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Lin DI, Quintanilha JCF, Danziger N, Lang L, Levitan D, Hayne C, Hiemenz MC, Smith DL, Albacker LA, Leibowitz J, Mata DA, Decker B, Lakis S, Patel NR, Graf RP, Elvin JA, Ross JS, Pattani V, Huang RSP, Wehn AK. Pan-tumor validation of a NGS fraction-based MSI analysis as a predictor of response to Pembrolizumab. NPJ Precis Oncol 2024; 8:204. [PMID: 39277692 PMCID: PMC11401835 DOI: 10.1038/s41698-024-00679-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2024] [Accepted: 08/26/2024] [Indexed: 09/17/2024] Open
Abstract
Microsatellite instability high (MSI-H) and mismatch repair deficient (dMMR) tumor status have been demonstrated to predict patient response to immunotherapies. We developed and validated a next-generation sequencing (NGS)-based companion diagnostic (CDx) to detect MSI-H solid tumors via a comprehensive genomic profiling (CGP) assay, FoundationOne®CDx (F1CDx). To determine MSI status, F1CDx calculates the fraction of unstable microsatellite loci across >2000 loci using a fraction-based (FB) analysis. Across solid tumor types, F1CDx demonstrated a high analytical concordance with both PCR (n = 264) and IHC (n = 279) with an overall percent agreement (OPA) of 97.7% and 97.8%, respectively. As part of a retrospective bridging clinical study from KEYNOTE-158 Cohort K and KEYNOTE-164, patients with MSI-H tumors as determined by F1CDx demonstrated an objective response rate (ORR) of 43.0% to pembrolizumab. In real-world cancer patients from a deidentified clinicogenomic database, F1CDx was at least equivalent in assessing clinical outcome following immunotherapy compared with MMR IHC. Demonstrated analytical and clinical performance of F1CDx led to the pan-tumor FDA approval in 2022 of F1CDx to identify MSI-H solid tumor patients for treatment with pembrolizumab. F1CDx is an accurate, reliable, and FDA-approved method for the identification of MSI-H tumors for treatment with pembrolizumab.
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Affiliation(s)
| | | | | | | | | | - Cynthia Hayne
- Beth Israel Deaconess Medical Center, Boston, MA, USA
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Kamburova ZB, Dimitrova PD, Dimitrova DS, Kovacheva KS, Popovska SL, Nikolova SE. Lynch-like syndrome with germline WRN mutation in Bulgarian patient with synchronous endometrial and ovarian cancer. Hered Cancer Clin Pract 2023; 21:13. [PMID: 37452354 PMCID: PMC10349469 DOI: 10.1186/s13053-023-00257-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 07/11/2023] [Indexed: 07/18/2023] Open
Abstract
BACKGROUND Synchronous endometrial and ovarian cancer (SEOC) accounts for 50-70% of all synchronous gynecology cancers in women. Approximately 14% of SEOC cases are caused by Lynch syndrome (LS). The widespread introduction of "universal screening" at LS (all cases with CRC and all EC cases diagnosed before age 60 should be tested for MMR deficiency) has led to an increasing number of suspected LS cases- MMR-deficient tumors without germline mutation in the MMR genes. These cases are attributed to the so-called Lynch-like syndrome (LLS). CASE PRESENTATION We present a case of LLS with a detected germline, likely pathogenic variant in the WRN gene. The proband was a woman diagnosed with SEOC at the age of 51 years. Histology of both tumors (endometrium and ovary) was endometroid and showed loss of MLH1 and PMS protein expression. Genetic testing by next generation sequencing (NGS) detected a germline mutation (in the heterozygous state) in the WRN gene - c.4109del, p.(Asn1370ThrfsTer23) in the proband. CONCLUSIONS The presented case contributes to the etiology of LLS and confirms the need for specific genetic testing, together with genetic counseling, in hereditary cancer syndromes. The use of combined information from clinicians, pathologists, genetic counselors, and data from NGS testing for cancer predisposition, clinical surveillance, and follow-up management in women with gynecology cancers, especially SEOC, could be improved.
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Affiliation(s)
- Zornitsa Bogomilova Kamburova
- Department of Medical Genetics, Medical University - Pleven, Pleven, Bulgaria.
- Center of Medical genetics, University Hospital "Dr. Georgi Stranski", Pleven, Bulgaria.
| | - Polina Damyanova Dimitrova
- Department of Pathoanatomy, Medical University - Pleven, University Hospital "Dr. Georgi Stranski" - Pleven, Pleven, Bulgaria
| | | | | | - Savelina Lubenova Popovska
- Department of Pathoanatomy, Medical University - Pleven, University Hospital "Dr. Georgi Stranski" - Pleven, Pleven, Bulgaria
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Genitourinary manifestations of Lynch syndrome in the urological practice. Asian J Urol 2022; 9:443-450. [DOI: 10.1016/j.ajur.2022.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Revised: 05/08/2022] [Accepted: 05/16/2022] [Indexed: 11/19/2022] Open
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Pauly N, Baert T, Schmutzler R, du Bois A, Schneider S, Rhiem K, Schömig-Markiefka B, Siemanowski J, Heikaus S, Traut A, Heitz F, Prader S, Ehmann S, Harter P, Ataseven B. Modern day screening for Lynch syndrome in endometrial cancer: the KEM experience. Arch Gynecol Obstet 2021; 304:975-984. [PMID: 33710393 DOI: 10.1007/s00404-021-06006-w] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 02/11/2021] [Indexed: 12/21/2022]
Abstract
PURPOSE Current guidelines for Lynch syndrome detection in endometrial cancer (EC) patients rely either on risk evaluation, based on personal/family history, or detection of mismatch repair (MMR) deficiency on tumor tissue. We present a combined screening algorithm for Lynch syndrome. METHODS In this study, 213 consecutive patients treated for EC at Kliniken Essen-Mitte between 2014 and 2018 were included. Personal/family history was evaluated by the Amsterdam II, revised Bethesda/German-DKG criteria and prediction model PREMM5. MMR testing was performed by immunohistochemistry (IHC) and/or polymerase chain reaction (PCR) based microsatellite analysis on tumor tissue. MLH1 promoter methylation analysis was performed in case of MLH1 loss or microsatellite instability. RESULTS Based on personal/family history 2/213 (Amsterdam II), 31/213 (revised Bethesda/German-DKG) and 149/213 (PREMM5) patients were identified as at risk for Lynch syndrome. MMR analysis was performed by IHC in 51.2%, by PCR in 32.4%, and in 16.4% of patients both methods were used. MMR deficiency was detected in 20.6% (44/213). Methylation analysis was performed in 27 patients of whom, 22 (81.4%) showed MLH1 promoter hypermethylation. Only 9% of MMR deficient patients were identified as at risk for Lynch syndrome by the revised Bethesda/German-DKG criteria. A pathogenic germline mutation was discovered in 3 out of 20 patients that underwent genetic testing. None of these patients were younger than 50 years or had a family history of Lynch syndrome-associated malignancies. CONCLUSION General MMR assessment is a feasible strategy to improve the detection of Lynch Syndrome in patients with EC.
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Affiliation(s)
- Nina Pauly
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany.
| | - Thaïs Baert
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
- Department of Oncology, Laboratory of Tumour Immunology and Immunotherapy, ImmunOvar Research Group, KU Leuven, Leuven, Belgium
| | - Rita Schmutzler
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany
| | - Andreas du Bois
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
| | - Stephanie Schneider
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
| | - Kerstin Rhiem
- Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Cologne, Germany
| | | | - Janna Siemanowski
- Institute of Pathology, University Hospital Cologne, Cologne, Germany
| | | | - Alexander Traut
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
| | - Florian Heitz
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
- Department for Gynecology With the Center for Oncologic Surgery, Charité Campus Virchow-Klinikum, Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität Zu Berlin, and Berlin Institute of Health, Berlin, Germany
| | - Sonia Prader
- Department of Gynecology, Hospital Brixen, Brixen, Südtirol, Italy
| | - Sarah Ehmann
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
| | - Philipp Harter
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
| | - Beyhan Ataseven
- Department of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte (KEM), Henricistrasse 92, 45136, Essen, Germany
- Department of Obstetrics and Gynecology, University Hospital, LMU Munich, Munich, Germany
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Schubert SA, Morreau H, de Miranda NFCC, van Wezel T. The missing heritability of familial colorectal cancer. Mutagenesis 2020; 35:221-231. [PMID: 31605533 PMCID: PMC7352099 DOI: 10.1093/mutage/gez027] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2019] [Accepted: 09/05/2019] [Indexed: 02/06/2023] Open
Abstract
Pinpointing heritability factors is fundamental for the prevention and early detection of cancer. Up to one-quarter of colorectal cancers (CRCs) occur in the context of familial aggregation of this disease, suggesting a strong genetic component. Currently, only less than half of the heritability of CRC can be attributed to hereditary syndromes or common risk loci. Part of the missing heritability of this disease may be explained by the inheritance of elusive high-risk variants, polygenic inheritance, somatic mosaicism, as well as shared environmental factors, among others. A great deal of the missing heritability in CRC is expected to be addressed in the coming years with the increased application of cutting-edge next-generation sequencing technologies, routine multigene panel testing and tumour-focussed germline predisposition screening approaches. On the other hand, it will be important to define the contribution of environmental factors to familial aggregation of CRC incidence. This review provides an overview of the known genetic causes of familial CRC and aims at providing clues that explain the missing heritability of this disease.
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Affiliation(s)
- Stephanie A Schubert
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Noel F C C de Miranda
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
| | - Tom van Wezel
- Department of Pathology, Leiden University Medical Center, Leiden University, Leiden, The Netherlands
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Yamazaki H, Takeshita S, Todo Y, Matsumiya H, Shimada C, Minobe S, Tsuruta T, Kato H. Imaging-based definition of lower uterine segment carcinoma to improve the detection sensitivity of probable Lynch syndrome. Jpn J Clin Oncol 2020; 50:270-275. [PMID: 31958127 DOI: 10.1093/jjco/hyz162] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2019] [Accepted: 10/05/2019] [Indexed: 11/13/2022] Open
Abstract
OBJECTIVE The aim of this study was to investigate a magnetic resonance imaging-based definition of lower uterine segment carcinoma. METHODS We retrospectively reviewed 587 consecutive patients with endometrial cancer who underwent hysterectomy. Lower uterine segment carcinoma was determined through pathological examination and magnetic resonance imaging assessment. For imaging assessment, the location of the inner lining of the uterus was classified into four equal parts on a sagittal section image. A tumor was defined as lower uterine segment carcinoma when its thickest part was located in the second or the third part from the uterine fundus. Lower uterine segment carcinoma was further divided into lower uterine segment in a narrow sense, upon which diagnosis was exclusively based on pathological findings, and lower uterine segment in a broad sense that were the remaining lower uterine segment carcinomas except lower uterine segment carcinomas in a narrow sense. The relationship between lower uterine segment carcinoma and probable Lynch syndrome was investigated. Patients with loss of MSH2, MSH6, and PMS2 expression or those with tumors with loss of MLH1 and absence of MLH1 promoter methylation were diagnosed as probable Lynch syndrome. RESULTS Lower uterine segment carcinoma was identified in 59 (10.2%) patients. Twenty-eight (47.5%) patients were categorized as lower uterine segment in a narrow sense and 31 (52.5%) as lower uterine segment in a broad sense. Among them, probable Lynch syndrome was identified in 12 (20.3%) cases. There was no difference in clinical profiles, including the prevalence of probable Lynch syndrome between the two categories. CONCLUSIONS A magnetic resonance imaging-based expanded definition of lower uterine segment carcinoma is likely to secure characteristics equivalent to a conventional pathology-based definition of lower uterine segment carcinoma. The novel definition of lower uterine segment carcinoma might improve the detection of probable Lynch syndrome.
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Affiliation(s)
- Hiroyuki Yamazaki
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
| | - Sho Takeshita
- Department of Obstetrics and Gynecology, Ichinomiya municipal hospital, Ichinomiya, Aichi, Japan
| | - Yukiharu Todo
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
| | - Hiroko Matsumiya
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
| | - Chisa Shimada
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
| | - Shinichiro Minobe
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
| | - Tomohiko Tsuruta
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
| | - Hidenori Kato
- Division of Gynecologic Oncology, National Hospital Organization, Hokkaido Cancer Center, Sapporo, Hokkaido, Japan, and
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Lynch Syndrome in Urologic Malignancies - What Does the Urologist Need to Know? Urology 2019; 134:24-31. [PMID: 31302137 DOI: 10.1016/j.urology.2019.07.004] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2019] [Revised: 06/13/2019] [Accepted: 07/05/2019] [Indexed: 12/24/2022]
Abstract
Lynch Syndrome (LS) entails a defective DNA mismatch repair system, which is the postreplicative proofreading and editing system, ensuring our genome's integrity. LS predisposes to several cancers, most commonly colorectal and endometrial cancers. LS occurs in approximately 1 in 250-1000 people. LS is associated with urological malignancies with upper tract urothelial carcinoma the most common, although still clinically underestimated. Other urologic malignancies possibly associated with LS include bladder, prostate, testis, and renal cell carcinoma. Ascertaining their true prevalence in LS is mandatory for their and their relatives' diagnosis and treatment. Awareness regarding identifying patients at risk for LS through assessment of personal and familial oncologic history is critical among urologists.
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Bertario L, Aste H, Arrigoni A, Fracasso P, Rossini FP, Rossetti C, Valanzano R. Clinical Aspects and Management of Hereditary Non-Polyposis Colorectal Cancer (HNPCC). TUMORI JOURNAL 2018; 82:117-21. [PMID: 8644373 DOI: 10.1177/030089169608200205] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Hereditary non-polyposis colorectal cancer (HNPCC) is an autosomical dominant trasmitted disease phenotypically defined according to the “Amsterdam criteria” as follows: at least 3 affected relatives, one of whom first degree relative of other two, at least two successive generations affected. Important cardinal features are: 1 prevalent proximal location of cancers (above splenic flexure); 2 multiple synchronous or methachronous large bowel cancers; 3 early age of onset (<50 years); 4 presence of extracolonic cancers (endometrium, stomach, urinary tract, skin). The treatment is essentially surgical and total colectomy with ileo-rectum anastomosis is already proposed as standard procedure with annual endoscopic examination of retained rectum. The screening of individuals at risk, so determined by the analysis of pedigree or the results of molecular tests, must be performed every 1-2 years by colonoscopy starting around the age of 25 years. In this review are described and analysed the spectrum of the disease with particular attention to the frequency and characteristics of extracolonic cancers. Moreover, the guidelines of the surveillance and screening are reported following the data of the literature and as proposed by the International Collaborative Group (ICG-HNPCC).
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Affiliation(s)
- L Bertario
- Divisione Chirurgia Apparato Digerente, Istituto Nazionale dei Tumori, Milano, Italy
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Dillon JL, Gonzalez JL, DeMars L, Bloch KJ, Tafe LJ. Universal screening for Lynch syndrome in endometrial cancers: frequency of germline mutations and identification of patients with Lynch-like syndrome. Hum Pathol 2017; 70:121-128. [PMID: 29107668 DOI: 10.1016/j.humpath.2017.10.022] [Citation(s) in RCA: 67] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2017] [Revised: 10/17/2017] [Accepted: 10/18/2017] [Indexed: 10/18/2022]
Abstract
Lynch syndrome (LS) is an inherited clinical syndrome characterized by a high risk of colorectal, endometrial (lifetime risk of up to 60%), ovarian, and urinary tract cancers. The diagnosis is confirmed by identification of germline mutations in the DNA mismatch repair genes MLH1, PMS2, MSH2, MSH6, or EPCAM. In 2015, our institution implemented universal screening of endometrial cancer (EC) hysterectomy specimens by mismatch repair immunohistochemistry (IHC) with reflex MLH1 promoter hypermethylation analysis for tumors with loss of MLH1/PMS2 expression. Patients with tumors negative for MLH1 methylation and those with a loss of the heterodimer pair MSH2 and MSH6, or isolated loss of either PMS2 or MSH6 were referred to the Familial Cancer Program for genetic counseling and consideration of germline testing. Between May 2015 to Dec 2016, 233 EC patients were screened by IHC for LS with a median age of 63 years. Sixty tumors (27%) had abnormal IHC staining results. Fifty-one (22%) harbored heterodimeric loss of MLH1 and PMS2, 49 of which showed MLH1 promoter methylation (1 failure, 1 negative). One showed loss of MLH1/PMS2 and MSH6, 2 showed loss of MSH2/MSH6, and 6 had isolated loss of MSH6 only. Ten patients underwent genetic counseling, and germline testing was performed in 8; LS was confirmed in 5 patients (2.1%). In addition, 3 patients with negative germline testing and presumed Lynch-like syndrome were identified and offered additional somatic testing. Universal screening for LS in EC patients has yielded positive results for identification of patients at risk for this inherited syndrome.
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Affiliation(s)
- Jessica L Dillon
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Jorge L Gonzalez
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH; The Geisel School of Medicine at Dartmouth, Hanover, NH, 03755
| | - Leslie DeMars
- Department of Obstetrics and Gynecology, Dartmouth-Hitchcock Medical Center, Lebanon, NH; The Geisel School of Medicine at Dartmouth, Hanover, NH, 03755
| | - Katarzyna J Bloch
- Familial Cancer Program, Dartmouth-Hitchcock Medical Center, Lebanon, NH
| | - Laura J Tafe
- Department of Pathology and Laboratory Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, NH; The Geisel School of Medicine at Dartmouth, Hanover, NH, 03755; Norris Cotton Cancer Center, Lebanon, NH, 03756.
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Vasen HFA, Velthuizen ME, Kleibeuker JH, Menko FH, Nagengast FM, Cats A, van der Meulen-de Jong AE, Breuning MH, Roukema AJ, van Leeuwen-Cornelisse I, de Vos Tot Nederveen Cappel WH, Wijnen JT. Hereditary cancer registries improve the care of patients with a genetic predisposition to cancer: contributions from the Dutch Lynch syndrome registry. Fam Cancer 2017; 15:429-35. [PMID: 26973060 PMCID: PMC4901115 DOI: 10.1007/s10689-016-9897-1] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The Dutch Hereditary Cancer Registry was established in 1985 with the support of the Ministry of Health (VWS). The aims of the registry are: (1) to promote the identification of families with hereditary cancer, (2) to encourage the participation in surveillance programs of individuals at high risk, (3) to ensure the continuity of lifelong surveillance examinations, and (4) to promote research, in particular the improvement of surveillance protocols. During its early days the registry provided assistance with family investigations and the collection of medical data, and recommended surveillance when a family fulfilled specific diagnostic criteria. Since 2000 the registry has focused on family follow-up, and ensuring the quality of surveillance programs and appropriate clinical management. Since its founding, the registry has identified over 10,000 high-risk individuals with a diverse array of hereditary cancer syndromes. All were encouraged to participate in prevention programmes. The registry has published a number of studies that evaluated the outcome of surveillance protocols for colorectal cancer (CRC) in Lynch syndrome, as well as in familial colorectal cancer. In 2006, evaluation of the effect of registration and colonoscopic surveillance on the mortality rate associated with colorectal cancer (CRC) showed that the policy led to a substantial decrease in the mortality rate associated with CRC. Following discovery of MMR gene defects, the first predictive model that could select families for genetic testing was published by the Leiden group. In addition, over the years the registry has produced many cancer risk studies that have helped to develop appropriate surveillance protocols. Hereditary cancer registries in general, and the Lynch syndrome registry in particular, play an important role in improving the clinical management of affected families.
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Affiliation(s)
- Hans F A Vasen
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands. .,Hereditary Cancer Registry, Leiden, The Netherlands.
| | - Mary E Velthuizen
- Department of Clinical Genetics, University Medical Centre, Utrecht, The Netherlands
| | - Jan H Kleibeuker
- Department of Gastroenterology and Hepatology, University Medical Centre Groningen, Groningen, The Netherlands
| | - Fred H Menko
- Cancer Family Clinic, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Fokke M Nagengast
- Department of Gastroenterology and Hepatology, Slingerland Ziekenhuis, Doetinchem, The Netherlands
| | - Annemieke Cats
- Department of Gastroenterology and Hepatology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Andrea E van der Meulen-de Jong
- Department of Gastroenterology and Hepatology, Leiden University Medical Centre, Albinusdreef 2, 2333 ZA, Leiden, The Netherlands
| | - Martijn H Breuning
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
| | - Anne J Roukema
- Department of Surgery, Elizabeth Hospital, Tilburg, The Netherlands
| | | | | | - Juul T Wijnen
- Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands
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Lin DI, Hecht JL. Targeted Screening With Combined Age- and Morphology-Based Criteria Enriches Detection of Lynch Syndrome in Endometrial Cancer. Int J Surg Pathol 2016; 24:297-305. [PMID: 26842347 DOI: 10.1177/1066896916629782] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Endometrial cancer is associated with Lynch syndrome in 2% to 6% of cases. Adequate screening may prevent of a second cancer and incident cancers in family members via risk-reducing strategies. The goal of the study was to evaluate the detection rate of Lynch syndrome via a targeted screening approach. In 2009, we incorporated targeted Lynch syndrome screening via immunohistochemistry for MLH1, PMS2, MSH2, and MSH6, followed by MLH1 promoter hypermethylation, in select cases of endometrial carcinoma. Criteria for patient selection included (1) all patients <50 years; (2) patients of any age with tumors showing features of microsatellite instability (lower uterine segment-centered tumors, hard to classify carcinomas, increased peritumoral or tumor infiltrating lymphocytes and cases with synchronous ovarian carcinomas); (3) clinician's request based on family or personal history; and (4) ad hoc retrospective testing based on the established criteria on patients discovered on follow-up visits. By using a targeted screening approach in a 4.5-year period, approximately 2.1% of endometrial cancers (7 of 328) were potentially associated with Lynch syndrome. Therefore, targeted screening with combined age and morphology based criteria enriches detection of Lynch syndrome in endometrial cancer. However, the detection rate is lower than the rates from published series that offer universal screening.
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Affiliation(s)
- Douglas I Lin
- Beth Israel Deaconess Medical Center, Boston, MA, USA.
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Neto N, Cunha TM. Do hereditary syndrome-related gynecologic cancers have any specific features? Insights Imaging 2015; 6:545-52. [PMID: 26337050 PMCID: PMC4569599 DOI: 10.1007/s13244-015-0425-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2015] [Revised: 07/20/2015] [Accepted: 07/29/2015] [Indexed: 12/21/2022] Open
Abstract
Abstract Hereditary syndromes are responsible for 10 % of gynaecologic cancers, among which hereditary breast-ovarian cancer and hereditary non-polyposis colon cancer syndromes, known as HBOC and Lynch syndromes respectively, present the highest relative risk. The latter predisposes to endometrial cancer and both contribute to ovarian cancer. Cowden syndrome-related endometrial cancer and the increased risk of ovarian, uterine and cervical cancers associated with Peutz-Jeghers syndrome, are also demonstrated, while Li-Fraumeni syndrome patients are prone to develop ovarian and endometrial cancers. Despite these syndromes’ susceptibility to gynaecologic cancers being consensual, it is still not clear whether these tumours have any epidemiologic, clinical, pathologic or imaging specific features that could allow any of the intervening physicians to raise suspicion of a hereditary syndrome in patients without known genetic risk. Moreover, controversy exists regarding both screening and surveillance schemes. Our literature review provides an updated perspective on the evidence-based specific features of tumours related to each of these syndromes as well as on the most accepted screening and surveillance guidelines. In addition, some illustrative cases are presented. Teaching Points • HBOC syndrome is mainly associated with ovarian HGSC, which arises in fallopian fimbriae. • LS-related endometrial tumours show histological diversity and predilection for lower uterine segment. • LS and CS-related ovarian cancers are mostly of non-serous type, usually endometrioid. • Ovarian SCTAT and cervical adenoma malignum are strongly associated with PJS. • Unfortunately, hereditary gynaecologic cancers do not seem to have distinctive imaging features.
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Affiliation(s)
- Nelson Neto
- Radiology Department, Centro Hospitalar de Lisboa Ocidental, Estrada do Forte do Alto do Duque, 1449-005, Lisboa, Portugal.
| | - Teresa Margarida Cunha
- Radiology Department, Instituto Português de Oncologia de Lisboa Francisco Gentil, Rua Professor Lima Basto, 1009-023, Lisboa, Portugal
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Abstract
Lynch syndrome, which is now recognized as the most common hereditary colorectal cancer condition, is characterized by the predisposition to a spectrum of cancers, primarily colorectal cancer and endometrial cancer. We chronicle over a century of discoveries that revolutionized the diagnosis and clinical management of Lynch syndrome, beginning in 1895 with Warthin's observations of familial cancer clusters, through the clinical era led by Lynch and the genetic era heralded by the discovery of causative mutations in mismatch repair (MMR) genes, to ongoing challenges.
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Affiliation(s)
- Henry T Lynch
- Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA
| | - Carrie L Snyder
- Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA
| | - Trudy G Shaw
- Department of Preventive Medicine and Public Health, Creighton University, 2500 California Plaza, Omaha, Nebraska 68178, USA
| | - Christopher D Heinen
- Center for Molecular Medicine, University of Connecticut Health Center, 263 Farmington Avenue, Farmington, Connecticut 06030-3101, USA
| | - Megan P Hitchins
- Department of Medicine (Oncology), Stanford Cancer Institute, Stanford University, Grant Building S169, 1291 Welch Road, Stanford, California 94305, USA
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Schlussel AT, Gagliano RA, Seto-Donlon S, Eggerding F, Donlon T, Berenberg J, Lynch HT. The evolution of colorectal cancer genetics-Part 1: from discovery to practice. J Gastrointest Oncol 2014; 5:326-35. [PMID: 25276405 DOI: 10.3978/j.issn.2078-6891.2014.069] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/03/2014] [Accepted: 07/22/2014] [Indexed: 01/26/2023] Open
Abstract
Colorectal cancer (CRC) is an increasing burden on our society. Identifying those who are at the greatest risk and improving triage for treatment will have the greatest impact on healthcare. CRC is a prime paradigm for cancer genetics: the majority of disease results from stages of progression lending itself to prevention by early detection of the pre-disease (neoplastic) state. Approximately 10% represent well defined hereditary cancer syndromes. Hereditary CRC has the added benefit that many are slow growing and family members are armed with the knowledge of potential risk of associated carcinomas and empowerment to reduce the disease burden. This knowledge provides the indication for early endoscopic and/or surgical intervention for prevention or treatment of an entire family cohort. The molecular basis of CRC allows enhanced characterization of carcinomas, leading to targeted therapies.
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Affiliation(s)
- Andrew T Schlussel
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
| | - Ronald A Gagliano
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
| | - Susan Seto-Donlon
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
| | - Faye Eggerding
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
| | - Timothy Donlon
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
| | - Jeffrey Berenberg
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
| | - Henry T Lynch
- 1 Department of Surgery, Tripler Army Medical Center, Honolulu, HI, USA ; 2 The University of Arizona Cancer Center @ Dignity Health-St. Joseph's Hospital and Medical Center, Phoenix, AZ, USA ; 3 Genetics Laboratory, Huntington Medical Research Institutes, Pasadena, CA, USA ; 4 Ohana Genetics, Inc., Honolulu, HI, USA ; 5 Department of Cell & Molecular Biology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA ; 6 Department of Oncology, Tripler Army Medical Center, Honolulu, HI, USA ; 7 Hereditary Cancer Institute, Department of Preventative Medicine, Creighton University School of Medicine, Omaha, NE, USA
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Abstract
The prevalence of gastric cancer associated with Lynch syndrome (LS) is highly variable, and the underlying histologic pathway or molecular mechanisms remain unclear. From 1995 to 2012, 15 patients had been treated for both gastric and colonic adenocarcinomas and diagnosed as LS. In all cases, pathologic review, immunohistochemical analysis for mismatch-repair proteins, and microsatellite instability (MSI) tests were performed. To confirm LS, germline mutation tests and multiplex ligation-dependent probe amplification were performed. All gastric and colonic carcinomas were MSI-high and lost expressions of MLH1/PMS2 in 11 (73%) cases and MSH2/MSH6 in 4 (27%) cases. Remarkably, in a patient with LS and germline mutation of MLH1 gene, pyloric gland adenoma (PGA) transformed to adenocarcinoma during follow-up. In 2 additional cases, PGA was found adjacent to advanced gastric cancers. All PGAs in LS patients were MSI-high and lost expression of mismatch-repair proteins (MLH1/PMS2 in 2 cases and MSH2/MSH6 in 1 case), whereas none of the 14 sporadic PGAs was MSI-high or had lost expression of mismatch-repair proteins. On the basis of these observations, although very rare, we suggest the possibility that PGA may be a precursor lesion to gastric adenocarcinoma in LS and that the mismatch-repair deficient pathway of carcinogenesis is involved early in the gastric carcinogenesis pathway.
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Guillén-Ponce C, Molina-Garrido MJ, Carrato A. Follow-up recommendations and risk-reduction initiatives for Lynch syndrome. Expert Rev Anticancer Ther 2014; 12:1359-67. [DOI: 10.1586/era.12.114] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
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Abstract
BACKGROUND Endometrial cancer is responsible for approximately 74 000 deaths annually among women worldwide. It is a heterogeneous disease comprising multiple histologic subtypes. In the US, the majority of deaths from endometrial carcinoma are attributed to the serous and endometrioid subtypes. An understanding of the fundamental genomic alterations that drive serous and endometrioid endometrial carcinomas lays the foundation for the identification of molecular markers that could improve the clinical management of patients presenting with these tumors. CONTENT We review the current state of knowledge regarding somatic genomic alterations that occur in serous and endometrioid endometrial tumors. We present this knowledge in a historical context by reviewing the genomic alterations that studies of individual genes and proteins have identified over the past 2 decades or so. We then review very recent comprehensive and systematic surveys of genomic, exomic, transcriptomic, epigenomic, and proteomic alterations in serous and endometrioid endometrial carcinomas. SUMMARY The recent mapping of the genomic landscape of serous and endometrioid endometrial carcinomas has produced the first comprehensive molecular classification of these tumors, which has distinguished 4 molecular subgroups: a POLE [polymerase (DNA directed), ε, catalytic subunit] ultramutated subgroup, a hypermutated/microsatellite-unstable subgroup, a copy number-low/microsatellite-stable subgroup, and a copy number-high subgroup. This molecular classification may ultimately serve to refine the diagnosis and treatment of women with endometrioid and serous endometrial tumors.
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Affiliation(s)
- Matthieu Le Gallo
- Cancer Genetics Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD
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19
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Abstract
Lynch syndrome has classically been defined by several predominant malignancies. Initial clinical criteria for diagnosis of Lynch syndrome would miss 40% of affected individuals. As time has passed, our understanding of Lynch syndrome has evolved and will continue to do so. The number of cancer types that are included in the Lynch phenotype is growing. This has allowed clinicians to redefine Lynch syndrome, at risk populations, screening needs, and diagnostic criteria. Inclusion of extracolonic malignancies and alternative genetic pathways gives new insight into the true prevalence and penetrance of Lynch syndrome.
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Affiliation(s)
- Brian J Bansidhar
- Department of Colon and Rectal Surgery, Saint Vincent Health Center, Erie, Pennsylvania
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20
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Phenotypic heterogeneity of hereditary gynecologic cancers: a report from the Creighton hereditary cancer registry. Fam Cancer 2013; 12:719-40. [DOI: 10.1007/s10689-013-9651-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
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21
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van Duijnhoven FJB, Botma A, Winkels R, Nagengast FM, Vasen HFA, Kampman E. Do lifestyle factors influence colorectal cancer risk in Lynch syndrome? Fam Cancer 2013; 12:285-93. [DOI: 10.1007/s10689-013-9645-8] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
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22
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Abstract
It is estimated that 5% to 10% of pancreatic cancer is familial. Although there is evidence of a major pancreatic cancer susceptibility gene, the majority of families with multiple cases of pancreatic cancer do not have an identifiable causative gene or syndrome. However, a subset of pancreatic cancer is attributable to known inherited cancer predisposition syndromes, including several hereditary breast cancer genes (BRCA1, BRCA2, and PALB2), CDKN2A, hereditary pancreatitis, hereditary nonpolyposis colorectal cancer, and Peutz-Jeghers syndrome. In addition to explaining a proportion of familial pancreatic cancer, individuals with these conditions are at increased risk for pancreatic cancer. Relatives from familial pancreatic cancer kindreds without one of these identifiable syndromes may have as high as a 32-fold risk of pancreatic cancer, depending on the number of affected first-degree relatives. Such high-risk individuals may benefit from increased surveillance, and strategies for early detection of pancreatic cancer are under evaluation.
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Skeldon SC, Semotiuk K, Aronson M, Holter S, Gallinger S, Pollett A, Kuk C, van Rhijn B, Bostrom P, Cohen Z, Fleshner NE, Jewett MA, Hanna S, Shariat SF, Van Der Kwast TH, Evans A, Catto J, Bapat B, Zlotta AR. Patients with Lynch syndrome mismatch repair gene mutations are at higher risk for not only upper tract urothelial cancer but also bladder cancer. Eur Urol 2012; 63:379-85. [PMID: 22883484 DOI: 10.1016/j.eururo.2012.07.047] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 07/25/2012] [Indexed: 12/13/2022]
Abstract
BACKGROUND Lynch syndrome (LS), or hereditary nonpolyposis colorectal cancer, is caused by mutations in mismatch repair (MMR) genes. An increased risk for upper tract urothelial carcinoma (UTUC) has been described in this population; however, data regarding the risk for bladder cancer (BCa) are sparse. OBJECTIVE To assess the risk of BCa in MMR mutation carriers and suggest screening and management recommendations. DESIGN, SETTING, AND PARTICIPANTS Cancer data from 1980 to 2007 were obtained from the Familial Gastrointestinal Cancer Registry in Toronto for 321 persons with known MMR mutations: mutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); mutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); mutS homolog 6 (E. coli) (MSH6); and PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Standardized incidence ratios from the Ontario Cancer Registry, using the Surveillance Epidemiology and End Results public database, were used to compare cancer risk in patients with MMR mutations with the Canadian population. Microsatellite instability analysis and immunohistochemistry (IHC) of the MMR proteins were also performed and the results compared with matched sporadic bladder tumors. RESULTS AND LIMITATIONS Eleven of 177 patients with MSH2 mutations (6.21%, p<0.001 compared with the Canadian population) were found to have BCa, compared with 3 of 129 patients with MLH1 mutations (2.32%, p>0.05). Of these 11 tumors, 81.8% lacked expression of MSH2 on IHC, compared with the matched sporadic cases, which all displayed normal expression of MSH2 and MLH1. The incidence of UTUC among MSH2 carriers was 3.95% (p<0.001), and all tumors were found to be deficient in MSH2 expression on IHC. Mutations in the intron 5 splice site and exon 7 of the MSH2 gene increased the risk of urothelial cancer. Limitations include possible inflated risk estimates due to ascertainment bias. CONCLUSIONS LS patients with MSH2 mutations are at an increased risk for not only UTUC but also BCa and could be offered appropriate screening.
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Affiliation(s)
- Sean C Skeldon
- Department of Surgical Oncology, Urology, Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada
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25
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Clinicopathological features and management of cancers in lynch syndrome. PATHOLOGY RESEARCH INTERNATIONAL 2012; 2012:350309. [PMID: 22619739 PMCID: PMC3350853 DOI: 10.1155/2012/350309] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 12/02/2011] [Accepted: 02/28/2012] [Indexed: 12/21/2022]
Abstract
Lynch syndrome (LS) is characterized by an autosomal dominant inheritance of the early onset of colorectal cancer (CRC) and endometrial cancer, as well as increased risk for several other cancers including gastric, urinary tract, ovarian, small bowel, biliary tract, and brain tumors. The syndrome is due to a mutation in one of the four DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6, or PMS2. The majority of LS patients and families can now be identified, and the underlying mutation detected using genetic diagnostics. Regular surveillance for CRC and endometrial cancer has proved beneficial for mutation carriers. However, screening for other tumors is also recommended even though experiences in the screening of these tumors is limited. Prophylactic colectomy, prophylactic hysterectomy, and bilateral salpingo-oophorectomy may be reasonable options for selected patients with LS. This paper describes the features and management of LS.
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26
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Garg K, Soslow RA. Familial Tumors of the Uterine Corpus. Surg Pathol Clin 2011; 4:243-59. [PMID: 26837294 DOI: 10.1016/j.path.2010.12.002] [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: 10/18/2022]
Abstract
Women with Lynch syndrome are at considerable risk for developing endometrial carcinoma, but current screening guidelines for detection of Lynch syndrome focus almost exclusively on colorectal carcinoma. Lynch syndrome associated colorectal and endometrial carcinomas have some important differences with implications for screening strategies. These differences are discussed in this review, along with the most effective screening criteria and testing methods for detection of Lynch syndrome in endometrial carcinoma patients.
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Affiliation(s)
- Karuna Garg
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
| | - Robert A Soslow
- Department of Pathology, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
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27
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Drescher KM, Sharma P, Lynch HT. Current hypotheses on how microsatellite instability leads to enhanced survival of Lynch Syndrome patients. Clin Dev Immunol 2010; 2010:170432. [PMID: 20631828 PMCID: PMC2901607 DOI: 10.1155/2010/170432] [Citation(s) in RCA: 47] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2010] [Accepted: 04/13/2010] [Indexed: 01/20/2023]
Abstract
High levels of microsatellite instability (MSI-high) are a cardinal feature of colorectal tumors from patients with Lynch Syndrome. Other key characteristics of Lynch Syndrome are that these patients experience fewer metastases and have enhanced survival when compared to patients diagnosed with microsatellite stable (MSS) colorectal cancer. Many of the characteristics associated with Lynch Syndrome including enhanced survival are also observed in patients with sporadic MSI-high colorectal cancer. In this review we will present the current state of knowledge regarding the mechanisms that are utilized by the host to control colorectal cancer in Lynch Syndrome and why these same mechanisms fail in MSS colorectal cancers.
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Affiliation(s)
- Kristen M Drescher
- Department of Medical Microbiology and Immunology, Creighton University School of Medicine, Omaha, NE 68178, USA.
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Cancer genetics and reproduction. Best Pract Res Clin Obstet Gynaecol 2009; 24:3-18. [PMID: 19864186 DOI: 10.1016/j.bpobgyn.2009.08.002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2009] [Accepted: 08/05/2009] [Indexed: 01/07/2023]
Abstract
Cancers of the reproductive organs (i.e., ovaries, uterus and testes), like other cancers, occur as a result of a multi-stage interaction of genetic and environmental factors. A small proportion of cancers of the reproductive organs occur as part of a recognised cancer syndrome, as a result of inheritance of mutations in highly penetrant cancer susceptibility genes (e.g., BRCA1, BRCA2, MLH1 or MSH2). Recognition of individuals and families with inherited cancer predisposition syndromes and individuals at high risk due to familial cancer clustering is fundamentally important for the management and treatment of the current cancer and for future prevention of further cancers for the individual and their extended family.
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29
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Abstract
One of the main challenges in the clinical management of familial colorectal cancer (CRC) remains the overlap of syndromes with different underlying genetic causes and the differentiated risk management of colorectal and associated malignancies. The Lynch syndrome (hereditary non-polyposis colorectal cancer, HNPCC) is characterized by the development of colorectal, endometrial, gastric and other cancers and is caused by a mutation in one of the mismatch repair (MMR) genes. Microsatellite instability (MSI) and/or immunohistochemistry (IHC) are important prognostic factors and may predict the response to chemotherapy. Familial adenomatous polyposis (FAP) may be seen as a counterpart to Lynch syndrome, responsible for <1% of all CRC cases. Recently the MUTYH gene has been identified as a further polyposis gene. The associated disorder has been termed MYH-associated polyposis (MAP) and displays an autosomal recessive pattern of inheritance. For clinical management, distinguishing between Lynch syndrome, attenuated FAP and MAP is important for risk assessment, surveillance recommendations and indication for prophylactic surgery.
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30
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Stigliano V, Assisi D, Cosimelli M, Palmirotta R, Giannarelli D, Mottolese M, Mete LS, Mancini R, Casale V. Survival of hereditary non-polyposis colorectal cancer patients compared with sporadic colorectal cancer patients. J Exp Clin Cancer Res 2008; 27:39. [PMID: 18803843 PMCID: PMC2559820 DOI: 10.1186/1756-9966-27-39] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2008] [Accepted: 09/19/2008] [Indexed: 01/26/2023] Open
Abstract
BACKGROUND Patients with hereditary non-poliposys colorectal cancer (HNPCC) have better prognosis than sporadic colorectal cancer (CRC). Aim of our retrospective study was to compare the overall survival between sporadic CRC and HNPCC patients. METHODS We analyzed a cohort of 40 (25 males and 15 females) HNPCC cases with a hospital consecutive series of 573 (312 males and 261 females) sporadic CRC observed during the period 1970-1993. In 15 HNPCC patients we performed mutational analysis for microsatellite instability. Survival rates were calculated by Kaplan-Meier method and compared with log rank test. RESULTS The median age at diagnosis of the primary CRC was 46.8 years in the HNPCC series versus 61 years in sporadic CRC group. In HNPCC group 85% had a right cancer location, vs. 57% in the sporadic cancer group. In the sporadic cancer group 61.6% were early-stages cancer (Dukes' A and B) vs. 70% in the HNPCC group (p = ns). The crude 5-years cumulative survival after the primary CRC was 94.2% in HNPCC patients vs. 75.3% in sporadic cancer patients (p < 0.0001). CONCLUSION Our results show that overall survival of colorectal cancer in patients with HNPCC is better than sporadic CRC patients. The different outcome probably relates to the specific tumorigenesis involving DNA mismatch repair dysfunction.
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Affiliation(s)
- Vittoria Stigliano
- Gastroenterology and Digestive Endoscopic Unit, Regina Elena Cancer Institute Via Elio Chianesi 53, 00144 Rome, Italy
| | - Daniela Assisi
- Gastroenterology and Digestive Endoscopic Unit, Regina Elena Cancer Institute Via Elio Chianesi 53, 00144 Rome, Italy
| | - Maurizio Cosimelli
- Department of Surgery, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Raffaele Palmirotta
- Department of Laboratory Medicine and Advanced Biotechnologies IRCCS San Raffaele Pisana, Via della Pisana 235, 00163 Rome, Italy
| | - Diana Giannarelli
- Biostatistic Unit, Regina Elena Cancer Institute Via Elio Chianesi 53, 00144 Rome, Italy
| | - Marcella Mottolese
- Department of Pathology Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy
| | - Lupe Sanchez Mete
- Gastroenterology and Digestive Endoscopic Unit, Regina Elena Cancer Institute Via Elio Chianesi 53, 00144 Rome, Italy
| | - Raffaello Mancini
- Department of Surgery, Regina Elena Cancer Institute, Via Elio Chianesi 53, 00144, Rome, Italy
| | - Vincenzo Casale
- Gastroenterology and Digestive Endoscopic Unit, Regina Elena Cancer Institute Via Elio Chianesi 53, 00144 Rome, Italy
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31
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Ponz de Leon M, Bertario L, Genuardi M, Lanza G, Oliani C, Ranzani GN, Rossi GB, Varesco L, Venesio T, Viel A. Identification and classification of hereditary nonpolyposis colorectal cancer (Lynch syndrome): adapting old concepts to recent advancements. Report from the Italian Association for the study of Hereditary Colorectal Tumors Consensus Group. Dis Colon Rectum 2007; 50:2126-34. [PMID: 17899274 DOI: 10.1007/s10350-007-9071-9] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2007] [Revised: 05/15/2007] [Accepted: 06/19/2007] [Indexed: 02/08/2023]
Abstract
Knowledge about hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome clearly evolved during the last 10 to 15 years much more rapidly than in the past century. Consequently, long-established concepts and attitudes that held for many years should now be changed or updated. With regard to classification, we suggest maintaining the eponym "Lynch syndrome" for families that have a well-documented deficiency of the DNA mismatch repair system, whereas "clinical hereditary nonpolyposis colorectal cancer" should be reserved for those families that meet the Amsterdam criteria but without evidence of mismatch repair impairment. Any family (or individual) meeting one or more of the Bethesda criteria can be considered as suspected HNPCC. For the identification of hereditary colorectal cancer molecular screening or the pedigree analysis show advantages and disadvantages; the ideal would be to combine the two approaches. Diffusion of the microsatellite instability test and of immunohistochemistry in the pathology laboratories might render in the immediate future molecular screening more realistic. Strict endoscopic surveillance of family members at risk (with first colonoscopy at age 20-25 years and then every 2-3 years) is needed only in families with documented alterations of the DNA mismatch repair. To a certain extent, our conclusions were similar to the recently proposed "European guidelines for the clinical management of HNPCC," although we prefer the term "clinical hereditary nonpolyposis colorectal cancer," instead of familial colorectal cancer, for families meeting the Amsterdam criteria but not having evidence of mismatch repair impairment.
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Affiliation(s)
- Maurizio Ponz de Leon
- Dipartimento di Medicine e Specialità Mediche, Università di Modena e Reggio Emilia, Via del Pozzo 71, 41100, Modena, Italy.
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32
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Dionigi G, Bianchi V, Rovera F, Boni L, Annoni M, Castano P, Villa F, Dionigi R. Genetic alteration in hereditary colorectal cancer. Surg Oncol 2007; 16 Suppl 1:S11-5. [PMID: 18023570 DOI: 10.1016/j.suronc.2007.10.020] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Colorectal cancer is a major cause of morbidity and mortality. Both genetic and environmental factors contribute to cancer aetiology. About 15-20% of all colorectal cancers are familial. Approximately 6% of colorectal cancers can be attributed to recognizable heritable germline mutations. The discovery of genes responsible for inherited forms of colorectal cancer have the potential to improve cancer risk assessment and counselling. Genetic testing for hereditary forms of colorectal cancer can confirm or reject diagnoses at the molecular level, determine surveillance intervals for at-risk persons, decrease the cost of surveillance by risk stratification, aid in surgical and chemoprevention decision-making, and help patients in family and career planning. This paper reviews the genetics behind genes and molecular study of the hereditary colorectal cancer. This may help the medical professionals especially internists, gastroenterologists, and oncologists to update their knowledge in this field.
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Affiliation(s)
- G Dionigi
- Department of Surgical Sciences, University of Insubria, Viale Borri 57, 21100 Varese, Italy.
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33
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Geary J, Sasieni P, Houlston R, Izatt L, Eeles R, Payne SJ, Fisher S, Hodgson SV. Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer 2007; 7:163-72. [PMID: 17939062 DOI: 10.1007/s10689-007-9164-6] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2007] [Accepted: 10/01/2007] [Indexed: 12/26/2022]
Abstract
The family histories of 130 individuals with documented hereditary non-polyposis colorectal cancer (HNPCC) (caused by mutations in mismatch-repair (MMR) genes MSH2 (n = 64), MLH1 (n = 62) or MSH6 (n = 4)) were obtained, and incidence of cancers in those families was compared to that in the general population. There were a total of 982 cancers in 723 individuals. Colorectal cancer (CRC) was the commonest type (64% and 55% in individuals from families with germline MLH1 and MSH2 mutations respectively). Median age at diagnosis of first CRC in MSH6 mutation families was 59 years compared to 45 years in both MLH1 and MSH2 mutation families. The relative risk (RR) of endometrial cancer was 55 in MSH2 mutation families, compared with 27 in MLH1 mutation families, and 37 in MSH6 mutation families; median age at diagnosis 49 years. Even within MSH2 families, endometrial cancer tended to cluster, with 28 of the 58 cases coming from families with three or more cases (P < 0.001). Absolute risk of endometrial cancer in MLH1 families was still greater than any other cancer (other than CRC). 5% of cancers in both MLH1 and MSH2 mutation families were gastric (RR = 12); 53% of these were diagnosed before 50 years. Seven cases of small intestinal cancer occurred in MSH2 and MLH1 mutation families (RR = 26). There were 13 cases of cancer of the ureter; all were in MSH2 families. These cancers tended to cluster within families (P < 0.001); three of seven families with urothelial cancer had such cases in two or more individuals; two others had kidney cancer. Nineteen of 27 ovarian cancers (70%) were in MSH2 mutation families and 70% of these were diagnosed before age 50 years. There were 9 cases of sebaceous skin cancer, 3 in two MLH1 and 6 in four MSH2 mutation families. Of 22 pancreatic cancers, 14 were known to be diagnosed before 60 years. Breast cancer RR was 1.7 overall. The type of mutation (truncating or other type, and site of mutation) showed no obvious correlation with the presence or absence of extra-colonic cancers in families.
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Affiliation(s)
- Johanne Geary
- Department of Medical Genetics, St George's University of London, Cranmer Terrace, London SW17 0RE, UK
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de Jong AE, Nagengast FM, Kleibeuker JH, van de Meeberg PC, van Wijk HJ, Cats A, Griffioen G, Vasen HFA. What is the appropriate screening protocol in Lynch syndrome? Fam Cancer 2006; 5:373-8. [PMID: 16826316 DOI: 10.1007/s10689-006-0008-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2005] [Accepted: 05/10/2006] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Lynch syndrome families have a substantial risk of developing colorectal cancer (CRC). The recommended surveillance protocol includes colonoscopy every 2 years from age 20-25 years. It is yet unknown whether annual screening of patients aged 40-60 years is more effective than bi-annual screening, whether patients who had an adenoma removed should be re-examined after a year and whether surveillance of second-degree relatives is indicated. The aim of this study was to address these issues. METHODS All carriers of a mismatch repair gene mutation who participated in the surveillance program were selected from the Dutch Lynch syndrome registry. The results of colonoscopy were prospectively collected. RESULTS A total of 666 mutation carriers were identified in 110 families. Fourty-one CRCs were detected during endoscopic follow-up, of which 34 (83%) were diagnosed between age 40 and 60 years. In five of 34 patients, CRC was diagnosed within 1 year after colonoscopy, eight cancers were diagnosed between 1 and 2 years and the remaining tumors more than 2 years after colonoscopy. All eight CRCs detected between 1 and 2 years were at local stage. At least one adenoma was diagnosed at 141 examinations. The risk of developing CRC during follow-up in carriers with an adenoma was similar as in carriers without an adenoma at the previous colonoscopy. 280 parent-child couples with at least one Lynch syndrome-related carcinoma were identified in 110 families. In only 19 (6.8%) of these couples, CRC developed earlier in the child than an Lynch syndrome-associated cancer in the parent. CONCLUSION The current surveillance protocol, i.e., bi-annual colonoscopy in first-degree relatives independent of age and endoscopic findings, appears to be appropriate.
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Affiliation(s)
- A E de Jong
- The Netherlands Foundation for the Detection of Hereditary Tumours, Leiden University Medical Center, Poortgebouw Zuid, 2333 AA, Leiden, The Netherlands
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Maul JS, Warner NR, Kuwada SK, Burt RW, Cannon-Albright LA. Extracolonic cancers associated with hereditary nonpolyposis colorectal cancer in the Utah Population Database. Am J Gastroenterol 2006; 101:1591-6. [PMID: 16863565 DOI: 10.1111/j.1572-0241.2006.00636.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND The data describing the extracolonic cancers associated with hereditary nonpolyposis colorectal cancer (HNPCC) are variable. METHODS We ascertained all Amsterdam I criteria-positive pedigrees (N = 18) in the Utah Population Database (UPDB). We identified the extracolonic cancers in the colorectal cancer cases (N = 65) in these pedigrees, and in their first- (N = 509) and second-degree (N = 1,611) relatives. Standardized morbidity ratios were estimated by comparing the observed rates of extracolonic cancer in defined sets of relatives of probands with population expected rates estimated internally from the UPDB. RESULTS The extracolonic cancers observed in significant excess in the 65 Amsterdam I criteria-positive colorectal cancer (CRC) cases in the UPDB were uterine (N = 3, p = 0.003), lip (N = 2, p = 0.007), stomach (N = 2, p = 0.009), female genitalia (N = 1, p = 0.004) and larynx (N = 1, p = 0.05). Extracolonic cancers observed in significant excess in the 509 first-degree relatives of the 65 colorectal cancer (CRC) cases in these Amsterdam I criteria pedigrees included: thyroid (N = 5, p = 0.0002) and prostate (N = 19, p = 0.002). Thyroid cancer (N = 6, p = 0.003) was found in significant excess in the second-degree relatives of the Amsterdam I criteria-positive CRC cases. CONCLUSIONS In this population-based examination of the extracolonic cancers at excess in classic HNPCC pedigrees (selected by Amsterdam I criteria) we not only observed many of the same cancers previously reported to be associated with HNPCC in both CRC probands and their relatives, but also identified several previously unreported associations. Although our sample size is small, this study is population based, lacks ascertainment and recall bias, and benefits from uniform, consistent diagnoses of all cancers in a statewide registry.
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Affiliation(s)
- John Scott Maul
- Department of Cancer Outreach and Prevention, Huntsman Cancer Institute, Salt Lake City, Utah, USA
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Möslein G, Ohmann C, Wenzel M. [Prophylactic surgery for hereditary non-polyposis colorectal cancer]. Chirurg 2005; 76:1135-44. [PMID: 16292564 DOI: 10.1007/s00104-005-1114-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/25/2022]
Abstract
The most frequent hereditary colorectal cancer predisposition is Lynch syndrome, or hereditary non-polyposis colorectal cancer. The option of prophylactic surgery relies on the penetrance of the genetic defect and the heterogeneity of the condition. Since 20% of all mutation carriers never move on to develop cancer, the purely prophylactic setting is not indicated. However, when colorectal cancer is diagnosed, the question arises if the patient may benefit from extended surgery -- total colectomy or (restorative) proctocolectomy. These patients should be entered into the ongoing prospective-randomized study by German Cancer Aid (http://www.hnpcc-studie.de). Due to substantially increased cancer risk and poor surveillance options, the endometrium and stomach are also subject to the question of prophylactic intervention.
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Affiliation(s)
- G Möslein
- Allgemein- und Viszeralchirurgie, Coloproktologie, St. Josefs Hospital Bochum-Linden.
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Lynch PM. Cancer screening guidelines and prevention factors for high-risk patients with a family history of colorectal cancer. CURRENT COLORECTAL CANCER REPORTS 2005. [DOI: 10.1007/s11888-005-0007-2] [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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Abstract
The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is due to mutations in the APC gene. HNPCC is due to a mutation in one of at least five mismatch repair genes. Identification of individuals with these conditions is important because colon cancer will occur in approximately 80% and onset is early. For FAP, protein truncation testing will identify the vast majority of mutations. For HNPCC, 80%-95% can be identified by microsatellite instability testing. A current U.S. study reports that 12% of consecutive colorectal cancers have high microsatellite instability and that, of this 12%, 25% have detectable mutations of MLH1, MSH2, or MSH6. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, offering of testing to relatives, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance.
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Affiliation(s)
- Peter T Rowley
- Department of Medicine and Division of Genetics, University of Rochester, Rochester, New York 14642, USA.
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Lucci-Cordisco E, Zollino M, Baglioni S, Mancuso I, Lecce R, Gurrieri F, Crucitti A, Papi L, Neri G, Genuardi M. A novel microdeletion syndrome with loss of the MSH2 locus and hereditary non-polyposis colorectal cancer. Clin Genet 2005; 67:178-82. [PMID: 15679831 DOI: 10.1111/j.1399-0004.2004.00390.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Constitutional chromosome deletions can predispose to the development of cancer with the phenotypic characteristics of inherited cancer syndromes, when the deleted region encompasses a tumour suppressor gene. Examples of such conditions are represented by the cytogenetic deletions associated with retinoblastoma, Wilms tumour and familial adenomatous polyposis. So far, no constitutional deletions involving the genes implicated in hereditary non-polyposis colorectal cancer (HNPCC) have been identified. This may be at least partially because of the lack of distinctive phenotypic manifestations in HNPCC. We describe the first case of a constitutional microdeletion associated with HNPCC. Suspicion of a microdeletion was prompted by the association of mental retardation, postnatal growth deficiency, minor congenital anomalies and early onset (37 years) sporadic colon cancer. The patient was found to harbour a microdeletion within chromosome 2p16-p21, including the MSH2 gene. Since there are very few reports of deletions of the 2p16-p21 region, our observation sets the grounds for the definition of a novel multiple congenital anomaly/mental retardation/cancer microdeletion syndrome.
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Affiliation(s)
- E Lucci-Cordisco
- Institute of Medical Genetics, Catholic University A. Gemelli School of Medicine, Rome, Italy
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Abstract
The principal Mendelian disorders predisposing to colorectal cancer are familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). FAP is caused by mutations in the adenomatous polyposis coli (APC) gene. HNPCC is caused by a mutation in one of at least five mismatch repair genes. It is important to identify individuals with these conditions because colon cancer will occur in at least 80% and onset is earlier than in the general population. Potential benefits of identification include improved compliance with recommended surveillance, early detection of polyps, reduction in cancer mortality, and reassurance for relatives found to be negative with attendant savings in the time and expense of surveillance. For classic FAP, the large number of polyps readily identifies affected persons. For HNPCC, identification of individuals meriting DNA sequencing requires either recognition of a suspect family history or finding high microsatellite instability in a tumor. Individuals accepting the offer of genetic counseling and DNA testing often have more cancers in their family, are motivated to inform relatives, have a larger social network, and have more confidence in their coping ability. Individuals who decline are often concerned about their own or their family's emotional reaction or fear discrimination.
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Affiliation(s)
- Peter T Rowley
- Department of Medicine and Division of Genetics, University of Rochester, Rochester, NY 14642, USA.
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Delaunoit T, Neczyporenko F, Limburg PJ, Erlichman C. Pathogenesis and risk factors of small bowel adenocarcinoma: a colorectal cancer sibling? Am J Gastroenterol 2005; 100:703-10. [PMID: 15743371 DOI: 10.1111/j.1572-0241.2005.40605.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Small bowel adenocarcinoma (SBA) is a very rare entity accounting for one-fourth of the small intestine neoplasms. Usually accompanied by nonspecific symptoms occurring late in the course of the disease, they are associated with a dismal prognosis. It appears that SBA shares several genetic characteristics with large bowel tumors, but also has unique features. The purpose of this article is to review pathogenesis and risks factors of SBA to better understand its molecular features as well as its resemblances and dissimilarities with colorectal cancer (CRC). Better understanding of sporadic and hereditary genetic pathways potentially involved will undoubtedly lead to better prevention and therapeutic management of this rare but aggressive disease.
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Affiliation(s)
- Thierry Delaunoit
- Department of Oncology, Molecular Medicine Program, and Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA
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de Jong AE, van Puijenbroek M, Hendriks Y, Tops C, Wijnen J, Ausems MGEM, Meijers-Heijboer H, Wagner A, van Os TAM, Bröcker-Vriends AHJT, Vasen HFA, Morreau H. Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 2004; 10:972-80. [PMID: 14871975 DOI: 10.1158/1078-0432.ccr-0956-3] [Citation(s) in RCA: 173] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE Immunohistochemistry (IHC) and microsatellite instability (MSI) analysis can be used to identify patients with a possible DNA mismatch repair defect [hereditary nonpolyposis colorectal carcinoma (HNPCC)]. The Bethesda criteria have been proposed to select families for determination of MSI. The aims of this study were to assess the yield of MSI analysis in families suspected for HNPCC, to compare the results of immunohistochemical staining and MSI analysis, and to assess the additional value of PMS2 staining. EXPERIMENTAL DESIGN Clinical data and tumors were collected from 725 individuals from 631 families with suspected HNPCC. MSI analysis was performed using eight markers including the 5 National Cancer Institute markers. Four immunohistochemical staining antibodies were used (MLH1, MSH2, MSH6 and PMS2). RESULTS A MSI-H (tumors with instability for >30% of the markers) phenotype in colorectal cancers (CRCs) was observed in 21-49% of families that met the various Bethesda criteria. In families with three cases of CRC diagnosed at age > 50 years, families with a solitary case of CRC diagnosed between ages 45 and 50 years, and families with one CRC case and a first-degree relative with a HNPCC-related cancer, one diagnosed between ages 45 and 50 years (all Bethesda-negative families), the yield of MSI-H was 10-26%. Immunohistochemical staining confirmed the MSI results in 93% of the cases. With IHC, adding PMS2 staining led to the identification of an additional 23% of subjects with an hMLH1 germ-line mutation (35 carriers were tested). CONCLUSIONS The Bethesda guidelines for MSI analysis should include families with three or more cases of CRC diagnosed at age > 50 years. The age at diagnosis of CRC in the original guidelines should be raised to 50 years. Routine IHC diagnostics for HNPCC should include PMS2 staining.
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Affiliation(s)
- Andrea E de Jong
- Department of Gastroenterology, Leiden University Medical Center, Albinusdreef 2, 2300 RC Leiden, the Netherlands
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Medina-Arana V, Barrios Y, Fernández-Peralta A, Jiménez A, Salido E, González F, González-Aguilera JJ. Tumour spectrum of non-polyposis colorectal cancer (Lynch syndrome) on the island of Tenerife and influence of insularity on the clinical manifestations. Eur J Cancer Prev 2004; 13:27-32. [PMID: 15075785 DOI: 10.1097/00008469-200402000-00005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Colorectal cancer is a complex disease from a genetic point of view because both genetic and environmental factors interact in its development. Only familial adenomatous polyposis (FAP) follows mendelian genetics, in that mutations of the APC gene lead to development of the tumours. Lynch syndrome is the most frequent form of hereditary colorectal cancer and appears to be associated with other types of extracolonic cancers. The genetic basis has been established as a defect in DNA mismatch repair genes, and there is genetic heterogeneity due to the involvement of several genes in this system. Germinal mutations in these genes predispose to appearance of the syndrome. The aim of this study is to describe the tumoral spectrum of 10 families, comprising a total of 488 individuals, from the island of Tenerife (Canary Islands) and to assess whether the geographical isolation of this population has changed any features of the tumoral spectrum of the syndrome in comparison with studies that cover larger geographical areas with more genetic exchange. From our results we can conclude that the genetic drift and consanguinity in this population with a demographic history of isolation did not significantly alter the tumoral spectrum of the syndrome. Our data confirm that families affected by Lynch syndrome are a high-risk population and should be closely monitored, since their careful supervision has been shown to be useful in preventing cancer. We also emphasize the importance of developing a complete family history that permits these families to be identified together with a mutational screening of DNA mismatch repair genes (mainly MLH1 and MSH2 genes) with the aim of a possible identification of members of a family that should be carefully monitored (the carriers of germline mutations in these genes), whereas the remaining members, originally, are no more at risk than the general population.
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Affiliation(s)
- V Medina-Arana
- Servicio de Cirugía General y Digestiva, Hospital Universitario de Canarias. Ofra-La Cuesta 38071, La Laguna, Tenerife, Spain
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Rafnar T, Thorlacius S, Steingrimsson E, Schierup MH, Madsen JN, Calian V, Eldon BJ, Jonsson T, Hein J, Thorgeirsson SS. The Icelandic Cancer Project--a population-wide approach to studying cancer. Nat Rev Cancer 2004; 4:488-92. [PMID: 15170451 DOI: 10.1038/nrc1371] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Thorunn Rafnar
- Iceland Genomics Corporation, Snorrabraut 60, 105 Reykjavik, Iceland
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De Jong AE, Morreau H, Van Puijenbroek M, Eilers PHC, Wijnen J, Nagengast FM, Griffioen G, Cats A, Menko FH, Kleibeuker JH, Vasen HFA. The role of mismatch repair gene defects in the development of adenomas in patients with HNPCC. Gastroenterology 2004; 126:42-8. [PMID: 14699485 DOI: 10.1053/j.gastro.2003.10.043] [Citation(s) in RCA: 133] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
BACKGROUND AND AIMS The adenoma-carcinoma sequence in hereditary nonpolyposis colorectal cancer (HNPCC) is accelerated. It remains unknown whether the mismatch repair (MMR) defect also promotes the development of adenomas. The aim of this study was to compare the risk of developing colorectal adenoma and carcinoma in HNPCC carriers and noncarriers (controls) and to compare the features of adenomas in both groups. METHODS Eighty-six families with a known MMR gene mutation from the Dutch HNPCC Registry were analyzed. Subjects with known mutation status with colonoscopies performed for the purpose of surveillance were selected for this study. Information on the surveillance examinations was obtained from medical reports. The histology of all adenomas was confirmed. Immunohistochemistry was performed in a subgroup of adenomas. RESULTS We identified 249 carriers and 247 controls. The proportion of subjects free of an adenoma at the age of 60 years was 29.7% for carriers and 70.8% for controls (P < 0.05). The adenomas in carriers were larger, and a higher proportion had villous components and/or high-grade dysplasia (P < 0.05, all analyses). The adenomas and carcinomas of the carriers were located predominantly in the proximal colon. Most adenomas showed absent staining of the MMR proteins. CONCLUSIONS This study indicates that the MMR defect is involved in the early stages of development of adenomas. We recommend immunohistochemical staining of large adenomas with high-grade dysplasia in young patients (younger than 50 years) to identify patients with suspected HNPCC.
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Affiliation(s)
- Andrea E De Jong
- Department of Gastroenterology, Leiden University Medical Center, Leiden, Netherlands
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Trimbath JD, Petersen GM, Erdman SH, Ferre M, Luce MC, Giardiello FM. Café-au-lait spots and early onset colorectal neoplasia: a variant of HNPCC? Fam Cancer 2003; 1:101-5. [PMID: 14574005 DOI: 10.1023/a:1013881832014] [Citation(s) in RCA: 73] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND Café-au-lait spots (CALS) are classically found in neurocutaneous syndromes such as neurofibromatosis, but have not been associated with hereditary colorectal cancer. However, review of hereditary colorectal cancer case reports reveals occasional description of CALS on physical exam. METHODS We describe the colonic and extracolonic phenotype in a family with CALS and early onset colorectal neoplasia (adenomas and/or cancer) and review 23 additional families reported in the literature. RESULTS Among the 24 families, 32/59 (54.2%) individuals had colorectal adenomas diagnosed at a mean age of 15.7 +/- 1.1 (SE) years (range 5-38 years). The majority (24/32, 75.0%) of persons at first colorectal examination had oligopolyposis (< 100 polyps) versus polyposis (> or = 100 polyps). Forty-two of 59 (71.2%) individuals were affected with colorectal cancer, diagnosed at a mean age of 31.9 +/- 2.7 years (range 5-70 years). A brain tumor was found in 28/59 (47.5%) affected individuals (4 families with 2 or more cases) with an overall mean age of diagnosis of 16.5 +/- 1.2. Lymphoma and/or leukemia was found in 8/24 (33.3%) families (one family with 3 cases). Two families had mutation of the mismatch repair gene, hPMS2 (1 with homozygous germline mutation), while two carried homozygous germline mutations of another mismatch repair gene, hMLH1. CONCLUSIONS Café-au-lait spots with early onset colorectal neoplasia may identify families with a variant of HNPCC characterized by oligopolyposis, glioblastoma at young age, and lymphoma. This variant may be caused by homozygous mutation of the mismatch repair genes, such as hPMS2 or hMLH1.
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Affiliation(s)
- J D Trimbath
- Department of medicine, The John Hopkins Hereditary Colorectal Cancer Registry, 550 N. Broadway, Suite 108, Baltimore, MD 21205-2011, USA.
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Möslein G. Clinical implications of molecular diagnosis in hereditary nonpolyposis colorectal cancer. Recent Results Cancer Res 2003; 162:73-8. [PMID: 12790322 DOI: 10.1007/978-3-642-59349-9_6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/16/2022]
Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is a hereditary cancer predisposition accounting for approximately 1%-5% of all colorectal cancers. Clinical management of HNPCC families is most challenging due to the following factors: (1) reduced penetrance of approximately 80%; (2) predisposition to cancer of the colorectum but also of the endometrium, urinary tract and small bowel; (3) broad inter- and intrafamilial heterogeneity; and (4) highly accelerated adenoma carcinoma sequence in the colorectum. To date, HNPCC may be defined either by the so-called Amsterdam I+II criteria or by detection of a mutation in one of the mismatch repair genes. Once the positive mutation has been identified, predictive testing of at-risk family members is available. Screening recommendations for clinically identified families, mutation carriers, and their unaffected at-risk relatives must be defined for clinical management. The question of prophylactic colectomy in HNPCC is also discussed.
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Affiliation(s)
- Gabriela Möslein
- Department of Surgery, Heinrich-Heine University, Moorenstr. 5, 40225 Düsseldorf, Germany
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Affiliation(s)
- John DeFrancisco
- Department of Medicine/Division of Gastroenterology, Vanderbilt University Medical School, Nashville, Tennessee 37232-2279, USA
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Drake AC, Campbell H, Porteous MEM, Dunlop MG. The contribution of DNA mismatch repair gene defects to the burden of gynecological cancer. Int J Gynecol Cancer 2003; 13:262-77. [PMID: 12801255 DOI: 10.1046/j.1525-1438.2003.13194.x] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Affiliation(s)
- A C Drake
- University of Edinburgh, Edinburgh, United Kingdom.
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Möslein G, Pistorius S, Saeger HD, Schackert HK. Preventive surgery for colon cancer in familial adenomatous polyposis and hereditary nonpolyposis colorectal cancer syndrome. Langenbecks Arch Surg 2003; 388:9-16. [PMID: 12690475 DOI: 10.1007/s00423-003-0364-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2003] [Accepted: 02/06/2003] [Indexed: 11/24/2022]
Abstract
BACKGROUND A better understanding of the molecular basis of hereditary colorectal cancer syndromes such as hereditary nonpolyposis colorectal cancer syndrome (HNPCC) and familial adenomatous polyposis (FAP) has profound consequences for both the diagnosis and (prophylactic) treatment of (pre)malignant neoplastic lesions. DISCUSSION Sequence analysis of the underlying genes for these conditions and the detection of disease-causing genetic alterations in an index patient enable predictive testing for individuals at risk within an affected family. However, the clinical implications of predictive molecular testing depend on the overall penetrance and variability in the expression of pathogenic mutations. The extent of these parameters differs considerably among the various known hereditary colorectal cancer syndromes. Hence the integration of genetic information into the daily surgical practice remains challenging. CONCLUSIONS This review provides an update on the indications for family assessment, purpose and limitations of the genetic testing and resulting recommendations for prophylactic surgery in FAP and HNPCC.
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Affiliation(s)
- Gabriela Möslein
- Klinik für Allgemeine und Unfallchirurgie, Moorenstrasse 5, 40225 Düsseldorf, Germany.
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