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1
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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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2
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Sleiman J, Farha N, Beard J, Bena J, Morrison S, Milicia S, Heald B, Kalady MF, Church J, Liska D, Mankaney G, Burke CA. Incidence and prevalence of advanced colorectal neoplasia in Lynch syndrome. Gastrointest Endosc 2023; 98:412-419.e8. [PMID: 37031913 DOI: 10.1016/j.gie.2023.04.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2023] [Revised: 02/24/2023] [Accepted: 04/04/2023] [Indexed: 04/11/2023]
Abstract
BACKGROUND AND AIMS Lynch syndrome (LS) is the most common hereditary cause of colorectal cancer (CRC) and endometrial cancer (EC). Although colonoscopy reduces CRC in LS, the protection is variable. We assessed the prevalence and incidence of neoplasia in LS during surveillance colonoscopy in the United States and factors associated with advanced neoplasia. METHODS Patients with LS undergoing ≥1 surveillance colonoscopy and with no personal history of invasive CRC or colorectal surgery were included. Prevalent and incident neoplasia was defined as occurring <6 months before and ≥6 months after germline diagnosis of LS, respectively. We assessed advanced adenoma (AA), CRC, and the impact of mismatch repair pathogenic variant (PV) and typical LS cancer history (personal history of EC and/or family history of EC/CRC) on outcome. RESULTS A total of 132 patients (inclusive of 112 undergoing prevalent and incident surveillance) were included. The median examination interval and duration of prevalent and incident surveillance was .88 and 1.06 years and 3.1 and 4.6 years, respectively. Prevalent and incident AA were detected in 10.7% and 6.1% and invasive CRC in 0% and 2.3% of patients. All incident CRC occurred in MSH2 and MLH1 PV carriers and only 1 (.7%) while under surveillance in our center. AAs were detected in both LS cancer history cohorts and represented in all PVs. CONCLUSIONS In a U.S. cohort of LS, advanced neoplasia rarely occurred over annual surveillance. CRC was diagnosed only in MSH2/MLH1 PV carriers. AAs occurred regardless of PV or LS cancer history. Prospective studies are warranted to confirm our findings.
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Affiliation(s)
- Joseph Sleiman
- Division of Gastroenterology, Hepatology and Nutrition at University of Pittsburgh School of Medicine, Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA
| | - Natalie Farha
- Department of Gastroenterology, Hepatology and Nutrition
| | - Jonathan Beard
- Section of Gastroenterology and Hepatology, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire, USA
| | - James Bena
- Department of Quantitative Health Science
| | | | - Susan Milicia
- Department of Colorectal Surgery; Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia
| | - Brandie Heald
- Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia; Department of Genomic Medical Institute, Cleveland Clinic, Cleveland, OH, USA
| | - Matthew F Kalady
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, Ohio, USA
| | - James Church
- Department of Surgery, Division of Colorectal Surgery & Inflammatory Bowel Disease Center, Columbia University Medical Center, Herbert Irving Pavilion, New York, New York, USA
| | - David Liska
- Department of Colorectal Surgery; Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia
| | - Gautam Mankaney
- Gastroenterology and Hepatology, Virginia Mason Franciscan Health, Seattle, Washington, USA
| | - Carol A Burke
- Department of Gastroenterology, Hepatology and Nutrition; Department of Colorectal Surgery; Sanford R. Weiss, M.D. Center for Hereditary Colorectal Neoplasia.
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Kudchadkar S, Ahmed S, Mukherjee T, Sagar J. Current guidelines in the surgical management of hereditary colorectal cancers. World J Gastrointest Oncol 2022; 14:833-841. [PMID: 35582097 PMCID: PMC9048527 DOI: 10.4251/wjgo.v14.i4.833] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2021] [Revised: 10/16/2021] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
Incidence of colorectal cancer (CRC) is on rise. While approximately 70% of all CRC cases are sporadic in nature, 20%-25% have familial aggregation and only < 5% is hereditary in origin. Identification of individuals with hereditary predilection for CRC is critical, as it has an impact on their overall surgical management including surgical timing, approach & technique and determines the role of prophylactic surgery and outcome. This review highlights the concept of hereditary CRC, provides insight into its molecular basis, possibility of its application into clinical practice and emphasizes the current treatment strategies with surgical management, based on the available international guidelines.
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Affiliation(s)
- Shantata Kudchadkar
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
| | - Safia Ahmed
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
| | - Tanmoy Mukherjee
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
| | - Jayesh Sagar
- Department of Colorectal Surgery, Luton & Dunstable University Hospital NHS Foundation Trust, Luton LU4 0DZ, United Kingdom
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Liao CK, Lin YC, Hsu YJ, Chern YJ, You JF, Chiang JM. Deciding the operation type according to mismatch repair status among hereditary nonpolyposis colorectal cancer patients: should a tailored approach be applied, or does one size fit all? Hered Cancer Clin Pract 2021; 19:29. [PMID: 34187536 PMCID: PMC8243908 DOI: 10.1186/s13053-021-00186-x] [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: 03/24/2021] [Accepted: 06/09/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Although extended colectomy (EC) was recommended for HNPCC patients, previous studies did not show significantly improved overall survival. Immunohistochemical (IHC) stain of mismatch repair (MMR) gene protein expression is now a feasible and reliable test clinically. Therefore, we tried to investigate whether we could use MMR IHC stain to select operation types in HNPCC patients. PATIENTS AND METHODS Between 1995 and 2013, 186 HNPCC patients were collected. Status of MMR protein expression, perioperative clinic-pathological variables and post-operative follow up status were analyzed by multivariate analyses. RESULTS Sixty-five percent (121 of 186) patients of these HNPCC patients demonstrated loss of at least one MMR protein. There were several significant differences existing between deficient MMR (dMMR) and proficient MMR (pMMR) subgroups in terms of clinic-pathological characteristics. With the average follow-up duration of 93.9 months, we observed significantly high risk of developing metachronous CRC between SC and EC subgroups (crude rate 8.5% vs. 0%, p = 0.035). However, no significant difference was observed among the presence of extra-colonic tumors (12.4% vs. 5.8%, p = 0.284). The positive and negative prediction rate of metachronous CRC in dMMR subgroup was 12.8 and 87.2% while 1.9 and 98.1% in the pMMR subgroup. Survival outcomes were significantly affected by MMR status and resection types by multivariate analysis. Significantly better OS in dMMR subgroup (HR = 0.479, 95% CI: 0.257-0.894, p = 0.021) comparing with pMMR subgroup was observed. However, significant improved DFS (HR = 0.367, 95% CI: 0.172-.0787, p = 0.010) but not significant for OS (HR = 0.510, 95% CI: 0.219-1.150, p = 0.103) for EC subgroup compared with SC subgroup. Differences existing among different subgroups by combing extent of resection and MMR status. In dMMR subgroup, SC, compared with EC, demonstrated significantly worse DFS by multivariate analyses (HR = 3.526, 95% CI: 1.346-9.236, p = 0.010) but not for OS (HR = 2.387, 95% CI: 0.788-7.229, p = 0.124), however, no significantly differences of OS and DFS in pMMR subgroup between SC and EC were found. CONCLUSIONS Significantly better overall survival and higher rate of metachronous CRC exist in dMMR subgroup of HNPCC patients comparing with pMMR subgroup. Extended colectomy significantly improved DFS and was thus recommended for dMMR subgroup but not pMMR subgroup of HNPCC patients.
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Affiliation(s)
- Chun-Kai Liao
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Yueh-Chen Lin
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Yu-Jen Hsu
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Yih-Jong Chern
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Jeng-Fu You
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305
| | - Jy-Ming Chiang
- Colorectal Section, Department of Surgery, Chang Gung Memorial Hospital, No. 5, Fuxing St., Guishan Dist,, Taoyuan, Taiwan, 33305. .,College of Medicine, Chang Gung University, Taoyuan, Taiwan.
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5
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Abstract
Lynch syndrome is one of the most common hereditary cancer syndromes and is characterized by the development of many cancers, such as colorectal cancer (CRC), endometrial cancer, ovarian cancer, stomach cancer and many other cancers. Lynch syndrome is caused by pathogenic germline variants in one of four DNA mismatch repair genes (MLH1, MSH2, MSH6, or PMS2) or by an EPCAM deletion. The MLH1 variant is correlated with the highest risk of CRC, while the MSH2 variant is correlated with the highest risk of other cancers. CRC is the most common cancer type that develops in individuals with Lynch syndrome, followed by endometrial cancer. Recent advances have been made to help us further understand the molecular pathogenesis of this disease and help improve diagnostic testing efficiency and surveillance strategies. Moreover, recent advances in immunotherapy provided by clinical trials also provide clinicians with more chances to better treat Lynch syndrome. This study aims to review many advances in the molecular genetics, clinical features, diagnosis, surveillance and treatment of Lynch syndrome.
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Affiliation(s)
- Xi Li
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China.,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China
| | - Guodong Liu
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China. .,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
| | - Wei Wu
- Department of Geriatric Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China. .,National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, 410008, China. .,Department of General Surgery, Xiangya Hospital, Central South University, Changsha, 410008, China.
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Distinct Mutational Profile of Lynch Syndrome Colorectal Cancers Diagnosed under Regular Colonoscopy Surveillance. J Clin Med 2021; 10:jcm10112458. [PMID: 34206061 PMCID: PMC8198627 DOI: 10.3390/jcm10112458] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 05/17/2021] [Accepted: 05/26/2021] [Indexed: 11/17/2022] Open
Abstract
Regular colonoscopy even with short intervals does not prevent all colorectal cancers (CRC) in Lynch syndrome (LS). In the present study, we asked whether cancers detected under regular colonoscopy surveillance (incident cancers) are phenotypically different from cancers detected at first colonoscopy (prevalent cancers). We analyzed clinical, histological, immunological and mutational characteristics, including panel sequencing and high-throughput coding microsatellite (cMS) analysis, in 28 incident and 67 prevalent LS CRCs (n total = 95). Incident cancers presented with lower UICC and T stage compared to prevalent cancers (p < 0.0005). The majority of incident cancers (21/28) were detected after previous colonoscopy without any pathological findings. On the molecular level, incident cancers presented with a significantly lower KRAS codon 12/13 (1/23, 4.3% vs. 11/21, 52%; p = 0.0005) and pathogenic TP53 mutation frequency (0/17, 0% vs. 7/21, 33.3%; p = 0.0108,) compared to prevalent cancers; 10/17 (58.8%) incident cancers harbored one or more truncating APC mutations, all showing mutational signatures of mismatch repair (MMR) deficiency. The proportion of MMR deficiency-related mutational events was significantly higher in incident compared to prevalent CRC (p = 0.018). In conclusion, our study identifies a set of features indicative of biological differences between incident and prevalent cancers in LS, which should further be monitored in prospective LS screening studies to guide towards optimized prevention protocols.
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7
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Ahadova A, Seppälä TT, Engel C, Gallon R, Burn J, Holinski-Feder E, Steinke-Lange V, Möslein G, Nielsen M, Ten Broeke SW, Laghi L, Dominguez-Valentin M, Capella G, Macrae F, Scott R, Hüneburg R, Nattermann J, Hoffmeister M, Brenner H, Bläker H, von Knebel Doeberitz M, Sampson JR, Vasen H, Mecklin JP, Møller P, Kloor M. The "unnatural" history of colorectal cancer in Lynch syndrome: Lessons from colonoscopy surveillance. Int J Cancer 2021; 148:800-811. [PMID: 32683684 DOI: 10.1002/ijc.33224] [Citation(s) in RCA: 61] [Impact Index Per Article: 15.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 06/12/2020] [Accepted: 06/24/2020] [Indexed: 12/14/2022]
Abstract
Individuals with Lynch syndrome (LS), one of the most common inherited cancer syndromes, are at increased risk of developing malignancies, in particular colorectal cancer (CRC). Regular colonoscopy with polypectomy is recommended to reduce CRC risk in LS individuals. However, recent independent studies demonstrated that a substantial proportion of LS individuals develop CRC despite regular colonoscopy. The reasons for this surprising observation confirmed by large prospective studies are a matter of debate. In this review, we collect existing evidence from clinical, epidemiological and molecular studies and interpret them with regard to the origins and progression of LS-associated CRC. Alongside with hypotheses addressing colonoscopy quality and pace of progression from adenoma to cancer, we discuss the role of alternative precursors and immune system in LS-associated CRC. We also identify gaps in current knowledge and make suggestions for future studies aiming at improved CRC prevention for LS individuals.
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Affiliation(s)
- Aysel Ahadova
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
- Cooperation Unit Applied Tumour Biology, German Cancer Research Centre (DKFZ), Heidelberg, Germany
- Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Toni T Seppälä
- Department of Surgery, Helsinki University Central Hospital, Helsinki, Finland
- Faculty of Medicine, University of Helsinki, Helsinki, Finland
- Surgical Oncology, Johns Hopkins Hospital, Baltimore, Maryland, USA
| | - Christoph Engel
- Department of Statistics and Epidemiology, Institute for Medical Informatics, University of Leipzig, Leipzig, Germany
| | - Richard Gallon
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle, UK
| | - John Burn
- International Centre for Life, Central Parkway, Newcastle upon, Tyne, UK
| | - Elke Holinski-Feder
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany
- Centre of Medical Genetics, Munich, Germany
| | - Verena Steinke-Lange
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Munich, Germany
- Centre of Medical Genetics, Munich, Germany
| | - Gabriela Möslein
- Centre for Hereditary Tumors, HELIOS Klinikum Wuppertal, University Witten-Herdecke, Wuppertal, Germany
| | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, the Netherlands
| | - Sanne W Ten Broeke
- Department of Clinical Genetics, University of Groningen, University Medical Centre Groningen, Groningen, the Netherlands
| | - Luigi Laghi
- Molecular Gastroenterology and Department of Gastroenterology, Humanitas Clinical and Research Center, Milan, Italy
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Mev Dominguez-Valentin
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Gabriel Capella
- Hereditary Cancer Program, Institut Catala d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Finlay Macrae
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia
| | - Rodney Scott
- University of Newcastle and the Hunter Medical Research Institute, Callaghan, Australia
| | - Robert Hüneburg
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
- National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Jacob Nattermann
- Department of Internal Medicine I, University Hospital Bonn, Bonn, Germany
- National Centre for Hereditary Tumor Syndromes, University Hospital Bonn, Bonn, Germany
| | - Michael Hoffmeister
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hermann Brenner
- Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany
- German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hendrik Bläker
- Institute of Pathology, University Hospital Leipzig, Leipzig, Germany
| | - Magnus von Knebel Doeberitz
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
| | - Julian R Sampson
- Institute of Medical Genetics, Division of Cancer and Genetics, Cardiff University School of Medicine, Cardiff, UK
| | - Hans Vasen
- Department of Gastroenterology & Hepatology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland
- Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Pål Møller
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, Oslo University Hospital, Oslo, Norway
| | - Matthias Kloor
- Department of Applied Tumour Biology, Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany
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Dueñas N, Navarro M, Teulé À, Solanes A, Salinas M, Iglesias S, Munté E, Ponce J, Guardiola J, Kreisler E, Carballas E, Cuadrado M, Matias-Guiu X, de la Ossa N, Lop J, Lázaro C, Capellá G, Pineda M, Brunet J. Assessing Effectiveness of Colonic and Gynecological Risk Reducing Surgery in Lynch Syndrome Individuals. Cancers (Basel) 2020; 12:E3419. [PMID: 33218006 PMCID: PMC7698735 DOI: 10.3390/cancers12113419] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2020] [Revised: 11/06/2020] [Accepted: 11/16/2020] [Indexed: 12/16/2022] Open
Abstract
BACKGROUND Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals. METHODS Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals; EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort. RESULTS Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (p = 0.04) and all-cause mortality cumulative incidence was 38.6% vs. 55.3% (p = 0.31), for ES and SS, respectively. Cumulative, incidence at 75 years was 11.2% vs. 46.3% for EC (p = 0.001) and 0% vs. 12.7% for OC (p N/A) and all-cause mortality cumulative incidence was 0% vs. 52.7% (p N/A), for RRGS vs. surveillance, respectively. CONCLUSIONS RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.
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Affiliation(s)
- Nuria Dueñas
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Matilde Navarro
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology, Badalona, 089016 Barcelona, Spain;
| | - Àlex Teulé
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
| | - Ares Solanes
- Hereditary Cancer Program, Catalan Institute of Oncology, Badalona, 089016 Barcelona, Spain;
| | - Mònica Salinas
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Sílvia Iglesias
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Elisabet Munté
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
| | - Jordi Ponce
- Department of Gynecology, Bellvitge University Hospital, 08908 Hospitalet de Llobregat, 089016 Barcelona, Spain;
| | - Jordi Guardiola
- Department of Gastroenterology, Bellvitge University Hospital, Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Esther Kreisler
- Department of General Surgery, Bellvitge University Hospital, Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Elvira Carballas
- Department of Gynecology, Trias i Pujol University Hospital, Badalona, 089016 Barcelona, Spain;
| | - Marta Cuadrado
- Department of General Surgery, Trias i Pujol University Hospital, Badalona, 089016 Barcelona, Spain;
| | - Xavier Matias-Guiu
- Department of Pathology, Bellvitge University Hospital, Hospitalet de Llobregat, 08908 Barcelona, Spain;
| | - Napoleón de la Ossa
- Department of Pathology, Trias i Pujol University Hospital, Badalona, 089016 Barcelona, Spain;
- Department of Pathology, Hospital General de Catalunya—Grupo Quironsalud, 08203 Barcelona, Spain
| | - Joan Lop
- Department of Pathology, Hospital del Mar Institute for Medical Research, 08003 Barcelona, Spain;
| | - Conxi Lázaro
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Gabriel Capellá
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Marta Pineda
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
| | - Joan Brunet
- Hereditary Cancer Program, Catalan Institute of Oncology-IDIBELL, ONCOBELL, Hospitalet de Llobregat, 08908 Barcelona, Spain; (N.D.); (M.N.); (À.T.); (M.S.); (S.I.); (E.M.); (C.L.); (G.C.); (M.P.)
- Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Instituto Salud Carlos III, 28029 Madrid, Spain
- Hereditary Cancer Program, Catalan Institute of Oncology-IDBIGI, 17007 Girona, Spain
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Prophylactic Gynecologic Surgery at Time of Colectomy Benefits Women with Lynch Syndrome and Colon Cancer: A Markov Cost-Effectiveness Analysis. Dis Colon Rectum 2020; 63:1393-1402. [PMID: 32969882 DOI: 10.1097/dcr.0000000000001681] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Women with Lynch syndrome who have completed childbearing should be offered prophylactic hysterectomy and bilateral salpingo-oophorectomy for gynecologic cancer prevention. The benefit of prophylactic gynecologic surgery at the time of colon cancer resection is unclear. OBJECTIVE This study aimed to compare the cost, quality of life, and likelihood of being alive and free from colon, endometrial, and ovarian cancer between operative choices for patients with Lynch syndrome undergoing surgery for colon cancer. DESIGN A Markov decision tree spanning 40 years was constructed for a hypothetical cohort of 30-year-old women with Lynch syndrome who had been diagnosed with colon cancer. Outcomes of 6 surgical strategies were compared, including segmental or total abdominal colectomy with or without hysterectomy alone or combined with bilateral salpingo-oophorectomy. SETTINGS A Markov cost-effectiveness analysis was performed at a single center. PATIENTS A literature search was performed identifying studies of patients with genetically diagnosed Lynch syndrome that described cost, risk of mortality, and quality of life after colon cancer resection and prophylactic gynecologic surgery. MAIN OUTCOME MEASURES The primary outcomes measured were quality-adjusted life-years and the likelihood of being alive and free from colon, endometrial, and ovarian cancer 40 years after surgery. RESULTS Women with Lynch syndrome who underwent a total abdominal colectomy and hysterectomy with bilateral salpingo-oophorectomy had the highest likelihood of being alive and cancer free. Total abdominal colectomy with hysterectomy was a close second, but yielded the largest amount of quality-adjusted life-years and lowest cost. LIMITATIONS This study is limited by the statistical method and quality of studies used. CONCLUSIONS Total abdominal colectomy with prophylactic hysterectomy at 30 years of age was the most cost-effective surgical choice in women with Lynch syndrome and colon cancer. The addition of bilateral salpingo-oophorectomy offered the highest event-free survival and lowest mortality. However, the additional morbidity of premature menopause of prophylactic salpingo-oophorectomy for younger women outweighed the benefit of ovarian cancer prevention. See Video Abstract at http://links.lww.com/DCR/B287. LA CIRUGÍA GINECOLÓGICA PROFILÁCTICA EN EL MOMENTO DE LA COLECTOMÍA BENEFICIA A LAS MUJERES CON SÍNDROME DE LYNCH Y CÁNCER DE COLON: UN ANÁLISIS DE COSTO-EFECTIVIDAD DE MARKOV: Las mujeres con síndrome de Lynch que han completado la maternidad deberían recibir histerectomía profiláctica y salpingooforectomía bilateral para la prevención del cáncer ginecológico. El beneficio de la cirugía ginecológica profiláctica en el momento de la resección del cáncer de colon no está claro.Comparar el costo, la calidad de vida y la probabilidad de estar viva y libre de cáncer de colon, endometrio y ovario entre las opciones quirúrgicas para pacientes con síndrome de Lynch sometidos a cirugía por cáncer de colon.Se construyó un árbol de decisión de Markov que abarca cuarenta años para una cohorte hipotética de mujeres de 30 años con síndrome de Lynch diagnosticadas con cáncer de colon. Se compararon los resultados de seis estrategias quirúrgicas, incluida la colectomía abdominal segmentaria o total con o sin histerectomía sola o combinada con salpingooforectomía bilateral.Se realizó un análisis de costo-efectividad de Markov en un solo centro.se realizó una búsqueda bibliográfica para identificar estudios de pacientes con síndrome de Lynch con diagnóstico genético que describieron el costo, el riesgo de mortalidad y la calidad de vida después de la resección del cáncer de colon y la cirugía ginecológica profiláctica.años de vida ajustados por calidad y probabilidad de estar vivo y libre de cáncer de colon, endometrio y ovario 40 años después de la cirugía.Las mujeres con síndrome de Lynch que se sometieron a una colectomía e histerectomía abdominal total con salpingooforectomía bilateral tuvieron la mayor probabilidad de estar vivas y libres de cáncer. La colectomía abdominal total con histerectomía fue un segundo lugar cercano, pero produjo la mayor cantidad de años de vida ajustados por calidad y el costo más bajo.Este estudio está limitado por el método estadístico y la calidad de los estudios utilizados.La colectomía abdominal total con histerectomía profiláctica a los 30 años fue la opción quirúrgica más rentable en mujeres con síndrome de Lynch y cáncer de colon. La adición de salpingooforectomía bilateral ofreció la mayor supervivencia libre de eventos y la menor mortalidad. Sin embargo, la morbilidad adicional de la menopausia prematura de la salpingooforectomía profiláctica para las mujeres más jóvenes superó el beneficio de la prevención del cáncer de ovario. Consulte Video Resumen en http://links.lww.com/DCR/B287. (Traducción-Dr. Yesenia Rojas-Khalil).
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10
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Golubicki M, Bonjoch L, Acuña-Ochoa JG, Díaz-Gay M, Muñoz J, Cuatrecasas M, Ocaña T, Iseas S, Mendez G, Cisterna D, Schubert SA, Nielsen M, van Wezel T, Goldberg Y, Pikarsky E, Robbio J, Roca E, Castells A, Balaguer F, Antelo M, Castellví-Bel S. Germline biallelic Mcm8 variants are associated with early-onset Lynch-like syndrome. JCI Insight 2020; 5:140698. [PMID: 32841224 PMCID: PMC7526538 DOI: 10.1172/jci.insight.140698] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 08/12/2020] [Indexed: 12/16/2022] Open
Abstract
Lynch syndrome is the most common cause of hereditary colorectal cancer (CRC), and it is characterized by DNA mismatch repair (MMR) deficiency. The term Lynch-like syndrome (LLS) is used for patients with MMR-deficient tumors and neither germline mutation in MLH1, MSH2, MSH6, PMS2, or EPCAM nor MLH1 somatic methylation. Biallelic somatic inactivation or cryptic germline MMR variants undetected during genetic testing have been proposed to be involved. Sixteen patients with early-onset LLS CRC were selected for germline and tumor whole-exome sequencing. Two potentially pathogenic germline MCM8 variants were detected in a male patient with LLS with fertility problems. A knockout cellular model for MCM8 was generated by CRISPR/Cas9 and detected genetic variants were produced by mutagenesis. DNA damage, microsatellite instability, and mutational signatures were monitored. DNA damage was evident for MCM8KO cells and the analyzed genetic variants. Microsatellite instability and mutational signatures in MCM8KO cells were compatible with the involvement of MCM8 in MMR. Replication in an independent familial cancer cohort detected additional carriers. Unexplained MMR-deficient CRC cases, even showing somatic biallelic MMR inactivation, may be caused by underlying germline defects in genes different than MMR genes. We suggest MCM8 as a gene involved in CRC germline predisposition with a recessive pattern of inheritance. MCM8 may be involved in germline predisposition to colorectal cancer in Lynch-like syndrome cases.
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Affiliation(s)
- Mariano Golubicki
- Oncology Section and.,Molecular Biology Laboratory, Hospital of Gastroenterology "Dr. C.B. Udaondo," Buenos Aires, Argentina
| | - Laia Bonjoch
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - José G Acuña-Ochoa
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Marcos Díaz-Gay
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Jenifer Muñoz
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Miriam Cuatrecasas
- Pathology Department, IDIBAPS, CIBEREHD, and Tumor Bank-Biobank, Hospital Clínic, Barcelona, Spain
| | - Teresa Ocaña
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | | | | | - Daniel Cisterna
- Molecular Biology Laboratory, Hospital of Gastroenterology "Dr. C.B. Udaondo," Buenos Aires, Argentina
| | | | - Maartje Nielsen
- Department of Clinical Genetics, Leiden University Medical Center, Leiden, Netherlands
| | | | - Yael Goldberg
- Recanati Genetics Institute, Rabin Medical Center, Petah Tikva, Israel
| | - Eli Pikarsky
- Lautenberg Center for Immunology and Cancer Research, Institute for Medical Research, Israel-Canada, Hebrew University-Hadassah Medical School, Jerusalem, Israel
| | | | | | - Antoni Castells
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Francesc Balaguer
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | | | - Sergi Castellví-Bel
- Gastroenterology Department, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
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11
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Carbone M, Arron ST, Beutler B, Bononi A, Cavenee W, Cleaver JE, Croce CM, D'Andrea A, Foulkes WD, Gaudino G, Groden JL, Henske EP, Hickson ID, Hwang PM, Kolodner RD, Mak TW, Malkin D, Monnat RJ, Novelli F, Pass HI, Petrini JH, Schmidt LS, Yang H. Tumour predisposition and cancer syndromes as models to study gene-environment interactions. Nat Rev Cancer 2020; 20:533-549. [PMID: 32472073 PMCID: PMC8104546 DOI: 10.1038/s41568-020-0265-y] [Citation(s) in RCA: 89] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/23/2020] [Indexed: 12/18/2022]
Abstract
Cell division and organismal development are exquisitely orchestrated and regulated processes. The dysregulation of the molecular mechanisms underlying these processes may cause cancer, a consequence of cell-intrinsic and/or cell-extrinsic events. Cellular DNA can be damaged by spontaneous hydrolysis, reactive oxygen species, aberrant cellular metabolism or other perturbations that cause DNA damage. Moreover, several environmental factors may damage the DNA, alter cellular metabolism or affect the ability of cells to interact with their microenvironment. While some environmental factors are well established as carcinogens, there remains a large knowledge gap of others owing to the difficulty in identifying them because of the typically long interval between carcinogen exposure and cancer diagnosis. DNA damage increases in cells harbouring mutations that impair their ability to correctly repair the DNA. Tumour predisposition syndromes in which cancers arise at an accelerated rate and in different organs - the equivalent of a sensitized background - provide a unique opportunity to examine how gene-environment interactions influence cancer risk when the initiating genetic defect responsible for malignancy is known. Understanding the molecular processes that are altered by specific germline mutations, environmental exposures and related mechanisms that promote cancer will allow the design of novel and effective preventive and therapeutic strategies.
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Affiliation(s)
- Michele Carbone
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA.
| | - Sarah T Arron
- STA, JEC, Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Bruce Beutler
- Center for Genetic Host Defense, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Angela Bononi
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Webster Cavenee
- Ludwig Institute, University of California, San Diego, San Diego, CA, USA
| | - James E Cleaver
- STA, JEC, Department of Dermatology, University of California, San Francisco, San Francisco, CA, USA
| | - Carlo M Croce
- Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH, USA
| | - Alan D'Andrea
- Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - William D Foulkes
- Department of Human Genetics, McGill University, Montreal, QC, Canada
| | - Giovanni Gaudino
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | | | - Elizabeth P Henske
- Center for LAM Research, Brigham & Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ian D Hickson
- Center for Chromosome Stability, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Paul M Hwang
- Cardiovascular Branch, National Institutes of Health, Bethesda, MD, USA
| | - Richard D Kolodner
- Ludwig Institute, University of California, San Diego, San Diego, CA, USA
| | - Tak W Mak
- Princess Margaret Cancer Center, University of Toronto, Toronto, ON, Canada
| | - David Malkin
- Division of Haematology/Oncology, Department of Paediatrics, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
| | - Raymond J Monnat
- Department Pathology, Washington University, Seattle, WA, USA
- Department of Genome Science, Washington University, Seattle, WA, USA
| | - Flavia Novelli
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
| | - Harvey I Pass
- Department of Cardiovascular Surgery, New York University, New York, NY, USA
| | - John H Petrini
- Molecular Biology Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Laura S Schmidt
- Urologic Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Basic Science Program, Frederick National Laboratory for Cancer Research, Frederick, MD, USA
| | - Haining Yang
- Thoracic Oncology, University of Hawaii Cancer Center, Honolulu, HI, USA
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12
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Sun CY, Chiang JM, Chen TC, Hung HY, You JF. Different surgical outcome and follow-up status between dMMR and pMMR colorectal cancer patients who fulfilled with Amsterdam-II criteria. World J Surg Oncol 2020; 18:195. [PMID: 32767993 PMCID: PMC7414700 DOI: 10.1186/s12957-020-01976-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2020] [Accepted: 07/30/2020] [Indexed: 11/17/2022] Open
Abstract
Background Although hereditary non-polyposis colorectal cancer (HNPCC) could be subtyped into proficient or deficient mismatch repair gene expression (pMMR or dMMR), distinct clinical features between these two subgroups patients were rarely reported. Methods We retrospectively analyzed 175 hereditary non-polyposis colorectal cancer (HNPCC) patients between January 1995 and December 2012. Cox proportional hazards model was used to compare the differences between two subgroups. Results Significant differences of disease free survival (DFS) and overall survival (OS) exist between dMMR and pMMR. In addition to other factors including younger mean age of diagnosis for dMMR patients (48.6 years vs. 54.3 years), operation type (more extended colectomy for dMMR 35.8% vs. 14.5%), tumor location (right colon predominance for dMMR 61.7% vs. 27.3% and more rectum cases for pMMR 41.8% vs. 11.7%), tumor differentiation (more poor differentiation for dMMR 23.3% vs. 9.0%), N staging (more N0 cases for dMMR 70.8% vs. 50.9%), more frequently presence of extra-colonic tumors for dMMR (16.7% vs.1.8%), and lower recurrence rates (9.1% vs.35.3%). Significantly different cumulative incidences of developing metachronous colorectal cancer were observed with 6.18 for pMMR patients and 20.57 person-years for dMMR patients (p < 0.001). Conclusions Distinct clinicopathological features significantly exist between dMMR and pMMR subtypes patient, MMR status should be consider to tailor operation types and follow up surveillance between these two subgroups patients who all fulfilled with Amsterdam-II criteria.
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Affiliation(s)
- Ci-Yuan Sun
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan. .,College of Medicine, Chang Gung University, No. 5, Fu-Hsing Rd. Kuei-Shan, Tao-Yuan, 333, Taiwan.
| | - Jy-Ming Chiang
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan.,Chang Gung University, College of Medicine, Tao-Yuan, Taiwan
| | - Tse-Ching Chen
- Chang Gung University, College of Medicine, Tao-Yuan, Taiwan.,Department of Pathology, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan
| | - Hsin-Yun Hung
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan
| | - Jeng-Fu You
- Division of Colon and Rectal Surgery, Department of Surgery, Chang Gung Memorial Hospital, Lin-Kou Medical Center, Tao-Yuan, Taiwan
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13
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Monahan KJ, Bradshaw N, Dolwani S, Desouza B, Dunlop MG, East JE, Ilyas M, Kaur A, Lalloo F, Latchford A, Rutter MD, Tomlinson I, Thomas HJW, Hill J. Guidelines for the management of hereditary colorectal cancer from the British Society of Gastroenterology (BSG)/Association of Coloproctology of Great Britain and Ireland (ACPGBI)/United Kingdom Cancer Genetics Group (UKCGG). Gut 2020; 69:411-444. [PMID: 31780574 PMCID: PMC7034349 DOI: 10.1136/gutjnl-2019-319915] [Citation(s) in RCA: 276] [Impact Index Per Article: 55.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 10/25/2019] [Accepted: 11/05/2019] [Indexed: 12/12/2022]
Abstract
Heritable factors account for approximately 35% of colorectal cancer (CRC) risk, and almost 30% of the population in the UK have a family history of CRC. The quantification of an individual's lifetime risk of gastrointestinal cancer may incorporate clinical and molecular data, and depends on accurate phenotypic assessment and genetic diagnosis. In turn this may facilitate targeted risk-reducing interventions, including endoscopic surveillance, preventative surgery and chemoprophylaxis, which provide opportunities for cancer prevention. This guideline is an update from the 2010 British Society of Gastroenterology/Association of Coloproctology of Great Britain and Ireland (BSG/ACPGBI) guidelines for colorectal screening and surveillance in moderate and high-risk groups; however, this guideline is concerned specifically with people who have increased lifetime risk of CRC due to hereditary factors, including those with Lynch syndrome, polyposis or a family history of CRC. On this occasion we invited the UK Cancer Genetics Group (UKCGG), a subgroup within the British Society of Genetic Medicine (BSGM), as a partner to BSG and ACPGBI in the multidisciplinary guideline development process. We also invited external review through the Delphi process by members of the public as well as the steering committees of the European Hereditary Tumour Group (EHTG) and the European Society of Gastrointestinal Endoscopy (ESGE). A systematic review of 10 189 publications was undertaken to develop 67 evidence and expert opinion-based recommendations for the management of hereditary CRC risk. Ten research recommendations are also prioritised to inform clinical management of people at hereditary CRC risk.
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Affiliation(s)
- Kevin J Monahan
- Family Cancer Clinic, St Mark's Hospital, London, UK
- Faculty of Medicine, Imperial College, London, UK
| | - Nicola Bradshaw
- Clinical Genetics, West of Scotland Genetics Services, Glasgow, Glasgow, UK
| | - Sunil Dolwani
- Gastroenterology, Cardiff and Vale NHS Trust, Cardiff, UK
| | - Bianca Desouza
- Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | | | - James E East
- Translational Gastroenterology Unit, John Radcliffe Hospital, Oxford, UK
- Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford, UK
| | - Mohammad Ilyas
- Faculty of Medicine & Health Sciences, Nottingham University, Nottingham, UK
| | - Asha Kaur
- Head of Policy and Campaigns, Bowel Cancer UK, London, UK
| | - Fiona Lalloo
- Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
| | | | - Matthew D Rutter
- Gastroenterology, University Hospital of North Tees, Stockton-on-Tees, UK
- Northern Institute for Cancer Research, Newcastle University, Newcastle upon Tyne, UK
| | - Ian Tomlinson
- Nuffield Department of Clinical Medicine, Wellcome Trust Centre for Human Genetics, Birmingham, UK
- Cancer Research Centre, University of Edinburgh, Edinburgh, UK
| | - Huw J W Thomas
- Family Cancer Clinic, St Mark's Hospital, London, UK
- Faculty of Medicine, Imperial College, London, UK
| | - James Hill
- Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK
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14
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Lappalainen J, Holmström D, Lepistö A, Saarnio J, Mecklin JP, Seppälä T. Incident colorectal cancer in Lynch syndrome is usually not preceded by compromised quality of colonoscopy. Scand J Gastroenterol 2019; 54:1473-1480. [PMID: 31829749 DOI: 10.1080/00365521.2019.1698651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Background: Lifetime incidence of colorectal cancer (CRC) especially in carriers of MLH1 and MSH2 pathogenic germline variants in mismatch repair genes is high despite ongoing colonoscopy surveillance. Lynch syndrome (LS) registries have been criticized for not reporting colonoscopy quality adequately.Methods: Prospective follow-up data from the national registry were combined with a retrospective assessment of the colonoscopy reports from Helsinki University Hospital electronic patients records in 2004-2019.Results: Total of 366 MLH1, MSH2 and MSH6 carriers underwent 1564 colorectal endoscopies (mean 4.3 per patient, range 1-10) at a single unit. At least one subsequent examination was performed on 336 patients.Bowel preparation was suboptimal (Boston Bowel Preparation Scale 0-2) on either right or left side of the colon in 12.9% of planned surveillance examinations. Caecal intubation rate for full-length colonoscopies was 98.9%. Adenoma detection rate (ADR) was 15.8% in 2004-2014 but substantially increased (21.9%) after introduction of high-definition (HD) technology in 2015-2019 (p = .004; 18.7% across all examinations).CRCs were detected in 23 cases. Nineteen cancers were detected after 977 optimal quality colonoscopies and 4 after 151 compromised quality (BBPS <3 or non-complete examination; p = .16). Advanced neoplasias were not more frequently reported after compromised quality examinations.Conclusion: The majority of LS-associated incident CRCs were detected after colonoscopies with proper bowel preparation and complete examination. There is a considerable time trend towards higher ADR after introducing HD technology of endoscopes. The effect of time trend in ADR to CRC incidence in LS needs to be studied in larger, prospective settings.
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Affiliation(s)
| | | | - Anna Lepistö
- Department of Abdominal Surgery, Helsinki University Central Hospital, Helsinki, Finland.,Research Program in Applied Tumor Genomics, University of Helsinki, Helsinki, Finland
| | - Juha Saarnio
- Department of Surgery, Oulu University Hospital, Oulu, Finland
| | - Jukka-Pekka Mecklin
- Department of Surgery, Central Finland Central Hospital, Jyväskylä, Finland.,Faculty of Sports and Health Sciences, University of Jyväskylä, Jyväskylä, Finland
| | - Toni Seppälä
- Department of Abdominal Surgery, Helsinki University Central Hospital, Helsinki, Finland.,Department of Surgical Oncology, Johns Hopkins University, Baltimore, MD, USA
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15
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Kim JY, Byeon JS. Genetic Counseling and Surveillance Focused on Lynch Syndrome. JOURNAL OF THE ANUS RECTUM AND COLON 2019; 3:60-68. [PMID: 31559369 PMCID: PMC6752118 DOI: 10.23922/jarc.2019-002] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 02/08/2019] [Indexed: 12/20/2022]
Abstract
Lynch syndrome is a hereditary cancer syndrome caused by germline mutations in one of several DNA mismatch repair genes. Lynch syndrome leads to an increased lifetime risk of various cancers, particularly colorectal, and endometrial cancers. After identifying patients suspected of having Lynch syndrome by clinical criteria, computational prediction models, and/or universal tumor testing, genetic testing is performed to confirm the diagnosis. Before and after genetic testing, genetic counseling should be provided. Genetic counseling should involve a detailed personal and family history, information on the disorder and genetic tests, discussion of the management and surveillance of the disease, career plan, family plan, and psychosocial support. Surveillance of colorectal cancer and other malignancies is of paramount importance for properly managing Lynch syndrome. This review focuses on important considerations in genetic counseling and the latest insights into the surveillance of individuals and families with Lynch syndrome.
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Affiliation(s)
- Jin Yong Kim
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Jeong-Sik Byeon
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
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16
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Antelo M, Golubicki M, Roca E, Mendez G, Carballido M, Iseas S, Cuatrecasas M, Moreira L, Sanchez A, Carballal S, Castells A, Boland CR, Goel A, Balaguer F. Lynch-like syndrome is as frequent as Lynch syndrome in early-onset nonfamilial nonpolyposis colorectal cancer. Int J Cancer 2019; 145:705-713. [PMID: 30693488 PMCID: PMC10423080 DOI: 10.1002/ijc.32160] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Revised: 12/04/2018] [Accepted: 01/10/2019] [Indexed: 12/27/2022]
Abstract
Early-onset (<50 years-old) nonpolyposis nonfamilial colorectal cancer (EO NP NF CRC) is a common clinical challenge. Although Lynch syndrome (LS) is associated with EO CRC, the frequency of this syndrome in the EO NF cases remains unknown. Besides, mismatch repair deficient (MMRd) CRCs with negative MMR gene testing have recently been described in up to 60% of cases and termed "Lynch-like syndrome" (LLS). Management and counseling decisions of these patients are complicated because of unconfirmed suspicions of hereditary cancer. To define the prevalence of MMR deficient CRCs, LS and LLS in patients with EO NP NF CRC, we recruited 102 patients with a first diagnosis of NP NF CRC ≤ 50 years old during 2003-2009 who underwent genetic counseling at our institution in Argentina. Tumor immunohistochemical (IHC) MMR for protein expression and microsatellite instability (MSI) status were evaluated, and in those with loss of MLH1 expression by IHC, somatic BRAF V600E mutation and both somatic and germline MLH1 methylation levels were studied. Tumors characterized as MMRd without somatic BRAF mutation nor MLH1 methylation were sent for germline analysis. Twenty one (20.6%) tumors were MMRd. Fourteen of 16 putative LS cases underwent germline testing: 6 pathogenic mutations were identified and 8 cases had no identifiable pathogenic mutations. The prevalence of LS and LLS in this cohort was 5.8% (6/102) and 7.8% (8/102), respectively. As a conclusion we found that 20% of patients with EO NP NF CRC have MMRd tumors, and at least half of these are likely to have LLS.
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Affiliation(s)
- Marina Antelo
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires, Argentina
- Collective Health Institute, National University of Lanús, Buenos Aires, Argentina
| | - Mariano Golubicki
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires, Argentina
| | - Enrique Roca
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires, Argentina
| | - Guillermo Mendez
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires, Argentina
| | - Marcela Carballido
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires, Argentina
| | - Soledad Iseas
- Oncology Section, Hospital of Gastroenterology “Dr. C. B. Udaondo”, Buenos Aires, Argentina
| | - Miriam Cuatrecasas
- Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’ Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Leticia Moreira
- Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’ Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - A Sanchez
- Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’ Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - S Carballal
- Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’ Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | - Antoni Castells
- Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’ Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
| | | | - Ajay Goel
- Center for Gastrointestinal Research, Center for Translational Genomics and Oncology, Baylor Scott/White Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX
| | - Francesc Balaguer
- Department of Gastroenterology, Hospital Clínic, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Institut d’ Investigacions Biomediques August Pi i Sunyer (IDIBAPS), University of Barcelona, Barcelona, Spain
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17
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Total abdominal colectomy is cost-effective in treating colorectal cancer in patients with genetically diagnosed Lynch Syndrome. Am J Surg 2019; 218:928-933. [PMID: 30904142 DOI: 10.1016/j.amjsurg.2019.03.011] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2019] [Revised: 03/10/2019] [Accepted: 03/13/2019] [Indexed: 11/21/2022]
Abstract
BACKGROUND Lynch syndrome (LS) has a 80% lifetime risk of developing colorectal cancer and metachronous cancer. No studies have examined the quality adjusted life expectancy after SEG or TAC for LS patients, which this study was aiming for. If TAC offers a higher quality adjusted life year (QALY) to SEG in LS patients, preoperative diagnosis of LS is critical as it alters the recommended surgical procedure. METHODS A Markov decision tree was constructed using Treeage software to compare QALY of LS patients following SEG or TAC. Probabilities, cost, and utility were obtained from literature. Cost-effectiveness analyses were performed. RESULTS TAC dominates SEG as both the life-saving and cost-saving strategy. TAC dominated SEG on QALY (17.80 vs 17.13 QALY) for a cohort of LS patients diagnosed at an average of 30 year old and followed every 2 years after initial surgery. CONCLUSIONS We conclude that TAC as the primary surgical option for LS patients diagnosed with Stage I-III colon cancer is cost-effective. Further cost-effectiveness study is recommended to include extra-colonic malignancies in LS patients.
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18
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Malik SS, Lythgoe MP, McPhail M, Monahan KJ. Metachronous colorectal cancer following segmental or extended colectomy in Lynch syndrome: a systematic review and meta-analysis. Fam Cancer 2019; 17:557-564. [PMID: 29189962 PMCID: PMC6182577 DOI: 10.1007/s10689-017-0062-2] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Around 5% of colorectal cancers are due to mutations within DNA mismatch repair genes, resulting in Lynch syndrome (LS). These mutations have a high penetrance with early onset of colorectal cancer at a mean age of 45 years. The mainstay of surgical management is either a segmental or extensive colectomy. Currently there is no unified agreement as to which management strategy is superior due to limited conclusive empirical evidence available. A systematic review and meta- analysis to evaluate the risk of metachronous colorectal cancer (MCC) and mortality in LS following segmental and extensive colectomy. A systematic review of the PubMed database was conducted. Studies were included/ excluded based on pre-specified criteria. To assess the risk of MCC and mortality attributed to segmental or extensive colectomies, relative risks (RR) were calculated and corresponding 95% confidence intervals (CI). Publication bias was investigated using funnel plots. Data about mortality, as well as patient ascertainment [Amsterdam criteria (AC), germline mutation (GM)] were also extracted. Statistical analysis was conducted using the R program (version 3.2.3). The literature search identified 85 studies. After further analysis ten studies were eligible for inclusion in data synthesis. Pooled data identified 1389 patients followed up for a mean of 100.7 months with a mean age of onset of 45.5 years of age. A total 1119 patients underwent segmental colectomies with an absolute risk of MCC in this group of 22.4% at the end of follow-up. The 270 patients who had extensive colectomies had a MCC absolute risk of 4.7% (0% in those with a panproctocolecomy). Segmental colectomy was significantly associated with an increased relative risk of MCC (RR = 5.12; 95% CI 2.88-9.11; Fig. 1), although no significant association with mortality was identified (RR = 1.65; 95% CI 0.90-3.02). There was no statistically significant difference in the risk of MCC between AC and GM cohorts (p = 0.5, Chi-squared test). In LS, segmental colectomy results in a significant increased risk of developing MCC. Despite the choice of segmental or extensive colectomies having no statistically significant impact on mortality, the choice of initial surgical management can impact a patient's requirement for further surgery. An extensive colectomy can result in decreased need for further surgery; reduced hospital stays and associated costs. The significant difference in the risk of MCC, following segmental or extensive colectomies should be discussed with patients when deciding appropriate management. An individualised approach should be utilised, taking into account the patient's age, co-morbidities and genotype. In order to determine likely germline-specific effects, or a difference in survival, larger and more comprehensive studies are required.
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Affiliation(s)
| | | | | | - Kevin J Monahan
- Imperial College London, London, UK. .,Family History of Bowel Cancer Clinic, West Middlesex University Hospital, Chelsea and Westminster Hospitals NHS Trust, London, TW7 6AF, UK.
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19
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Sheel ARG, Harrison S, Sarantitis I, Nicholson JA, Hanna T, Grocock C, Raraty M, Ramesh J, Farooq A, Costello E, Jackson R, Chapman M, Smith A, Carter R, Mckay C, Hamady Z, Aithal GP, Mountford R, Ghaneh P, Hammel P, Lerch MM, Halloran C, Pereira SP, Greenhalf W. Identification of Cystic Lesions by Secondary Screening of Familial Pancreatic Cancer (FPC) Kindreds Is Not Associated with the Stratified Risk of Cancer. Am J Gastroenterol 2019; 114:155-164. [PMID: 30353057 DOI: 10.1038/s41395-018-0395-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Intraductal papillary mucinous neoplasms (IPMNs) are associated with risk of pancreatic ductal adenocarcinoma (PDAC). It is unclear if an IPMN in individuals at high risk of PDAC should be considered as a positive screening result or as an incidental finding. Stratified familial pancreatic cancer (FPC) populations were used to determine if IPMN risk is linked to familial risk of PDAC. METHODS This is a cohort study of 321 individuals from 258 kindreds suspected of being FPC and undergoing secondary screening for PDAC through the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer (EUROPAC). Computerised tomography, endoscopic ultrasound of the pancreas and magnetic resonance imaging were used. The risk of being a carrier of a dominant mutation predisposing to pancreatic cancer was stratified into three even categories (low, medium and high) based on: Mendelian probability, the number of PDAC cases and the number of people at risk in a kindred. RESULTS There was a median (interquartile range (IQR)) follow-up of 2 (0-5) years and a median (IQR) number of investigations per participant of 4 (2-6). One PDAC, two low-grade neuroendocrine tumours and 41 cystic lesions were identified, including 23 IPMN (22 branch-duct (BD)). The PDAC case occurred in the top 10% of risk, and the BD-IPMN cases were evenly distributed amongst risk categories: low (6/107), medium (10/107) and high (6/107) (P = 0.63). CONCLUSIONS The risk of finding BD-IPMN was independent of genetic predisposition and so they should be managed according to guidelines for incidental finding of IPMN.
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Affiliation(s)
- A R G Sheel
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - S Harrison
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - I Sarantitis
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - J A Nicholson
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - T Hanna
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - C Grocock
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - M Raraty
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - J Ramesh
- Department of Gastroenterology, The Royal Liverpool University Hospital, London, UK
| | - A Farooq
- Department of Radiology, The Royal Liverpool University Hospital, London, UK
| | - E Costello
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - R Jackson
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - M Chapman
- Institute for Liver & Digestive Health, University College London, London, UK
| | - A Smith
- Department of Pancreatico-Biliary Surgery, Leeds Teaching Hospital Trust, Leeds, UK
| | - R Carter
- West of Scotland Pancreatic unit, Glasgow Royal Infirmary, Glasgow, UK
| | - C Mckay
- West of Scotland Pancreatic unit, Glasgow Royal Infirmary, Glasgow, UK
| | - Z Hamady
- Department of Hepatobiliary and Pancreatic Diseases, University Hospital Southampton, Southampton, UK
| | - G P Aithal
- NIHR Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham, NG7 2UH, UK
| | - R Mountford
- Mersey Regional Molecular Genetics Laboratory, Liverpool Women's Hospital, Liverpool, UK
| | - P Ghaneh
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - P Hammel
- Service de Gastroentérologie-Pancréatologie, Pôle des Maladies de l'Appareil Digestif, Hôpital Beaujon, 92118, Clichy Cedex, France
| | - M M Lerch
- Department of Medicine A, University Medicine Greifswald, Sauerbruch-Strasse, 17475, Greifswald, Germany
| | - C Halloran
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
| | - S P Pereira
- Institute for Liver & Digestive Health, University College London, London, UK
| | - W Greenhalf
- Department of Molecular and Clinical Cancer Medicine, Institute of Translational Medicine, University of Liverpool, Liverpool, L69 3GA, UK
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20
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A Novel MLH1 Initiation Codon Mutation (c.3G>T) in a Large Chinese Lynch Syndrome Family with Different Onset Age and mRNA Expression Level. BIOMED RESEARCH INTERNATIONAL 2018; 2018:1460835. [PMID: 30539002 PMCID: PMC6261076 DOI: 10.1155/2018/1460835] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/16/2018] [Revised: 10/26/2018] [Accepted: 11/04/2018] [Indexed: 01/17/2023]
Abstract
Lynch syndrome is a genetically and clinically heterogeneous disorder; it is caused by a germline mutation in DNA mismatch repair (MMR) genes. Individuals with a heterozygous mutation in MLH1 have an increased risk for developing colorectal cancer. Here we described a 5-generation Chinese Lynch syndrome family with different severity and onset age. A novel heterozygous germline mutation (c.3G>T, p.Met1Ile) in MLH1 gene was discovered by next generation sequencing. Our study also revealed by qPCR that the MLH1 mRNA expression in peripheral blood of patients in this family was remarkably lower than that of the unaffected carriers and non-carriers. The research results indicated that the mRNA expression level may provide predictive suggestions of treatment and management for carriers with the initiation codon mutation of MLH1 in this family. Further studies are undertaken in this family as well as other families with Lynch syndrome to interrogate the exact reasons affecting the MLH1 mRNA expression level and whether mRNA expression in peripheral blood could be a significant factor for early diagnosis and surveillance of Lynch syndrome.
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21
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Leddin D, Lieberman DA, Tse F, Barkun AN, Abou-Setta AM, Marshall JK, Samadder NJ, Singh H, Telford JJ, Tinmouth J, Wilkinson AN, Leontiadis GI. Clinical Practice Guideline on Screening for Colorectal Cancer in Individuals With a Family History of Nonhereditary Colorectal Cancer or Adenoma: The Canadian Association of Gastroenterology Banff Consensus. Gastroenterology 2018; 155:1325-1347.e3. [PMID: 30121253 DOI: 10.1053/j.gastro.2018.08.017] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS A family history (FH) of colorectal cancer (CRC) increases the risk of developing CRC. These consensus recommendations developed by the Canadian Association of Gastroenterology and endorsed by the American Gastroenterological Association, aim to provide guidance on screening these high-risk individuals. METHODS Multiple parallel systematic review streams, informed by 10 literature searches, assembled evidence on 5 principal questions around the effect of an FH of CRC or adenomas on the risk of CRC, the age to initiate screening, and the optimal tests and testing intervals. The GRADE (Grading of Recommendation Assessment, Development and Evaluation) approach was used to develop the recommendations. RESULTS Based on the evidence, the Consensus Group was able to strongly recommend CRC screening for all individuals with an FH of CRC or documented adenoma. However, because most of the evidence was very-low quality, the majority of the remaining statements were conditional ("we suggest"). Colonoscopy is suggested (recommended in individuals with ≥2 first-degree relatives [FDRs]), with fecal immunochemical test as an alternative. The elevated risk associated with an FH of ≥1 FDRs with CRC or documented advanced adenoma suggests initiating screening at a younger age (eg, 40-50 years or 10 years younger than age of diagnosis of FDR). In addition, a shorter interval of every 5 years between screening tests was suggested for individuals with ≥2 FDRs, and every 5-10 years for those with FH of 1 FDR with CRC or documented advanced adenoma compared to average-risk individuals. Choosing screening parameters for an individual patient should consider the age of the affected FDR and local resources. It is suggested that individuals with an FH of ≥1 second-degree relatives only, or of nonadvanced adenoma or polyp of unknown histology, be screened according to average-risk guidelines. CONCLUSIONS The increased risk of CRC associated with an FH of CRC or advanced adenoma warrants more intense screening for CRC. Well-designed prospective studies are needed in order to make definitive evidence-based recommendations about the age to commence screening and appropriate interval between screening tests.
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Affiliation(s)
- Desmond Leddin
- Graduate Entry Medical School, University of Limerick, Ireland; Department of Medicine, Dalhousie University, Halifax, Nova Scotia, Canada.
| | - David A Lieberman
- Division of Gastroenterology, Oregon Health and Science University, Portland, Oregon
| | - Frances Tse
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - Alan N Barkun
- Division of Gastroenterology, McGill University Health Centre, McGill University, Montreal, Quebec, Canada
| | - Ahmed M Abou-Setta
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - John K Marshall
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
| | - N Jewel Samadder
- Division of Gastroenterology and Hepatology, Department of Clinical Genomics, Mayo Clinic, Phoenix, Arizona
| | - Harminder Singh
- Department of Community Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada; Section of Gastroenterology, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Jennifer J Telford
- Division of Gastroenterology, St Paul's Hospital, University of British Columbia, Vancouver, British Columbia, Canada
| | - Jill Tinmouth
- Department of Medicine, Sunnybrook and Women's College Health Sciences Centre, Toronto, Ontario, Canada
| | - Anna N Wilkinson
- Department of Family Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Grigorios I Leontiadis
- Division of Gastroenterology and Farncombe Family Digestive Health Research Institute, McMaster University, Hamilton, Ontario, Canada
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22
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Update on the role of chromoendoscopy in colonoscopic surveillance of patients with Lynch syndrome. Eur J Gastroenterol Hepatol 2018; 30:1116-1124. [PMID: 30044237 DOI: 10.1097/meg.0000000000001214] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
(Virtual) chromoendoscopy (CE) improves the detection of small or flat colorectal polyps; however, the evidence in high-risk groups, such as patients of Lynch syndrome (LS), is low. Our aim was to identify and update the evidence for the recommendations regarding surveillance of LS patients, for which the current underlying evidence for use of (virtual) CE was explored. A systematic literature search in PubMed, EMBASE, and Cochrane library was conducted, for all studies comparing (virtual) CE with white-light endoscopy in LS patients. Studies are explained in detail, with special attention to study design, type of (virtual) CE, and timing of polypectomy. Eight studies (409 patients) were included. Five were nonrandomized back-to-back studies and three were randomized back-to-back studies (one parallel and two cross-over design). In six studies the polyps were directly removed, while in two studies polyps were removed only during the second caecal withdrawal. Five studies researched CE with indigo carmine and three studies investigated virtual CE. Due to the heterogeneity between studies, no statistical analysis could be performed. There was a large variety in study design, timing of polypectomy, different (virtual) CE techniques and the patients that were included. Based on current literature, no firm conclusions can be drawn with respect to the additional value of (virtual) CE in the surveillance of patients with LS. However, training of endoscopists in detection and removal of nonpolypoid colorectal neoplasms is crucial, as well as stricter adherence to LS surveillance guidelines in daily clinical practice. For future research, standardization in study designs is needed.
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23
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Seppälä T, Pylvänäinen K, Evans DG, Järvinen H, Renkonen-Sinisalo L, Bernstein I, Holinski-Feder E, Sala P, Lindblom A, Macrae F, Blanco I, Sijmons R, Jeffries J, Vasen H, Burn J, Nakken S, Hovig E, Rødland EA, Tharmaratnam K, de Vos Tot Nederveen Cappel WH, Hill J, Wijnen J, Jenkins M, Genuardi M, Green K, Lalloo F, Sunde L, Mints M, Bertario L, Pineda M, Navarro M, Morak M, Frayling IM, Plazzer JP, Sampson JR, Capella G, Möslein G, Mecklin JP, Møller P. Colorectal cancer incidence in path_MLH1 carriers subjected to different follow-up protocols: a Prospective Lynch Syndrome Database report. Hered Cancer Clin Pract 2017; 15:18. [PMID: 29046738 PMCID: PMC5635542 DOI: 10.1186/s13053-017-0078-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/08/2017] [Accepted: 10/02/2017] [Indexed: 12/31/2022] Open
Abstract
Background We have previously reported a high incidence of colorectal cancer (CRC) in carriers of pathogenic MLH1 variants (path_MLH1) despite follow-up with colonoscopy including polypectomy. Methods The cohort included Finnish carriers enrolled in 3-yearly colonoscopy (n = 505; 4625 observation years) and carriers from other countries enrolled in colonoscopy 2-yearly or more frequently (n = 439; 3299 observation years). We examined whether the longer interval between colonoscopies in Finland could explain the high incidence of CRC and whether disease expression correlated with differences in population CRC incidence. Results Cumulative CRC incidences in carriers of path_MLH1 at 70-years of age were 41% for males and 36% for females in the Finnish series and 58% and 55% in the non-Finnish series, respectively (p > 0.05). Mean time from last colonoscopy to CRC was 32.7 months in the Finnish compared to 31.0 months in the non-Finnish (p > 0.05) and was therefore unaffected by the recommended colonoscopy interval. Differences in population incidence of CRC could not explain the lower point estimates for CRC in the Finnish series. Ten-year overall survival after CRC was similar for the Finnish and non-Finnish series (88% and 91%, respectively; p > 0.05). Conclusions The hypothesis that the high incidence of CRC in path_MLH1 carriers was caused by a higher incidence in the Finnish series was not valid. We discuss whether the results were influenced by methodological shortcomings in our study or whether the assumption that a shorter interval between colonoscopies leads to a lower CRC incidence may be wrong. This second possibility is intriguing, because it suggests the dogma that CRC in path_MLH1 carriers develops from polyps that can be detected at colonoscopy and removed to prevent CRC may be erroneous. In view of the excellent 10-year overall survival in the Finnish and non-Finnish series we remain strong advocates of current surveillance practices for those with LS pending studies that will inform new recommendations on the best surveillance interval. Electronic supplementary material The online version of this article (10.1186/s13053-017-0078-5) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Toni Seppälä
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Post Box 340, 00029 Helsinki, Finland.,Finnish Lynch Syndrome registry, Helsinki University Hospital, Helsinki, Finland
| | - Kirsi Pylvänäinen
- Finnish Lynch Syndrome registry, Helsinki University Hospital, Helsinki, Finland.,Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland
| | - Dafydd Gareth Evans
- Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.,Manchester Centre for Genomic Medicine, Institute of Human Development, MAHSC, University of Manchester, Manchester, UK
| | - Heikki Järvinen
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Post Box 340, 00029 Helsinki, Finland.,Finnish Lynch Syndrome registry, Helsinki University Hospital, Helsinki, Finland
| | - Laura Renkonen-Sinisalo
- Department of Surgery, Helsinki University Hospital and University of Helsinki, Post Box 340, 00029 Helsinki, Finland.,Genome-Scale Biology Research Program, University of Helsinki, Helsinki, Finland
| | - Inge Bernstein
- Danish HNPCC Register, Hvidovre University Hospital, Copenhagen, Denmark.,Department Surgical Gastroenterology, Aalborg University Hospital, Aalborg, Denmark
| | - Elke Holinski-Feder
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, 80336 Munich, Germany.,MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3-5, 80335 Munich, Germany
| | - Paola Sala
- Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milan, Italy
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Finlay Macrae
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia.,Department of Medicine, Melbourne University, Melbourne, Australia
| | - Ignacio Blanco
- Hereditary Cancer Program. Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Rolf Sijmons
- Department of Genetics, University of Groningen, University Medical Center Groningen, Groningen, the Netherlands
| | - Jacqueline Jeffries
- Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN UK
| | - Hans Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Leiden, the Netherlands
| | - John Burn
- Institute of Human Genetics, Newcastle upon Tyne, UK
| | - Sigve Nakken
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway
| | - Eivind Hovig
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway.,Institute of Cancer Genetics and Informatics, The Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway.,Department of Informatics, University of Oslo, Oslo, Norway
| | - Einar Andreas Rødland
- Department of Tumor Biology, Institute of Cancer Research, The Norwegian Radium Hospital, part of Oslo University Hospital, Oslo, Norway
| | | | | | - James Hill
- Department of Surgery, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Juul Wijnen
- Department of Clinical Genetics and Department of Human Genetics Leiden University Medical Centre, Leiden, The Netherlands
| | - Mark Jenkins
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Parkville, VIC Australia
| | | | - Kate Green
- Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Fiona Lalloo
- Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
| | - Lone Sunde
- Danish HNPCC Register, Hvidovre University Hospital, Copenhagen, Denmark.,Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.,Department of Biomedicine, Aarhus University, Aarhus, Denmark
| | - Miriam Mints
- Department of Women's and Children's health, Division of Obstetrics and Gynecology, Karolinska Institutet, Karolinska University Hospital, Solna S171 76, Stockholm, Sweden
| | - Lucio Bertario
- Unit of Hereditary Digestive Tract Tumors IRCCS Istituto Nazionale Tumori Milan, Milan, Italy
| | - Marta Pineda
- Hereditary Cancer Program. Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Matilde Navarro
- Hereditary Cancer Program. Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Monika Morak
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, Klinikum der Universität München, Ziemssenstr. 1, 80336 Munich, Germany.,MGZ - Medizinisch Genetisches Zentrum, Bayerstr. 3-5, 80335 Munich, Germany
| | - Ian M Frayling
- Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN UK
| | - John-Paul Plazzer
- Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia
| | - Julian R Sampson
- Institute of Medical Genetics, Cardiff University School of Medicine, Heath Park, Cardiff, CF14 4XN UK
| | - Gabriel Capella
- Hereditary Cancer Program. Institut Català d'Oncologia-IDIBELL, L'Hospitalet de Llobregat, Barcelona, Spain
| | - Gabriela Möslein
- Center for Hereditary Tumors, HELIOS University Hospital Wuppertal, University Witten/Herdecke, Witten, Germany.,Department für Humanmedizin, Universität Witten/Herdecke, Witten, Germany
| | - Jukka-Pekka Mecklin
- Department of Education and Science, Central Finland Health Care District, Jyväskylä, Finland.,University of Eastern Finland, Kuopio, Finland
| | - Pål Møller
- Research Group Inherited Cancer, The Norwegian Radium Hospital, Department of Medical Genetics, Oslo University Hospital, Oslo, Norway
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Pokharel HP, Hacker NF, Andrews L. Hereditary gynaecologic cancers in Nepal: a proposed model of care to serve high risk populations in developing countries. Hered Cancer Clin Pract 2017; 15:12. [PMID: 28936272 PMCID: PMC5604345 DOI: 10.1186/s13053-017-0072-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2017] [Accepted: 09/05/2017] [Indexed: 12/15/2022] Open
Abstract
Background Endometrial, ovarian and breast cancers are paradigms for global health disparity. Women living in the developing world continue to present in later stages of disease and have fewer options for treatment than those in developed countries. Risk reducing surgery is of proven benefit for women at high risk of gynaecological cancer. There is no specific model for identification and management of such women in the developing world. Methods We have integrated data from our published audit of a major gynaecological oncology centre at Royal Hospital for Women in Australia, with data from our survey and a focus group discussion of Nepalese gynaecological health care professionals regarding genetic testing, and findings from the literature. These data have been used to identify current barriers to multidisciplinary gynaecological oncology care in developing nations, and to develop a model to integrate hereditary cancer services into cancer care in Nepal, as a paradigm for other developing nations. Results The ability to identify women with hereditary gynaecological cancer in developing nations is influenced by their late presentation (if active management is declined or not appropriate), limited access to specialised services and cultural and financial barriers. In order to include genetic assessment in multidisciplinary gynaecological cancer care, education needs to be provided to all levels of health care providers to enable reporting of family history, and appropriate ordering of investigations. Training of genetic counsellors is needed to assist in the interpretation of results and extending care to unaffected at-risk relatives. Novel approaches will be required to overcome geographic and financial barriers, including mainstreaming of genetic testing, telephone counselling, use of mouth swabs and utilisation of international laboratories. Conclusion Women in Nepal have yet to receive benefits from the advances in early cancer diagnosis and management. There is a potential of extending the benefits of hereditary cancer diagnosis in Nepal due to the rapid fall in the cost of genetic testing and the ability to collect DNA from a buccal swab through appropriate training of the gynaecological carers.
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Affiliation(s)
- Hanoon P Pokharel
- Gynaecologic Cancer Centre, Royal Hospital for Women, Sydney, Australia.,School of Women's and Children's Health, UNSW, Sydney, Australia.,Department of Obstetrics and Gynaecology, B.P Koirala Institute of Health Sciences, Dharan, Nepal
| | - Neville F Hacker
- Gynaecologic Cancer Centre, Royal Hospital for Women, Sydney, Australia.,School of Women's and Children's Health, UNSW, Sydney, Australia
| | - Lesley Andrews
- Hereditary Cancer Clinic, Prince of Wales Hospital, Sydney, Australia.,School of Medicine, UNSW, Sydney, Australia
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Anele CC, Adegbola SO, Askari A, Rajendran A, Clark SK, Latchford A, Faiz OD. Risk of metachronous colorectal cancer following colectomy in Lynch syndrome: a systematic review and meta-analysis. Colorectal Dis 2017; 19:528-536. [PMID: 28407411 DOI: 10.1111/codi.13679] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2016] [Accepted: 01/26/2017] [Indexed: 12/23/2022]
Abstract
AIM Lynch syndrome (LS) accounts for 2-4% of all colorectal cancer (CRC) cases, and is associated with an increased risk of developing metachronous colorectal cancer (mCRC). The role of extended colectomy in LS CRC is controversial. There are limited studies comparing the risk of mCRC following segmental colectomy and extended colectomy. The objective of this systematic review is to evaluate the risk of developing mCRC following segmental and extended colectomy for LS CRC and endoscopic compliance. METHOD A systematic review of major databases was performed using predefined terms. All original articles published in English comparing the risk of mCRC in LS patients after segmental and extended colectomy from 1950 to January 2016 were included. RESULTS The search retrieved 324 studies. Six studies involving 871 patients met the inclusion criteria. Of these, 705 (80.9%) underwent segmental colectomy and 166 (19.1%) extended colectomy. Average follow-up was 91.2 months. The mCRC rate was 22.8% and 6% in the segmental and extended colectomy groups, respectively. The segmental group were over four times more likely to develop mCRC (OR 4.02, 95% CI: 2.01-8.04, P < 0.0001). mCRC occurred in patients after segmental colectomy despite 1-2-yearly postoperative endoscopic surveillance. CONCLUSION This result suggests that extended colectomy reduces the risk of mCRC by over four-fold compared with segmental colectomy. mCRC occurred in the segmental group despite postoperative endoscopic surveillance. This needs to be borne in mind when deciding on the appropriate surgical management of LS patients with CRC. We recommend that extended colectomy should be considered for patients with confirmed LS CRC.
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Affiliation(s)
- C C Anele
- Department of Surgery and Cancer, Imperial College London, London, UK.,St Mark's Hospital and Academic Institute, Middlesex, UK
| | - S O Adegbola
- Department of Surgery and Cancer, Imperial College London, London, UK.,St Mark's Hospital and Academic Institute, Middlesex, UK
| | - A Askari
- Surgical Epidemiology Trials and Outcomes Centre, St Mark's Hospital and Academic Institute, Middlesex, UK
| | - A Rajendran
- Department of Gastroenterology, St Mark's Hospital and Academic Institute, Middlesex, UK
| | - S K Clark
- Department of Surgery and Cancer, Imperial College London, London, UK.,St Mark's Hospital and Academic Institute, Middlesex, UK
| | - A Latchford
- Department of Gastroenterology, St Mark's Hospital and Academic Institute, Middlesex, UK
| | - O D Faiz
- Department of Surgery and Cancer, Imperial College London, London, UK.,St Mark's Hospital and Academic Institute, Middlesex, UK
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Inoki K, Nakajima T, Sekine S, Sugano K, Tsukamoto S, Yamada M, Mutoh M, Sakamoto T, Matsuda T, Sekiguchi M, Ushiama M, Yoshida T, Sakamoto H, Kanemitsu Y, Saito Y. Depressed-type submucosal invasive colorectal cancer in a patient with Lynch syndrome diagnosed using short-interval colonoscopy. Dig Endosc 2016; 28:749-754. [PMID: 27500781 DOI: 10.1111/den.12707] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 07/27/2016] [Accepted: 08/01/2016] [Indexed: 12/24/2022]
Abstract
Although regular colonoscopy surveillance is recommended for patients with Lynch syndrome (LS) who underwent partial colectomy, the appropriate interval has not been determined. We report a case of colorectal cancer (CRC) detected by short-interval surveillance colonoscopy (SC) in a patient with LS having a past history of partial colectomy. A 65-year-old man underwent sigmoidectomy for advanced CRC. His family history revealed that his two younger brothers had CRC in their twenties and thirties, respectively, and the patient met with the criteria in the Revised Bethesda Guidelines. After confirming the loss of MSH2 protein expression in the primary tumor, subsequent genetic testing showed germline mutation with a large deletion of exon 7-14 in the MSH2 gene, indicating a diagnosis of LS. After the diagnosis of LS, the patient underwent annual SC. Three years after the initial surgery, superficial submucosal invasive cancer was detected. Subsequently, SC after a 6-month interval revealed a deep submucosal invasive cancer (7 mm in diameter). Although additional surgery was recommended, considering his comorbidities, regular SC rather than colectomy was selected. Even shorter-interval SC carried out within a year is not sufficient to detect endoscopically resectable tumors in some high-risk LS cases.
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Affiliation(s)
- Kazuya Inoki
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Takeshi Nakajima
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan. .,Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.
| | - Shigeki Sekine
- Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.,Molecular Pathology Division, National Cancer Center Research Institute, Tokyo, Japan
| | - Kokichi Sugano
- Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.,Oncogene Research Unit/Cancer Prevention Unit, Tochigi Cancer Center Research Institute, Tochigi, Japan
| | - Shunsuke Tsukamoto
- Colorectal Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Masayoshi Yamada
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.,Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Michihiro Mutoh
- Division of Cancer Prevention Research, National Cancer Center Research Institute, Tokyo, Japan
| | - Taku Sakamoto
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
| | - Takahisa Matsuda
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.,Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.,Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Masau Sekiguchi
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan.,Cancer Screening Division, Research Center for Cancer Prevention and Screening, National Cancer Center, Tokyo, Japan
| | - Mineko Ushiama
- Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.,Group for Cancer Development and Progression, Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Teruhiko Yoshida
- Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.,Group for Cancer Development and Progression, Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Hiromi Sakamoto
- Genetic Medicine and Services, National Cancer Center Hospital, Tokyo, Japan.,Group for Cancer Development and Progression, Division of Genetics, National Cancer Center Research Institute, Tokyo, Japan
| | - Yukihide Kanemitsu
- Colorectal Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yutaka Saito
- Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan
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Kim TJ, Kim ER, Hong SN, Kim YH, Huh JW, Park YA, Cho YB, Yun SH, Kim HC, Lee WY, Kim K, Kim K, Chang DK. Survival Outcome and Risk of Metachronous Colorectal Cancer After Surgery in Lynch Syndrome. Ann Surg Oncol 2016; 24:1085-1092. [PMID: 27766559 DOI: 10.1245/s10434-016-5633-1] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Indexed: 01/13/2023]
Abstract
BACKGROUND The survival benefit of extensive colectomy is controversial in Lynch syndrome, and risk factors for metachronous colorectal cancer (CRC) after segmental colectomy are unclear. OBJECTIVE The aim of this study was to investigate the survival outcome and risk of metachronous CRC after surgery in Lynch syndrome patients diagnosed with their first CRC. METHODS Overall, 106 patients with Lynch syndrome who underwent surgery for CRC were included in the study. The demographics, genotype, clinicopathological characteristics of the index CRC, and follow-up data were reviewed from a single-institution Lynch syndrome database. RESULTS Of 30 patients who underwent extensive surgery, no metachronous CRC was developed during a mean follow-up of 68.1 months. Of 76 patients who underwent segmental colectomy, 13 (17.1 %) developed metachronous CRC during a mean follow-up of 77.2 months. The cumulative risk of metachronous CRC was 8.4 % at 5 years and 20.4 % at 10 years after segmental colectomy. No difference in overall and CRC-specific survival was observed between segmental colectomy and extensive colectomy (p = 0.277 and p = 0.659, respectively). A 25 cm or longer resection of bowel decreased the risk of metachronous CRC after segmental colectomy compared with less extensive resection (hazard ratio 0.10, 95 % confidence interval 0.01-0.86). Annual surveillance colonoscopy did not decrease the risk of metachronous CRC compared with less frequent surveillance colonoscopy. Although not statistically significant, none of the MSH6 gene mutation carriers were diagnosed with metachronous CRC. CONCLUSIONS Although no survival benefit was identified, surgeons and patients might consider extensive colectomy to prevent metachronous CRC in Lynch syndrome patients regardless of their clinicopathological characteristics.
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Affiliation(s)
- Tae Jun Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Eun Ran Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Sung Noh Hong
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Young-Ho Kim
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jung Wook Huh
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yoon Ah Park
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Yong Beom Cho
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Seong Hyeon Yun
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Hee Cheol Kim
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Woo Yong Lee
- Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kiyoun Kim
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Kyunga Kim
- Biostatistics and Clinical Epidemiology Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Dong Kyung Chang
- Division of Gastroenterology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.
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Karlitz JJ, Sherrill MR, DiGiacomo DV, Hsieh MC, Schmidt B, Wu XC, Chen VW. Factors Associated With the Performance of Extended Colonic Resection vs. Segmental Resection in Early-Onset Colorectal Cancer: A Population-Based Study. Clin Transl Gastroenterol 2016; 7:e163. [PMID: 27077958 PMCID: PMC4855160 DOI: 10.1038/ctg.2016.17] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2016] [Accepted: 02/22/2016] [Indexed: 02/07/2023] Open
Abstract
OBJECTIVES: Early-onset colorectal cancer (CRC) incidence rates are rising. This group is susceptible to heritable conditions (i.e., Lynch syndrome (LS)) and inflammatory bowel disease (IBD) with high metachronous CRC rates after segmental resection. Hence, extended colonic resection (ECR) is often performed and considered generally in young patients. As there are no population-based studies analyzing resection extent in early-onset CRC, we used CDC Comparative Effectiveness Research (CER) data to assess state-wide operative practices. METHODS: Using CER and Louisiana Tumor Registry data, all CRC patients aged ≤50 years, diagnosed in Louisiana in 2011, who underwent surgery in 2011–2012 were retrospectively analyzed. Prevalence of, and the factors associated with operation type (ECR including subtotal/total/proctocolectomy vs. segmental resection) were evaluated. RESULTS: Of 2,427 CRC patients, 274 were aged ≤50 years. In all, 234 underwent surgery at 53 unique facilities and 6.8% underwent ECR. Statistically significant ECR-associated factors included age ≤45 years, polyposis, synchronous/metachronous LS-associated cancers, and IBD. Abnormal microsatellite instability (MSI) was not ECR-associated. ECR was not performed in sporadic CRC. CONCLUSIONS: ECR is performed in the setting of clinically obvious associated high-risk features (polyposis, IBD, synchronous/metachronous cancers) but not in isolated/sporadic CRC. However, attention must be paid to patients with seemingly lower risk characteristics (isolated CRC, no polyposis), as LS can still be present. In addition, the presumed sporadic group requires further study as metachronous CRC risk in early-onset sporadic CRC has not been well-defined, and some may harbor undefined/undiagnosed hereditary conditions. Abnormal MSI (LS risk) is not associated with ECR; abnormal MSI results often return postoperatively after segmental resection has already occurred, which is a contributing factor.
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Affiliation(s)
- Jordan J Karlitz
- Department of Medicine, Division of Gastroenterology, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Meredith R Sherrill
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Daniel V DiGiacomo
- Department of Medicine, Tulane University School of Medicine, New Orleans, Louisiana, USA
| | - Mei-Chin Hsieh
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Beth Schmidt
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Xiao-Cheng Wu
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
| | - Vivien W Chen
- Epidemiology Program, Louisiana Tumor Registry, LSU Health Sciences Center School of Public Health, New Orleans, Louisiana, USA
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30
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Advances in Hereditary Colorectal and Pancreatic Cancers. Clin Ther 2016; 38:1600-21. [PMID: 27045993 DOI: 10.1016/j.clinthera.2016.03.017] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2016] [Revised: 03/05/2016] [Accepted: 03/08/2016] [Indexed: 12/19/2022]
Abstract
PURPOSE Innovations in genetic medicine have led to improvements in the early detection, prevention, and treatment of cancer for patients with inherited risks of gastrointestinal cancer, particularly hereditary colorectal cancer and hereditary pancreatic cancer. METHODS This review provides an update on recent data and key advances that have improved the identification, understanding, and management of patients with hereditary colorectal cancer and hereditary pancreatic cancer. FINDINGS This review details recent and emerging data that highlight the developing landscape of genetics in hereditary colorectal and pancreatic cancer risk. A summary is provided of the current state-of-the-art practices for identifying, evaluating, and managing patients with suspected hereditary colorectal cancer and pancreatic cancer risk. The impact of next-generation sequencing technologies in the clinical diagnosis of hereditary gastrointestinal cancer and also in discovery efforts of new genes linked to familial cancer risk are discussed. Emerging targeted therapies that may play a particularly important role in the treatment of patients with hereditary forms of colorectal cancer and pancreatic cancer are also reviewed. Current approaches for pancreatic cancer screening and the psychosocial impact of such procedures are also detailed. IMPLICATIONS Given the availability of new diagnostic, risk-reducing, and therapeutic strategies that exist for patients with hereditary risk of colorectal or pancreatic cancer, it is imperative that clinicians be vigilant about evaluating patients for hereditary cancer syndromes. Continuing to advance genetics research in hereditary gastrointestinal cancers will allow for more progress to be made in personalized medicine and prevention.
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31
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Féau S, Caulet M, Lecomte T. What is the Best Colonoscopy Surveillance for Lynch Syndrome Patients? CURRENT COLORECTAL CANCER REPORTS 2016. [DOI: 10.1007/s11888-016-0314-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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32
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Jenkins Wessling E, Lanspa SJ. Colonoscopy and chromoscopy in hereditary colorectal cancer syndromes. Fam Cancer 2016; 15:453-5. [PMID: 26892866 DOI: 10.1007/s10689-016-9881-9] [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: 11/30/2022]
Abstract
With hereditary colorectal cancer prevention studies it is difficult to demonstrate reduced mortality. Large populations are needed with well characterized genetics followed over a long period of time. Those studies do exist for standard white light colonoscopy surveillance in Lynch syndrome, but not for newer technologies including chromoscopy. For these newer technologies adenoma detection rate becomes the stand-in for mortality, and the assumption is made that surveillance efficacy impacts cancer occurrence. Though well-designed and important work exists in this area, the data do not support firm conclusions regarding the use of chromoscopy in Lynch syndrome.
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Affiliation(s)
- Erin Jenkins Wessling
- Department of Gastroenterology, Creighton University, 2500 California Plaza, Criss II, Room 117A, Omaha, NE, 68178, USA
| | - Stephen J Lanspa
- Department of Gastroenterology, Creighton University, 2500 California Plaza, Criss II, Room 117A, Omaha, NE, 68178, USA.
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33
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Diagnosis of Lynch syndrome before colorectal resection: does it matter? Tech Coloproctol 2016; 20:203-5. [DOI: 10.1007/s10151-016-1433-7] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2016] [Accepted: 01/22/2016] [Indexed: 10/22/2022]
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Sijmons RH, Hofstra RMW. Review: Clinical aspects of hereditary DNA Mismatch repair gene mutations. DNA Repair (Amst) 2015; 38:155-162. [PMID: 26746812 DOI: 10.1016/j.dnarep.2015.11.018] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Revised: 09/28/2015] [Accepted: 11/30/2015] [Indexed: 12/15/2022]
Abstract
Inherited mutations of the DNA Mismatch repair genes MLH1, MSH2, MSH6 and PMS2 can result in two hereditary tumor syndromes: the adult-onset autosomal dominant Lynch syndrome, previously referred to as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) and the childhood-onset autosomal recessive Constitutional Mismatch Repair Deficiency syndrome. Both conditions are important to recognize clinically as their identification has direct consequences for clinical management and allows targeted preventive actions in mutation carriers. Lynch syndrome is one of the more common adult-onset hereditary tumor syndromes, with thousands of patients reported to date. Its tumor spectrum is well established and includes colorectal cancer, endometrial cancer and a range of other cancer types. However, surveillance for cancers other than colorectal cancer is still of uncertain value. Prophylactic surgery, especially for the uterus and its adnexa is an option in female mutation carriers. Chemoprevention of colorectal cancer with aspirin is actively being investigated in this syndrome and shows promising results. In contrast, the Constitutional Mismatch Repair Deficiency syndrome is rare, features a wide spectrum of childhood onset cancers, many of which are brain tumors with high mortality rates. Future studies are very much needed to improve the care for patients with this severe disorder.
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Affiliation(s)
- Rolf H Sijmons
- Department of Genetics, University of Groningen, University Medical Center Groningen, Hanzeplein 1, P.O. Box 30001, 9700RB, Groningen, The Netherlands.
| | - Robert M W Hofstra
- Department of Clinical Genetics, Erasmus Medical Center Rotterdam, P.O. Box 2040, 3000CA Rotterdam, The Netherlands.
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Targeted DNA Sequencing Detects Mutations Related to Susceptibility among Familial Non-medullary Thyroid Cancer. Sci Rep 2015; 5:16129. [PMID: 26530882 PMCID: PMC4632085 DOI: 10.1038/srep16129] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 10/08/2015] [Indexed: 01/13/2023] Open
Abstract
Some studies have demonstrated that familial non-medullary thyroid cancer (FNMTC) has a more aggressive clinical behavior compared to sporadic NMTC (SNMTC). However, FNMTC is difficult to differentiate from SNMTC by the morphology and immunohistochemistry. Although genes responsible for FNMTC were unclear, screening for rare germline mutations on known important tumor suppressor genes might offer more insights on predicting susceptibility to FNMTC. Here, a customized panel was designed to capture all exons of 31 cancer susceptive genes possibly related to FNMTC. Using next-generation sequencing we performed deep sequencing to achieve 500× coverage of the targeted regions. At the end 45 variants were identified in 29 of 47 familial patients and 6 of 16 sporadic patients. Notably, several germline mutations were found matching between paired FNMTC patients from the same family, including APC L292F and A2778S, BRAF D22N, MSH6 G355S and A36V, MSH2 L719F, MEN1 G508D, BRCA1 SS955S, BRCA2 G2508S, and a GNAS inframe insertion. We demonstrated a novel approach to help diagnose and elucidate the genetic cause of the FNMTC patients, and assess whether their family members are exposed to a higher genetic risk. The findings would also provide insights on monitoring the potential second cancers for thyroid cancer patients.
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Kochi M, Shimomura M, Hinoi T, Niitsu H, Yano T, Mukai S, Sawada H, Miguchi M, Saito Y, Adachi T, Ishizaki Y, Egi H, Ohdan H. Total colectomy for multiple metachronous colon cancers in a patient with Lynch syndrome. Surg Case Rep 2015; 1:78. [PMID: 26380806 PMCID: PMC4564456 DOI: 10.1186/s40792-015-0081-x] [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: 04/16/2015] [Accepted: 09/01/2015] [Indexed: 10/25/2022] Open
Abstract
Lynch syndrome (LS) is a disorder caused by mismatch repair gene mutations, which have been recognized to be associated with an increased frequency of colorectal and extracolorectal tumors. However, it remains controversial as to whether total or segmental colectomy should be performed to treat colorectal cancer in patients with LS. A 58-year-old male underwent total colectomy with ileostomy for advanced transverse colon cancer. He was also found to have LS based on his characteristic family history and the findings of a preoperative examination, including a microsatellite instability analysis of past multiple metachronous cancers. The postoperative histological findings showed mucinous adenocarcinoma without lymph node metastasis, and the loss of the MSH2 protein expression was confirmed on an immunohistochemical examination. The present case provided important information on the clinical management of multiple developing metachronous colorectal cancers in patients with LS.
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Affiliation(s)
- Masatoshi Kochi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Manabu Shimomura
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Takao Hinoi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Hiroaki Niitsu
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Takuya Yano
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Shoichiro Mukai
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Hiroyuki Sawada
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Masashi Miguchi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Yasufumi Saito
- Department of surgery, Hiroshima General Hospital of West Japan Railway Company, 3-1-36 Futabanosato, Higashi-ku, Hiroshima, 732-0057 Japan
| | - Tomohiro Adachi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Yasuyo Ishizaki
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Hiroyuki Egi
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
| | - Hideki Ohdan
- Department of Gastroenterological and Transplant Surgery, Applied Life Sciences, Institute of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, Hiroshima, 734-8551 Japan
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Ladabaum U, Ford JM, Martel M, Barkun AN. American Gastroenterological Association Technical Review on the Diagnosis and Management of Lynch Syndrome. Gastroenterology 2015; 149:783-813.e20. [PMID: 26226576 DOI: 10.1053/j.gastro.2015.07.037] [Citation(s) in RCA: 47] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Affiliation(s)
- Uri Ladabaum
- Division of Gastroenterology/Hepatology, Stanford University School of Medicine, Stanford, California
| | - James M Ford
- Division of Oncology, Department of Medicine, Stanford University School of Medicine, Stanford, California
| | - Myriam Martel
- Division of Gastroenterology, McGill University Health Center, McGill University, Montreal, Quebec, Canada
| | - Alan N Barkun
- Division of Gastroenterology, McGill University Health Center, McGill University, Montreal, Quebec, Canada; Division of Epidemiology and Biostatistics and Occupational Health, McGill University Health Center, McGill University, Montreal, Quebec, Canada
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DNA Mismatch Repair Status Predicts Need for Future Colorectal Surgery for Metachronous Neoplasms in Young Individuals Undergoing Colorectal Cancer Resection. Dis Colon Rectum 2015. [PMID: 26200678 DOI: 10.1097/dcr.0000000000000391] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
BACKGROUND The treatment of colorectal cancer in young patients involves both management of the incident cancer and consideration of the possibility of Lynch syndrome and the development of metachronous colorectal cancers. OBJECTIVE This study aims to assess the prognostic role of DNA mismatch repair deficiency and extended colorectal resection for metachronous colorectal neoplasia risk in young patients with colorectal cancer. DESIGN, SETTING, AND PATIENTS This is a retrospective review of 285 patients identified in our GI cancer registry with colorectal cancer diagnosed at 35 years or younger in the absence of polyposis. MAIN OUTCOME MEASURES Using univariate and multivariate analysis, we assessed the prognostic role of mismatch repair deficiency and standard clinicopathologic characteristics, including the extent of resection, on the rate of developing metachronous colorectal neoplasia requiring resection. RESULTS Mismatch repair deficiency was identified in biospecimens from 44% of patients and was significantly associated with an increased risk for metachronous colorectal neoplasia requiring resection (10-year cumulative risk, 13.5% ± 4.2%) compared with 56% of patients with mismatch repair-intact colorectal cancer (10-year cumulative risk, 5.8% ± 3.3%; p = 0.011). In multivariate analysis, mismatch repair deficiency was associated with a HR of 3.65 (95% CI, 1.44-9.21; p = 0.006) for metachronous colorectal neoplasia, whereas extended resection with ileorectal or ileosigmoid anastomosis significantly decreased the risk of metachronous colorectal neoplasia (HR, 0.21; 95% CI, 0.05-0.90; p = 0.036). LIMITATIONS This study had a retrospective design, and, therefore, recommendations for colorectal cancer surgery and screening were not fully standardized. Quality of life after colorectal cancer surgery was not assessed. CONCLUSIONS Young patients with colorectal cancer with molecular hallmarks of Lynch syndrome were at significantly higher risk for the development of subsequent colorectal neoplasia. This risk was significantly reduced in those who underwent extended resection compared with segmental resection.
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Brosens LAA, Offerhaus GJA, Giardiello FM. Hereditary Colorectal Cancer: Genetics and Screening. Surg Clin North Am 2015; 95:1067-80. [PMID: 26315524 DOI: 10.1016/j.suc.2015.05.004] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer and the third leading cause of cancer death in men and women in the United States. About 30% of patients with CRC report a family history of CRC. However, only 5% of CRCs arise in the setting of a well-established mendelian inherited disorder. In addition, serrated polyposis is a clinically defined syndrome with multiple serrated polyps in the colorectum and an increased CRC risk for which the genetics are unknown. This article focuses on genetic and clinical aspects of Lynch syndrome, familial adenomatous polyposis, and MUTYH-associated polyposis.
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Affiliation(s)
- Lodewijk A A Brosens
- Department of Pathology, University Medical Center Utrecht (H04-312), Heidelberglaan 100, Utrecht 3584 CX, The Netherlands; Department of Pathology, The Johns Hopkins University School of Medicine, CRB 2, Room 345, 1550 Orleans Street, Baltimore, MD 21231, USA.
| | - G Johan A Offerhaus
- Department of Pathology, University Medical Center Utrecht (H04-312), Heidelberglaan 100, Utrecht 3584 CX, The Netherlands
| | - Francis M Giardiello
- Department of Medicine, Oncology Center, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 431, Baltimore, MD 21205, USA; Department of Pathology, The Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 431, Baltimore, MD 21205, USA.
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Hereditary Non-polyposis Colorectal Cancer: Prevention and Therapeutic Options. CURRENT COLORECTAL CANCER REPORTS 2015. [DOI: 10.1007/s11888-015-0265-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Lourensz K, Jones I. Considerations and management of a patient with three metachronous cancers in association with Lynch syndrome and ileal Crohn's disease: A case report. Int J Surg Case Rep 2015; 10:73-5. [PMID: 25805613 PMCID: PMC4430090 DOI: 10.1016/j.ijscr.2015.03.034] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2015] [Accepted: 03/17/2015] [Indexed: 12/13/2022] Open
Abstract
We describe a patient with three metachronous tumors in association with Lynch syndrome and ileal Crohn’s disease. Surgical management strategies need to be carefully considered and individualized to ensure the best oncologic and functional outcome for the patient. A sound knowledge of the clinical features of Lynch syndrome is critical to ensure adequate surveillance for early detection of anticipated neoplasms. The use of immunosuppressive drugs in the medical management of Crohn’s disease needs to be undertaken with the knowledge that such drugs might have an impact on oncologic outcome. Introduction Lynch syndrome and Crohn’s disease are two entirely separate conditions but each have major gastrointestinal characteristics and carry a substantial increase in the risk of intestinal malignancy. Their co-existence in the patient who is the subject of this report dictated the need for an individualised treatment plan to deal with both conditions adequately. Presentation of case We report a case of a 51 year old female with a past medical history that includes Lynch syndrome and small bowel Crohn’s disease. Over a period of fifteen months, she developed three separate primary metachronous tumors in her endometrium, colon and duodenum. Discussion A patient with a combination of Lynch syndrome and ileal Crohn’s disease presents significant therapeutic implications that are not usually present when these conditions are treated in isolation. Conclusion The surgical treatment of patients with Lynch syndrome requires a sound knowledge of the possible neoplastic conditions that can arise in the syndrome. Early detection is paramount, either by implementation of evidence based surveillance programs or at least by a heightened clinical awareness of the features of this disease. Ideally this will result in both reduced surgical morbidity and improved oncologic outcome. Furthermore, the medical treatment of Crohn’s disease in a patient with tumors arising from Lynch syndrome must be undertaken with at least a consideration of the possibility that the use of immunosuppressive medication might increase the risk of cancer recurrence.
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Affiliation(s)
- Kaleb Lourensz
- Colorectal Surgery Unit, Royal Melbourne Hospital, Grattan St, Parkville, Victoria 3050, Australia.
| | - Ian Jones
- Colorectal Surgery Unit, Royal Melbourne Hospital, Grattan St, Parkville, Victoria 3050, Australia; Clinical Professorial Fellow, Department of Surgery, The University of Melbourne, Victoria 3050, Australia
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42
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Liska D, Kalady MF. Colorectal Surgery in Lynch Syndrome Patients: When and How? CURRENT COLORECTAL CANCER REPORTS 2015. [DOI: 10.1007/s11888-015-0262-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
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Samadder NJ, Jasperson K, Burt RW. Hereditary and common familial colorectal cancer: evidence for colorectal screening. Dig Dis Sci 2015; 60:734-47. [PMID: 25501924 DOI: 10.1007/s10620-014-3465-z] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2014] [Accepted: 11/24/2014] [Indexed: 12/20/2022]
Abstract
Colorectal cancer (CRC) is the fourth most common cancer among men and women. Between 3 and 6% of all CRCs are attributed to well-defined inherited syndromes, including Lynch syndrome, familial adenomatous polyposis, MUTYH-associated polyposis and several hamartomatous conditions. Up to 30% of CRC cases exhibit common familial risk, likely related to a combination of inherited factors and environment. Identification of these patients through family history and appropriate genetic testing can provide estimates of cancer risk that inform appropriate cancer screening, surveillance and/or preventative interventions. This article examines the colon cancer syndromes, their genetic basis, clinical management and evidence supporting colorectal screening. It also deals with the category of common (non-syndromic) familial risk including risk determination and screening guidelines.
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Affiliation(s)
- N Jewel Samadder
- High Risk GI Cancers Program, Huntsman Cancer Institute, University of Utah, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA,
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44
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ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol 2015; 110:223-62; quiz 263. [PMID: 25645574 PMCID: PMC4695986 DOI: 10.1038/ajg.2014.435] [Citation(s) in RCA: 1060] [Impact Index Per Article: 106.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2014] [Accepted: 12/01/2014] [Indexed: 02/06/2023]
Abstract
This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (maternal and/or paternal) should be documented for all diagnoses, especially in first- and second-degree relatives. When indicated, genetic testing for a germline mutation should be done on the most informative candidate(s) identified through the family history evaluation and/or tumor analysis to confirm a diagnosis and allow for predictive testing of at-risk relatives. Genetic testing should be conducted in the context of pre- and post-test genetic counseling to ensure the patient's informed decision making. Patients who meet clinical criteria for a syndrome as well as those with identified pathogenic germline mutations should receive appropriate surveillance measures in order to minimize their overall risk of developing syndrome-specific cancers. This guideline specifically discusses genetic testing and management of Lynch syndrome, familial adenomatous polyposis (FAP), attenuated familial adenomatous polyposis (AFAP), MUTYH-associated polyposis (MAP), Peutz-Jeghers syndrome, juvenile polyposis syndrome, Cowden syndrome, serrated (hyperplastic) polyposis syndrome, hereditary pancreatic cancer, and hereditary gastric cancer.
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45
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Bikhchandani J, Lynch HT. Commentary on 'Colonoscopy screening compliance and outcomes in patients with Lynch syndrome'. Colorectal Dis 2015; 17:46-9. [PMID: 25536883 DOI: 10.1111/codi.12841] [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: 02/08/2023]
Affiliation(s)
- Jai Bikhchandani
- Creighton University, 2500 California Plaza, Omaha, Nebraska, 68102, USA
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46
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Newton K, Green K, Lalloo F, Evans DG, Hill J. Colonoscopy screening compliance and outcomes in patients with Lynch syndrome. Colorectal Dis 2015; 17:38-46. [PMID: 25213040 DOI: 10.1111/codi.12778] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2014] [Accepted: 07/15/2014] [Indexed: 12/14/2022]
Abstract
AIM Colonic surveillance reduces the lifetime risk of colorectal cancer in patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer) from 60 to 80% to 10% and confers a 7-year survival advantage. The British Society of Gastroenterologists recommends colonoscopy at least every 2 years from the age of 25. Currently in the UK, genetic diagnosis is made by a regional genetics service, and screening recommendations are made to the referring clinician. The aim of this study was to investigate compliance with and the effectiveness of large bowel surveillance in Lynch syndrome. METHOD A retrospective longitudinal study of Lynch syndrome mutation carriers on the Regional Familial Colorectal Cancer Registry under and not under screening was conducted. To investigate screening compliance, patients were included if they were alive at the start of the study. Data were gathered on timeliness, quality and outcome of screening. To examine the effectiveness of screening, the cumulative incidence of colorectal cancer was estimated using Kaplan-Meier curves and the screened population compared with patients not being screened. RESULTS A total of 227 Lynch syndrome mutation carriers were under screening at 26 hospitals. We assessed 439 colonoscopies for timeliness, of which 68% were compliant (interval < 27 months). Compliance on the 1 November 2011 was 87%. The cumulative incidence of colorectal cancer to the age of 70 was 25% (95% CI 17-32%) in the surveillance population and 81% (95% CI 78-84%) in 689 mutation-positive patients not being screened (P < 0.0001). CONCLUSION Overall, 68% of colonoscopies were on time. The incidence of colorectal cancer was greatly reduced by screening but remained significant. Patients with Lynch syndrome need proactive surveillance management.
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Affiliation(s)
- K Newton
- Department of General Surgery, Manchester Royal Infirmary, Manchester, UK
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47
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Niv Y, Moeslein G, Vasen HF, Karner-Hanusch J, Lubinsky J, Gasche C. Quality of colonoscopy in Lynch syndrome. Endosc Int Open 2014; 2:E252-5. [PMID: 26135102 PMCID: PMC4423269 DOI: 10.1055/s-0034-1377920] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2014] [Accepted: 07/07/2014] [Indexed: 12/14/2022] Open
Abstract
Lynch syndrome (LS) accounts for 2 - 4 % of all colorectal cancers. Affected family members have a germline mutation in one of the DNA mismatch repair genes MLH1, PMS2, MSH2, or MSH6, and a lifetime risk for development of colorectal cancer of 25 - 75 %. Current guidelines recommend annual to biannual surveillance colonoscopy in mutation carriers. Several factors may predict failure to prevent interval cancer in LS: more lesions in the right colon; more flat ("non polypoid") and lateral growing polyps; small adenomas may already harbor high grade dysplasia or a high percentage of villous component and become advanced adenomas; there is a short duration of the adenoma - carcinoma sequence; synchronous lesions have high prevalence; patients are younger and less tolerant to colonoscopy (need more sedation); and repeated colonoscopies are needed for lifelong surveillance (patient experience is important for compliance). In order to prevent cancer in LS patients, surveillance colonoscopy should be performed in an endoscopic unit experienced with LS, every 1 - 2 years, starting at age 20 - 25 years, or 10 years younger than the age of first diagnosis in the family (whichever is first), and yearly after the age of 40 years. Colonoscopy in LS patients should be a very meticulous and precise procedure (i. e. taking sufficient withdrawal time, documentation of such warranted), with removal of all of the polyps, special attention to the right colon and alertness to flat lesions. Following quality indicators such as successful cleansing of the colon and removal of every polyp will probably improve prevention of interval cancers. At this moment, none of the new endoscopic techniques have shown convincing superiority over conventional high resolution white light colonoscopy.
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Affiliation(s)
- Yaron Niv
- Rabin Medical Center, Tel Aviv University – Gastroenterology, Petach Tikva, Israel,Corresponding author Professor Yaron Niv, MD Rabin Medical Center39 Jabotinski StreetPetach TikvaIsrael+972-3-9210313
| | - Gabriela Moeslein
- Helios St. Josefs-Hospital – Gastroenterology, Bochum-Linden, Germany
| | - Hans F.A. Vasen
- Leiden University Medical Center – Gastroenterology, Leiden, The Netherlands
| | - Judith Karner-Hanusch
- Division of Surgery and of Gastroenterology and Hepatology and Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
| | - Jan Lubinsky
- Pomeranian Medical University – Pathology, Szczecin, Poland
| | - Christoph Gasche
- Division of Surgery and of Gastroenterology and Hepatology and Christian Doppler Laboratory on Molecular Cancer Chemoprevention, Medical University of Vienna, Vienna, Austria
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48
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Shigeyasu K, Tanakaya K, Nagasaka T, Aoki H, Fujiwara T, Sugano K, Ishikawa H, Yoshida T, Moriya Y, Furukawa Y, Goel A, Takeuchi H. Early detection of metachronous bile duct cancer in Lynch syndrome: report of a case. Surg Today 2014; 44:1975-81. [PMID: 23896635 PMCID: PMC4162978 DOI: 10.1007/s00595-013-0669-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2012] [Accepted: 06/03/2013] [Indexed: 01/08/2023]
Abstract
Lynch syndrome is an autosomal dominant disease associated with a high incidence of colorectal, endometrial, stomach, ovarian, pancreatic, ureter and renal pelvis, bile duct and brain tumors. The syndrome can also include sebaceous gland adenomas and keratoacanthomas, and carcinoma of the small bowel. The lifetime risk for bile duct cancer in patients with Lynch syndrome is approximately 2 %. The present report describes a case of Lynch syndrome with metachronous bile duct cancer diagnosed at an early stage. The patient was a 73-year-old Japanese male who underwent a successful left lobectomy of the liver, and there was no sign of recurrence for 2 years postoperative. However, this patient harbored a germline mutation in MLH1, which prompted diagnostic examinations for noncolorectal tumors when a periodic surveillance blood examination showed abnormal values of hepatobiliary enzymes. Although most patients with bile duct cancer are diagnosed at an advanced stage, the bile duct cancer was diagnosed at an early stage in the present patient due to the observation of the gene mutation and the preceding liver tumor. This case illustrates the importance of continuous surveillance for extracolonic tumors, including bile duct cancer, in patients with Lynch syndrome.
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49
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Nebgen DR, Lu KH, Rimes S, Keeler E, Broaddus R, Munsell MF, Lynch PM. Combined colonoscopy and endometrial biopsy cancer screening results in women with Lynch syndrome. Gynecol Oncol 2014; 135:85-9. [PMID: 25149916 DOI: 10.1016/j.ygyno.2014.08.017] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2014] [Revised: 08/05/2014] [Accepted: 08/08/2014] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Endometrial biopsy (EMBx) and colonoscopy performed under the same sedation is termed combined screening and has been shown to be feasible and to provide a less painful and more satisfactory experience for women with Lynch syndrome (LS). However, clinical results of these screening efforts have not been reported. The purpose of this study was to evaluate the long-term clinical outcomes and patient compliance with serial screenings over the last 10.5 years. METHODS We retrospectively analyzed the data for 55 women with LS who underwent combined screening every 1-2 years between 2002 and 2013. Colonoscopy and endometrial biopsy were performed by a gastroenterologist and a gynecologist, with the patient under conscious sedation. RESULTS Out of 111 screening visits in these 55 patients, endometrial biopsies detected one simple hyperplasia, three complex hyperplasia, and one endometrioid adenocarcinoma (FIGO Stage 1A). Seventy-one colorectal polyps were removed in 29 patients, of which 29 were tubular adenomas. EMBx in our study detected endometrial cancer in 0.9% (1/111) of surveillance visits, and premalignant hyperplasia in 3.6% (4/111) of screening visits. No interval endometrial or colorectal cancers were detected. CONCLUSIONS Combined screening under sedation is feasible and less painful than EMBx alone. Our endometrial pathology detection rates were comparable to yearly screening studies. Our results indicate that screening of asymptomatic LS women with EMBx every 1-2 years, rather than annually, is effective in the early detection of (pre)cancerous lesions, leading to their prompt definitive management, and potential reduction in endometrial cancer.
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Affiliation(s)
- Denise R Nebgen
- Department of Gynecologic Oncology and Reproductive Medicine, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
| | - Karen H Lu
- Department of Gynecologic Oncology and Reproductive Medicine, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Sue Rimes
- Department of Gynecologic Oncology and Reproductive Medicine, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Elizabeth Keeler
- Department of Gynecologic Oncology and Reproductive Medicine, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Russell Broaddus
- Department of Pathology, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Mark F Munsell
- Department of Biostatistics, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Patrick M Lynch
- Department of Gastroenterology, Hepatology, and Nutrition, The University Of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
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50
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Giardiello FM, Allen JI, Axilbund JE, Boland CR, Burke CA, Burt RW, Church JM, Dominitz JA, Johnson DA, Kaltenbach T, Levin TR, Lieberman DA, Robertson DJ, Syngal S, Rex DK. Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi-Society Task Force on colorectal cancer. Gastroenterology 2014; 147:502-26. [PMID: 25043945 DOI: 10.1053/j.gastro.2014.04.001] [Citation(s) in RCA: 346] [Impact Index Per Article: 31.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
The Multi-Society Task Force, in collaboration with invited experts, developed guidelines to assist health care providers with the appropriate provision of genetic testing and management of patients at risk for and affected with Lynch syndrome as follows: Figure 1 provides a colorectal cancer risk assessment tool to screen individuals in the office or endoscopy setting; Figure 2 illustrates a strategy for universal screening for Lynch syndrome by tumor testing of patients diagnosed with colorectal cancer; Figures 3-6 provide algorithms for genetic evaluation of affected and at-risk family members of pedigrees with Lynch syndrome; Table 10 provides guidelines for screening at-risk and affected persons with Lynch syndrome; and Table 12 lists the guidelines for the management of patients with Lynch syndrome. A detailed explanation of Lynch syndrome and the methodology utilized to derive these guidelines, as well as an explanation of, and supporting literature for, these guidelines are provided.
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Affiliation(s)
| | - John I Allen
- Yale University School of Medicine, New Haven, Connecticut
| | | | | | | | | | | | - Jason A Dominitz
- VA Puget Sound Health Care System, Seattle, Washington; University of Washington, Seattle, Washington
| | | | | | | | | | - Douglas J Robertson
- White River Junction VA Medical Center, White River Junction, Vermont; Geisel School of Medicine at Dartmouth, White River Junction, Vermont
| | - Sapna Syngal
- Brigham and Women's Hospital, Boston, Massachusetts; Dana Farber Cancer Institute, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts
| | - Douglas K Rex
- Indiana University School of Medicine, Indianapolis, Indiana
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