 1) detailed the perspectives of participants in population genetic screening programs and 2) described the barriers, facilitators, perceptions, and outcomes related to population genetic screening programs among patients, healthcare providers, and the public. We excluded articles that 1) focused on direct-to-consumer or risk-based genetic testing and 2) were published before January 2000. Thirty articles met these criteria. Barriers and facilitators to population genetic screening were organized by the Social Ecological Model and further categorized by themes. We found that research in population genetic screening has focused on stakeholder attitudes with all included studies designed to elucidate individuals' perceptions. Additionally, inadequate knowledge and perceived limited clinical utility presented a barrier for healthcare provider uptake. There were very few studies that conducted long-term follow-up and evaluation of population genetic screening. Our findings suggest that these and other factors, such as prescreen counseling and education, may play a role in the adoption and implementation of population genetic screening. Future studies to investigate macro-level determinants, strategies to increase provider buy-in and knowledge, delivery models for prescreen counseling, and long-term outcomes of population genetic screening are needed for the effective design and implementation of such programs. Systematic Review Registration: https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42020198198.
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Affiliation(s)
- Emily C Shen
- College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,UNC Lineberger Comprehensive Cancer Center, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Swetha Srinivasan
- Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States
| | - Lauren E Passero
- Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States
| | - Caitlin G Allen
- Department of Public Health Science, College of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Madison Dixon
- Department of Behavioral, Social, and Health Education Science, Rollins School of Public Health, Emory University, Atlanta, GA, United States
| | - Kimberly Foss
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Brianna Halliburton
- College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Laura V Milko
- Department of Genetics, School of Medicine, University of North Carolina, Chapel Hill, NC, United States
| | - Amelia K Smit
- The Daffodil Centre, University of Sydney, A Joint Venture with Cancer Council NSW, Sydney, NSW, Australia.,Melanoma Institute Australia, University of Sydney, Sydney, NSW, Australia
| | - Rebecca Carlson
- Health Sciences Library, University of North Carolina, Chapel Hill, NC, United States
| | - Megan C Roberts
- Division of Pharmaceutical Outcomes and Policy, Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, NC, United States
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Tedjasaputra TR, Hatta M, Massi MN, Natzir R, Bukhari A, Masadah R, Parewangi ML, Prihantono P, Nariswati R, Tedjasaputra V. Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor. World J Gastrointest Pathophysiol 2021; 12:130-142. [DOI: 10.4291/wjgp.v12.i6.130] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Affiliation(s)
- Tjahjadi Robert Tedjasaputra
- Department of Internal Medicine, Tarakan General Hospital, Medical Faculty University of Hasanuddin, Jakarta 10720, DKI Jakarta, Indonesia
| | - Mochammad Hatta
- Department of Immunology and Biomolecular, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Muh Nasrum Massi
- Department of Microbiology, Faculty of Medicine, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry Meidcal Faculty, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Agussalim Bukhari
- Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rina Masadah
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Muh Lutfi Parewangi
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rinda Nariswati
- Department of Statistic, School of Computer Science, Bina Nusantara University Jakarta, Jakarta 11530, Indonesia
| | - Vincent Tedjasaputra
- American Association for the Advancement of Science (AAAS), Science and Technology Policy Fellow, Alexandria, VA 22314, United States
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Tedjasaputra TR, Hatta M, Massi MN, Natzir R, Bukhari A, Masadah R, Parewangi ML, Prihantono P, Nariswati R, Tedjasaputra V. Prediction of hereditary nonpolyposis colorectal cancer using mRNA MSH2 quantitative and the correlation with nonmodifiable factor. World J Gastrointest Pathophysiol 2021; 12:134-146. [PMID: 34877027 PMCID: PMC8611184 DOI: 10.4291/wjgp.v12.i6.134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 03/13/2021] [Accepted: 10/11/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hereditary non-polyposis colon cancer is a dominantly inherited syndrome of colorectal cancer (CRC), with heightened risk for younger population. Previous studies link its susceptibility to the DNA sequence polymorphism along with Amsterdam and Bethesda criteria. However, those fail in term of applicability. AIM To determine a clear cut-off of MSH2 gene expression for CRC heredity grouping factor. Further, the study also aims to examine the association of risk factors to the CRC heredity. METHODS The cross-sectional study observed 71 respondents from May 2018 to December 2019 in determining the CRC hereditary status through MSH2 mRNA expression using reverse transcription-polymerase chain reaction and the disease's risk factors. Data were analyzed through Chi-Square, Fischer exact, t-test, Mann-Whitney, and multiple logistics. RESULTS There are significant differences of MSH2 within CRC group among tissue and blood; yet, negative for significance between groups. Through the blood gene expression fifth percentile, the hereditary CRC cut-off is 11059 fc, dividing the 40 CRC respondents to 32.5% with hereditary CRC. Significant risk factors include age, family history, and staging. Nonetheless, after multivariate control, age is just a confounder. Further, the study develops a probability equation with area under the curve 82.2%. CONCLUSION Numerous factors have significant relations to heredity of CRC patients. However, true important factors are staging and family history, while age and others are confounders. The study also established a definite cut-off point for heredity CRC based on mRNA MSH2 expression, 11059 fc. These findings shall act as concrete foundations on further risk factors and/or genetical CRC future studies.
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Affiliation(s)
- Tjahjadi Robert Tedjasaputra
- Department of Internal Medicine, Tarakan General Hospital, Medical Faculty University of Hasanuddin, Jakarta 10720, DKI Jakarta, Indonesia
| | - Mochammad Hatta
- Department of Immunology and Biomolecular, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Muh Nasrum Massi
- Department of Microbiology, Faculty of Medicine, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Rosdiana Natzir
- Department of Biochemistry Meidcal Faculty, University of Hasanuddin, Makassar 90245, South Sulawesi, Indonesia
| | - Agussalim Bukhari
- Department of Nutrition, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rina Masadah
- Department of Pathology Anatomy, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Muh Lutfi Parewangi
- Department of Internal Medicine, Faculty of Medicine, Hasanuddin University, Makassar 20945, South Sulawesi, Indonesia
| | - Prihantono Prihantono
- Department of Surgery, Faculty of Medicine, Hasanuddin University, Makassar 90245, South Sulawesi, Indonesia
| | - Rinda Nariswati
- Department of Statistic, School of Computer Science, Bina Nusantara University Jakarta, Jakarta 11530, Indonesia
| | - Vincent Tedjasaputra
- American Association for the Advancement of Science (AAAS), Science and Technology Policy Fellow, Alexandria, VA 22314, United States
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Alblas M, Peterse EFP, Du M, Zauber AG, Steyerberg EW, van Leeuwen N, Lansdorp-Vogelaar I. Cost-effectiveness of prophylactic hysterectomy in first-degree female relatives with Lynch syndrome of patients diagnosed with colorectal cancer in the United States: a microsimulation study. Cancer Med 2021; 10:6835-6844. [PMID: 34510779 PMCID: PMC8495276 DOI: 10.1002/cam4.4080] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2020] [Revised: 04/15/2021] [Accepted: 05/28/2021] [Indexed: 12/16/2022] Open
Abstract
Background To evaluate the cost‐effectiveness of prophylactic hysterectomy (PH) in women with Lynch syndrome (LS). Methods We developed a microsimulation model incorporating the natural history for the development of hyperplasia with and without atypia into endometrial cancer (EC) based on the MISCAN‐framework. We simulated women identified as first‐degree relatives (FDR) with LS of colorectal cancer patients after universal testing for LS. We estimated costs and benefits of offering this cohort PH, accounting for reduced quality of life after PH and for having EC. Three minimum ages (30/35/40) and three maximum ages (70/75/80) were compared to no PH. Results In the absence of PH, the estimated number of EC cases was 300 per 1,000 women with LS. Total associated costs for treatment of EC were $5.9 million. Offering PH to FDRs aged 40–80 years was considered optimal. This strategy reduced the number of endometrial cancer cases to 5.4 (−98%), resulting in 516 quality‐adjusted life years (QALY) gained and increasing the costs (treatment of endometrial cancer and PH) to $15.0 million (+154%) per 1,000 women. PH from earlier ages was more costly and resulted in fewer QALYs, although this finding was sensitive to disutility for PH. Conclusions Offering PH to 40‐ to 80‐year‐old women with LS is expected to add 0.5 QALY per person at acceptable costs. Women may decide to have PH at a younger age, depending on their individual disutility for PH and premature menopause.
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Affiliation(s)
- Maaike Alblas
- Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Elisabeth F P Peterse
- Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.,Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Mengmeng Du
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ann G Zauber
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ewout W Steyerberg
- Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands.,Department of Biomedical Data Sciences, Leiden University Medical Center, Leiden, The Netherlands
| | - Nikki van Leeuwen
- Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Iris Lansdorp-Vogelaar
- Department of Public Health, Erasmus MC-University Medical Center Rotterdam, Rotterdam, The Netherlands
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40
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Abstract
The incidence and mortality associated with colorectal cancer (CRC) diagnosed in patients under the age of 50 have been steadily increasing. The exact etiology of these epidemiologic trends is unclear. This chapter will provide a comprehensive review on the topic of early age onset colorectal cancer (EAO-CRC), defined as colorectal cancer (CRC) diagnosed in patients under the age of 50. Topics reviewed will include the epidemiology of EAO-CRC around the world, clinical and pathological features of EAO-CRC in contrast to later age onset CRC (CRC diagnosed on those over the age of 50) and the observed molecular and somatic characteristics. This chapter will review the etiologies to EAO-CRC and the established, as well as proposed risk factors for disease. Evidence-based approaches to prevention, early detection, treatment and survivorship will be presented.
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Affiliation(s)
- Swati G Patel
- Division of Gastroenterology & Hepatology, University of Colorado Anschutz Medical Campus, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, CO, United States.
| | - Caitlin C Murphy
- Division of Epidemiology, Department of Population & Data Sciences, University of Texas Southwestern Medical Center, Dallas, TX, United States
| | - Christopher H Lieu
- Division of Medical Oncology, Gastrointestinal Medical Oncology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Heather Hampel
- Division of Human Genetics, Biospecimen Research, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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41
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Bernstedt SW, Björk J, Fritzell K, Spigelman AD, Björck E, Backman AS. Room for improvement: One third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer. Hered Cancer Clin Pract 2021; 19:18. [PMID: 33579353 PMCID: PMC7881447 DOI: 10.1186/s13053-021-00171-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2020] [Accepted: 01/19/2021] [Indexed: 11/13/2022] Open
Abstract
Background Lynch syndrome is caused by germline mutations in the mismatch repair genes and is characterised by a familial accumulation of colorectal and other cancers. Earlier identification of Lynch syndrome patients enables surveillance and might reduce the risk of cancer. It is important to explore whether today’s clinical care discovers patients with Lynch syndrome suitable for surveillance in time. This study aimed to describe what led to a diagnosis of Lynch syndrome in the cohort referred to the Hereditary Gastrointestinal Cancer Unit, Karolinska University Hospital, Solna, Sweden for gastrointestinal surveillance. Methods This was a descriptive study. Data from 1975 to 2018 were collected and compiled as a database. Age at diagnosis was calculated from the date when a pathogenic MMR gene mutation was confirmed, from the period June 1994–September 2018. Data were collected from patient protocols prospectively during patient consultations and medical records retrospectively. Criteria for inclusion were registration at the outpatient clinic and a confirmed mismatch repair gene mutation. Results A total of 305 patients were eligible for inclusion. Three major reasons for diagnosis were identified: 1. Predictive testing of a previously known mutation in the family (62%, mean age 37), 2. A family history of Lynch associated tumours (9%, mean age 37), 3. A diagnosis of cancer (29%, mean age 51). The proportion diagnosed due to cancer has not changed over time. Conclusion A high proportion of patients (29%) were identified with Lynch syndrome after they had been diagnosed with an associated cancer, which suggests that there is significant room for improvement in the diagnosis of patients with Lynch syndrome before cancer develops.
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Affiliation(s)
- Sophie Walton Bernstedt
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden
| | - Jan Björk
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden.,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden.,Patient flow Hereditary Cancer, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden
| | - Kaisa Fritzell
- Patient flow Hereditary Cancer, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden.,Department of Neurobiology, Care Sciences and Society, Division of Nursing, Karolinska Institutet, Stockholm, Sweden
| | - Allan D Spigelman
- St Vincent's Genetics Clinic, The Kinghorn Cancer Centre, Sydney, Australia.,St Vincent's Clinical School, UNSW, Sydney, Australia
| | - Erik Björck
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.,Clinical Genetics, Karolinska University Laboratory, Karolinska University Hospital, Stockholm, Sweden
| | - Ann-Sofie Backman
- Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden. .,Division of Gastroenterology, Medical Unit Gastroenterology, Dermatovenereology and Rheumatology, Karolinska University Hospital, Stockholm, Sweden. .,Patient flow Hereditary Cancer, Cancer Theme, Karolinska University Hospital, Stockholm, Sweden.
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Gallon R, Gawthorpe P, Phelps RL, Hayes C, Borthwick GM, Santibanez-Koref M, Jackson MS, Burn J. How Should We Test for Lynch Syndrome? A Review of Current Guidelines and Future Strategies. Cancers (Basel) 2021; 13:406. [PMID: 33499123 PMCID: PMC7865939 DOI: 10.3390/cancers13030406] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/18/2021] [Accepted: 01/20/2021] [Indexed: 12/13/2022] Open
Abstract
International guidelines for the diagnosis of Lynch syndrome (LS) recommend molecular screening of colorectal cancers (CRCs) to identify patients for germline mismatch repair (MMR) gene testing. As our understanding of the LS phenotype and diagnostic technologies have advanced, there is a need to review these guidelines and new screening opportunities. We discuss the barriers to implementation of current guidelines, as well as guideline limitations, and highlight new technologies and knowledge that may address these. We also discuss alternative screening strategies to increase the rate of LS diagnoses. In particular, the focus of current guidance on CRCs means that approximately half of Lynch-spectrum tumours occurring in unknown male LS carriers, and only one-third in female LS carriers, will trigger testing for LS. There is increasing pressure to expand guidelines to include molecular screening of endometrial cancers, the most frequent cancer in female LS carriers. Furthermore, we collate the evidence to support MMR deficiency testing of other Lynch-spectrum tumours to screen for LS. However, a reliance on tumour tissue limits preoperative testing and, therefore, diagnosis prior to malignancy. The recent successes of functional assays to detect microsatellite instability or MMR deficiency in non-neoplastic tissues suggest that future diagnostic pipelines could become independent of tumour tissue.
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Affiliation(s)
| | | | | | | | | | | | | | - John Burn
- Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK; (P.G.); (R.L.P.); (C.H.); (G.M.B.); (M.S.-K.); (M.S.J.)
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43
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Evans DG, Lalloo F, Ryan NA, Bowers N, Green K, Woodward ER, Clancy T, Bolton J, McVey RJ, Wallace AJ, Newton K, Hill J, McMahon R, Crosbie EJ. Advances in genetic technologies result in improved diagnosis of mismatch repair deficiency in colorectal and endometrial cancers. J Med Genet 2021; 59:328-334. [PMID: 33452216 PMCID: PMC8961751 DOI: 10.1136/jmedgenet-2020-107542] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2020] [Revised: 12/17/2020] [Accepted: 12/23/2020] [Indexed: 11/04/2022]
Abstract
Background Testing cancers for mismatch repair deficiency (dMMR) by immunohistochemistry (IHC) is a quick and inexpensive means of triaging individuals for germline Lynch syndrome testing. The aim of this study was to evaluate tumour dMMR and the prevalence of Lynch syndrome in patients referred to the Manchester Centre for Genomic Medicine, which serves a population of 5.6 million. Methods Tumour testing used IHC for MMR proteins with targeted BRAF and MLH1 promotor methylation testing followed by germline mutation and somatic testing as appropriate. Results In total, 3694 index tumours were tested by IHC (2204 colorectal cancers (CRCs), 739 endometrial cancers (ECs) and 761 other), of which 672/3694 (18.2%) had protein loss, including 348 (9.4%) with MLH1 loss. MLH1 loss was significantly higher for 739 ECs (15%) vs 2204 CRCs (10%) (p=0.0003) and was explained entirely by higher rates of somatic MLH1 promoter hypermethylation (87% vs 41%, p<0.0001). Overall, 65/134 (48.5%) patients with MLH1 loss and no MLH1 hypermethylation or BRAF c.1799T>A had constitutional MLH1 pathogenic variants. Of 456 patients with tumours showing loss of MSH2/MSH6, 216 (47.3%) had germline pathogenic variants in either gene. Isolated PMS2 loss was most suggestive of a germline MMR variant in 19/26 (73%). Of those with no germline pathogenic variant, somatic testing identified likely causal variants in 34/48 (71%) with MLH1 loss and in MSH2/MSH6 in 40/47 (85%) with MSH2/MSH6 loss. Conclusions Reflex testing of EC/CRC leads to uncertain diagnoses in many individuals with dMMR following IHC but without germline pathogenic variants or MLH1 hypermethylation. Tumour mutation testing is effective at decreasing this by identifying somatic dMMR in >75% of cases.
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Affiliation(s)
- D Gareth Evans
- Division of Evolution and Genomic Medicine, The University of Manchester, Manchester, UK.,Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Fiona Lalloo
- Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Neil Aj Ryan
- Division of Cancer Sciences, The University of Manchester, Manchester, UK.,Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Naomi Bowers
- Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Kate Green
- Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Emma R Woodward
- Division of Evolution and Genomic Medicine, The University of Manchester, Manchester, UK.,Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Tara Clancy
- Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - James Bolton
- Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Rhona J McVey
- Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Andrew J Wallace
- Clinical Genetics Service, Manchester Centre for Genomic Medicine, North-West Genomics Laboratory Hub, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Katy Newton
- Department of Surgery, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - James Hill
- Department of Surgery, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Raymond McMahon
- Department of Pathology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
| | - Emma J Crosbie
- Division of Cancer Sciences, The University of Manchester, Manchester, UK .,Department of Obstetrics and Gynaecology, Manchester University NHS Foundation Trust, Manchester, Greater Manchester, UK
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44
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Advanced adenomas may be a red flag for hereditary cancer syndromes. Hered Cancer Clin Pract 2021; 19:8. [PMID: 33436027 PMCID: PMC7805122 DOI: 10.1186/s13053-020-00164-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 12/30/2020] [Indexed: 11/21/2022] Open
Abstract
Background 16–25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer. Aim Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps. Methods We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range. Results A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance. Conclusions 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes.
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45
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Jia X, Burugula BB, Chen V, Lemons RM, Jayakody S, Maksutova M, Kitzman JO. Massively parallel functional testing of MSH2 missense variants conferring Lynch syndrome risk. Am J Hum Genet 2021; 108:163-175. [PMID: 33357406 PMCID: PMC7820803 DOI: 10.1016/j.ajhg.2020.12.003] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 12/03/2020] [Indexed: 12/20/2022] Open
Abstract
The lack of functional evidence for the majority of missense variants limits their clinical interpretability and poses a key barrier to the broad utility of carrier screening. In Lynch syndrome (LS), one of the most highly prevalent cancer syndromes, nearly 90% of clinically observed missense variants are deemed “variants of uncertain significance” (VUS). To systematically resolve their functional status, we performed a massively parallel screen in human cells to identify loss-of-function missense variants in the key DNA mismatch repair factor MSH2. The resulting functional effect map is substantially complete, covering 94% of the 17,746 possible variants, and is highly concordant (96%) with existing functional data and expert clinicians’ interpretations. The large majority (89%) of missense variants were functionally neutral, perhaps unexpectedly in light of its evolutionary conservation. These data provide ready-to-use functional evidence to resolve the ∼1,300 extant missense VUSs in MSH2 and may facilitate the prospective classification of newly discovered variants in the clinic.
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46
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Ryan NAJ, McMahon RFT, Ramchander NC, Seif MW, Evans DG, Crosbie EJ. Lynch syndrome for the gynaecologist. THE OBSTETRICIAN & GYNAECOLOGIST : THE JOURNAL FOR CONTINUING PROFESSIONAL DEVELOPMENT FROM THE ROYAL COLLEGE OF OBSTETRICIANS & GYNAECOLOGISTS 2021; 23:9-20. [PMID: 33679238 PMCID: PMC7898635 DOI: 10.1111/tog.12706] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Accepted: 04/20/2020] [Indexed: 02/06/2023]
Abstract
KEY CONTENT Lynch syndrome is an autosomal dominant condition closely associated with colorectal, endometrial and ovarian cancer.Women with Lynch syndrome are at increased risk of both endometrial and ovarian cancer and should be offered personalised counselling regarding family planning, red flag symptoms and risk-reducing strategies.Surveillance for gynaecological cancer in women with Lynch syndrome remains controversial; more robust data are needed to determine its effectiveness.Universal testing for Lynch syndrome in endometrial cancer is being adopted by centres across Europe and is now recommended by the National Institute for Health and Care Excellence; thus, gynaecologists must become familiar with testing strategies and their results.Testing strategies involve risk stratification of cancers based on phenotypical features and definitive germline testing. LEARNING OBJECTIVES To define the pathogenesis of Lynch syndrome and its associated gynaecological cancers.To understand the testing strategies for Lynch syndrome in women with gynaecological cancer.To learn how best to counsel women with Lynch syndrome regarding gynaecological cancer and risk-reducing strategies to enable informed decision-making. ETHICAL ISSUES Offering gynaecological surveillance despite a lack of robust evidence for its clinical effectiveness may falsely reassure women and delay risk-reducing hysterectomy.Genetic testing may yield variants of unknown significance with ill-defined clinical implications, which can lead to confusion and anxiety.Genetic testing has implications not only for the individual, but also for the whole family, so expert counselling is crucial.
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Affiliation(s)
- Neil AJ Ryan
- Obstetrics and Gynaecology Specialty Registrar and Honorary Clinical LecturerCentre for Academic Women’s HealthUniversity of BristolBristolUK
| | - Raymond FT McMahon
- Consultant Histopathologist and Emeritus Professor of Medical EducationDepartment of HistopathologyManchester University NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
| | - Neal C Ramchander
- Foundation Programme DoctorDivision of Cancer SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterSt Mary's HospitalManchesterUK
| | - Mourad W Seif
- Consultant Gynaecologist and Honorary Senior LecturerDivision of GynaecologySt Mary’s HospitalManchester University NHS Foundation TrustManchester Academic Health Science CentreManchesterUK
| | - D Gareth Evans
- Professor of Medical Genetics and Cancer Epidemiology and Honorary Consultant in Medical GeneticsDivision of Evolution and Genomic MedicineUniversity of ManchesterSt Mary's HospitalManchesterUK
| | - Emma J Crosbie
- Professor of Gynaecology Oncology and Honorary Consultant Gynaecological OncologistDivision of Cancer SciencesFaculty of Biology, Medicine and HealthUniversity of ManchesterSt Mary's HospitalManchesterUK
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47
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Srinivasan S, Won NY, Dotson WD, Wright ST, Roberts MC. Barriers and facilitators for cascade testing in genetic conditions: a systematic review. Eur J Hum Genet 2020; 28:1631-1644. [PMID: 32948847 PMCID: PMC7784694 DOI: 10.1038/s41431-020-00725-5] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 08/21/2020] [Accepted: 09/01/2020] [Indexed: 12/23/2022] Open
Abstract
Cascade testing is the process of offering genetic counseling and testing to at-risk relatives of an individual who has been diagnosed with a genetic condition. It is critical for increasing the identification rates of individuals with these conditions and the uptake of appropriate preventive health services. The process of cascade testing is highly varied in clinical practice, and a comprehensive understanding of factors that hinder or enhance its implementation is necessary to improve this process. We conducted a systematic review to identify barriers and facilitators for cascade testing and searched PubMed, CINAHL via EBSCO, Web of Science, EMBASE, and the Cochrane Library for articles published from the databases' inception to November 2018. Thirty articles met inclusion criteria. Barriers and facilitators identified from these studies at the individual-level were organized into the following categories: (1) demographics, (2) knowledge, (3) attitudes, beliefs, and emotional responses of the individual, and (4) perceptions of relatives, relatives' responses, and attitudes toward relatives. At the interpersonal-level, barriers and facilitators were categorized as (1) family communication-, support- and dynamics-, and (2) provider-factors. Finally, barriers at the environmental-level relating to accessibility of genetic services were also identified. Our findings suggest that several individual, interpersonal and environmental factors may play a role in cascade testing. Future studies to further investigate these barriers and facilitators are needed to inform future interventions for improving the implementation of cascade testing for genetic conditions in clinical practice.
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Affiliation(s)
- Swetha Srinivasan
- Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Nae Yeon Won
- Department of Orthopaedic Surgery, University of California, San Francisco, CA, USA
| | - W David Dotson
- Office of Genomics and Precision Public Health, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - Sarah T Wright
- UNC Health Sciences Library, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Megan C Roberts
- Division of Pharmaceutical Outcomes and Policy, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
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48
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Underutilization of Lynch Syndrome Screening at Two Large Veterans Affairs Medical Centers. Dig Dis Sci 2020; 65:3305-3315. [PMID: 32500284 DOI: 10.1007/s10620-020-06340-0] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/12/2018] [Accepted: 05/12/2020] [Indexed: 12/09/2022]
Abstract
BACKGROUND Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, yet is grossly under-recognized. Multiple professional societies recommend screening all CRCs for LS by performing tumor testing. The veterans affairs system has not adopted universal tumor testing as a national performance metric and leaves screening for LS to clinical care at individual sites. AIMS Describe adherence to LS screening in the VA system. METHODS Dual-center, retrospective review of all CRCs diagnosed between 2010 and 2016. Rates of tumor testing, personal and family history of cancer were extracted from the medical record. Univariate and multivariate regression analysis was performed to determine predictors of tumor-based screening for LS. RESULTS A total of 421 cancers were reviewed. 15.1% of all cancers underwent either MSI and/or IHC for LS screening over the study period. There was improvement in LS screening from 3% of all CRCs in 2010 to 45% of all CRCs in 2016. 34% and 70% of patients did not have documentation of CRC in first- and second-degree relatives, respectively. Of the 73 patients who met one of the Revised Bethesda Criteria or had a PREMM1,2,6 score of ≥ 5, 34% and 56% underwent tumor testing, respectively. Younger age, non-Caucasian race, meeting Bethesda or PREMM1,2,6 criteria and right-sided tumor location were predictors of undergoing tumor testing. CONCLUSIONS CRC tumor screening for LS is grossly inadequate when left to routine clinical care. Our results lend support to implementation of reflexive universal tumor testing within the VA system.
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49
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Spinosa D, Acosta T, Wong J, Kurtovic K, Mewshaw J, Collins S, Kauff N, Havrilesky LJ, Strickland KC, Previs RA. Universal screening for Lynch syndrome in uterine cancer patients: A quality improvement initiative. Gynecol Oncol 2020; 160:169-174. [PMID: 33393478 PMCID: PMC7577655 DOI: 10.1016/j.ygyno.2020.10.016] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/14/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVE To determine the feasibility and effectiveness of a quality improvement initiative (QI) to adopt universal screening for Lynch syndrome in uterine cancer patients at an institution that previously employed age-based screening. METHODS Prior to the initiative, tumors of patients with uterine cancer diagnosed at age ≤ 60 years were screened for mismatch repair deficiency (MMR) and microsatellite instability (MSI). The QI process change model adopted universal testing of all uterine cancer specimens and implemented provider training, standardized documentation, and enhanced use of the electronic medical record (EMR). We compared screening rates, results of screening, follow up of abnormal results, and final diagnoses from the pre- and post-implementation periods. RESULTS Pre- and post-implementation screening rates for women age ≤ 60 years at the time of diagnosis were 45/78 (57.7%) and 64/68 (94.5%), respectively. The screening rate for all patients with uterine cancer increased from 73/190 (38.4%) to 172/182 (94.5%). The rate of abnormal screening results increased from 15/190 (7.9%) to 44/182 (24.0%) cases. Genetics referral rates among screen positives increased from 3/15 (20.0%) to 16/44 (36.4%). Germline diagnoses increased from 2/190 (1.1%) with two Lynch syndrome diagnoses to 4/182 (2.2%) including three Lynch syndrome diagnoses and one BRCA1 germline diagnosis. The number of patients errantly not screened decreased from at least 32 patients to 3 patients after the intervention. CONCLUSIONS Adherence to screening guidelines significantly improved after interventions involving provider education, optimal use of the EMR, and simplification of screening indications. These interventions are feasible at other institutions and translatable to other screening indications.
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Affiliation(s)
- Daniel Spinosa
- Department of Obstetrics & Gynecology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America.
| | - Tatiana Acosta
- Department of Obstetrics & Gynecology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Janice Wong
- Department of Obstetrics & Gynecology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Kelli Kurtovic
- Department of Obstetrics & Gynecology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Jennifer Mewshaw
- Division of Gynecologic Oncology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Sarah Collins
- Division of Gynecologic Oncology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Noah Kauff
- Clinical Cancer Genetics, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Laura J Havrilesky
- Division of Gynecologic Oncology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Kyle C Strickland
- Department of Pathology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
| | - Rebecca A Previs
- Division of Gynecologic Oncology, Duke Cancer Institute, Duke University Health System, Durham, North Carolina, United States of America
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50
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Lowery JT, Weber TK, Ahnen DJ, Schroy III PC, Levell CL, Smith RA. An action plan to address the rising burden of colorectal cancer in younger adults. COLORECTAL CANCER 2020. [DOI: 10.2217/crc-2020-0004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Aim: The National Colorectal Cancer Roundtable convened a national Summit to discuss the causes of early-onset colorectal cancer and clinical challenges to mitigating burden of this disease. Materials & methods: Information presented was synthesized through scientific consensus building to determine priorities for new research and practice change. Results: Research priorities include evaluating role of novel risk factors, understanding natural history and identifying ways to implement evidenced-based practices for identifying and managing at-risk persons. Practice change should focus on adoption of guidelines for collecting family history, screening in young adults at risk, provider and population awareness about risk and symptoms, and universal tumor testing. Conclusion: Successful implementation of strategies to address research and practice change will require collaboration from multiple partners.
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Affiliation(s)
- Jan T Lowery
- Center for Personalized Medicine, University of Colorado, Aurora, CO 80045, USA
| | - Thomas K Weber
- Northwell Health, Professor of Surgery, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, New York, NY 10028, USA
| | - Dennis J Ahnen
- Gastroenterology of the Rockies, University of Colorado School of Medicine & Director of Genetics Program, Aurora, CO 80045, USA
| | - Paul C Schroy III
- Boston University School of Medicine, Section of Gastroenterology, Boston, MA 02118, USA
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