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Cama A, Genuardi M, Guanti G, Radice P, Varesco L. Molecular Genetics of Hereditary Non-Polyposis Colorectal Cancer (HNPCC). TUMORI JOURNAL 2018; 82:122-35. [PMID: 8644374 DOI: 10.1177/030089169608200206] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
The story of the molecular genetics of HNPCC is one of astonishingly rapid achievements. In just 16 months, from May 1993 to September 1994, four different genes, namely hMSH2, hMLH1, hPMS1 and hPMS2 have been identified and demonstrated to be associated with the disease. Their cloning was facilitated by the finding that tumor cells in HNPCC patients display a hypermutability of DNA short tandem repeats (microsatellite instability). In fact, HNPCC associated genes are the human counterparts of genetic elements known to control the fidelity of DNA replication in lower organisms. So far, more than 50 germline mutations of hMSH2 and hMLH1 genes have been reported in HNPCC kindreds. In addition, somatic mutations have been documented in hereditary as well as sporadic cancers. Unfortunately, the molecular diagnosis of HNPCC is hampered by the lack of mutational “hot spots” and of clearly defined genotype-phenotype correlations and different screening methods are to be employed for the analysis of affected and at-risk individuals.
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Affiliation(s)
- A Cama
- Cattedra di Patologia Generale, Università Gabriele D'Annuzio, Chieti,Italy
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Cheng THT, Thompson D, Painter J, O’Mara T, Gorman M, Martin L, Palles C, Jones A, Buchanan DD, Ko Win A, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Giles GG, Pharoah P, Peto J, Cox A, Swerdlow A, Couch F, Cunningham JM, Goode EL, Winham SJ, Lambrechts D, Fasching P, Burwinkel B, Brenner H, Brauch H, Chang-Claude J, Salvesen HB, Kristensen V, Darabi H, Li J, Liu T, Lindblom A, Hall P, de Polanco ME, Sans M, Carracedo A, Castellvi-Bel S, Rojas-Martinez A, Aguiar Jnr S, Teixeira MR, Dunning AM, Dennis J, Otton G, Proietto T, Holliday E, Attia J, Ashton K, Scott RJ, McEvoy M, Dowdy SC, Fridley BL, Werner HMJ, Trovik J, Njolstad TS, Tham E, Mints M, Runnebaum I, Hillemanns P, Dörk T, Amant F, Schrauwen S, Hein A, Beckmann MW, Ekici A, Czene K, Meindl A, Bolla MK, Michailidou K, Tyrer JP, Wang Q, Ahmed S, Healey CS, Shah M, Annibali D, Depreeuw J, Al-Tassan NA, Harris R, Meyer BF, Whiffin N, Hosking FJ, Kinnersley B, Farrington SM, Timofeeva M, Tenesa A, Campbell H, Haile RW, Hodgson S, Carvajal-Carmona L, Cheadle JP, Easton D, Dunlop M, Houlston R, Spurdle A, et alCheng THT, Thompson D, Painter J, O’Mara T, Gorman M, Martin L, Palles C, Jones A, Buchanan DD, Ko Win A, Hopper J, Jenkins M, Lindor NM, Newcomb PA, Gallinger S, Conti D, Schumacher F, Casey G, Giles GG, Pharoah P, Peto J, Cox A, Swerdlow A, Couch F, Cunningham JM, Goode EL, Winham SJ, Lambrechts D, Fasching P, Burwinkel B, Brenner H, Brauch H, Chang-Claude J, Salvesen HB, Kristensen V, Darabi H, Li J, Liu T, Lindblom A, Hall P, de Polanco ME, Sans M, Carracedo A, Castellvi-Bel S, Rojas-Martinez A, Aguiar Jnr S, Teixeira MR, Dunning AM, Dennis J, Otton G, Proietto T, Holliday E, Attia J, Ashton K, Scott RJ, McEvoy M, Dowdy SC, Fridley BL, Werner HMJ, Trovik J, Njolstad TS, Tham E, Mints M, Runnebaum I, Hillemanns P, Dörk T, Amant F, Schrauwen S, Hein A, Beckmann MW, Ekici A, Czene K, Meindl A, Bolla MK, Michailidou K, Tyrer JP, Wang Q, Ahmed S, Healey CS, Shah M, Annibali D, Depreeuw J, Al-Tassan NA, Harris R, Meyer BF, Whiffin N, Hosking FJ, Kinnersley B, Farrington SM, Timofeeva M, Tenesa A, Campbell H, Haile RW, Hodgson S, Carvajal-Carmona L, Cheadle JP, Easton D, Dunlop M, Houlston R, Spurdle A, Tomlinson I. Meta-analysis of genome-wide association studies identifies common susceptibility polymorphisms for colorectal and endometrial cancer near SH2B3 and TSHZ1. Sci Rep 2015; 5:17369. [PMID: 26621817 PMCID: PMC4664893 DOI: 10.1038/srep17369] [Show More Authors] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2015] [Accepted: 10/28/2015] [Indexed: 11/17/2022] Open
Abstract
High-risk mutations in several genes predispose to both colorectal cancer (CRC) and endometrial cancer (EC). We therefore hypothesised that some lower-risk genetic variants might also predispose to both CRC and EC. Using CRC and EC genome-wide association series, totalling 13,265 cancer cases and 40,245 controls, we found that the protective allele [G] at one previously-identified CRC polymorphism, rs2736100 near TERT, was associated with EC risk (odds ratio (OR) = 1.08, P = 0.000167); this polymorphism influences the risk of several other cancers. A further CRC polymorphism near TERC also showed evidence of association with EC (OR = 0.92; P = 0.03). Overall, however, there was no good evidence that the set of CRC polymorphisms was associated with EC risk, and neither of two previously-reported EC polymorphisms was associated with CRC risk. A combined analysis revealed one genome-wide significant polymorphism, rs3184504, on chromosome 12q24 (OR = 1.10, P = 7.23 × 10(-9)) with shared effects on CRC and EC risk. This polymorphism, a missense variant in the gene SH2B3, is also associated with haematological and autoimmune disorders, suggesting that it influences cancer risk through the immune response. Another polymorphism, rs12970291 near gene TSHZ1, was associated with both CRC and EC (OR = 1.26, P = 4.82 × 10(-8)), with the alleles showing opposite effects on the risks of the two cancers.
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Affiliation(s)
- Timothy HT Cheng
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Deborah Thompson
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Jodie Painter
- The Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
| | - Tracy O’Mara
- The Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
| | - Maggie Gorman
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Lynn Martin
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Claire Palles
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Angela Jones
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
| | - Daniel D. Buchanan
- Oncogenomics Group, Genetic Epidemiology Laboratory, Department of Pathology, The University of Melbourne, Victoria, Australia
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - Aung Ko Win
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - John Hopper
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - Mark Jenkins
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
| | - Noralane M. Lindor
- Department of Health Sciences Research, Mayo Clinic, Scottsdale, AZ, USA
| | - Polly A. Newcomb
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA
| | - Steve Gallinger
- Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, Canada
| | - David Conti
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Fred Schumacher
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Graham Casey
- Department of Preventive Medicine, University of Southern California, Los Angeles, CA, USA
| | - Graham G Giles
- Centre for Epidemiology and Biostatistics, The University of Melbourne, Victoria, Australia
- Cancer Epidemiology Centre, Cancer Council Victoria, Melbourne, Australia
- Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Paul Pharoah
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Julian Peto
- London School of Hygiene and Tropical Medicine, London, UK
| | - Angela Cox
- Sheffield Cancer Research Centre, Department of Oncology, University of Sheffield, Sheffield, UK
| | - Anthony Swerdlow
- Division of Genetics and Epidemiology, Institute of Cancer Research, Sutton, UK and 17 Division of Breast Cancer Research, Institute of Cancer Research, London, UK
| | - Fergus Couch
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Julie M Cunningham
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
| | - Ellen L Goode
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | - Stacey J Winham
- Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA
| | | | - Peter Fasching
- University of California at Los Angeles, Department of Medicine, Division of Hematology/Oncology, David Geffen School of Medicine, Los Angeles, CA, USA
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Barbara Burwinkel
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, Germany
| | - Hermann Brenner
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, Germany
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Hiltrud Brauch
- Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology Stuttgart, University of Tuebingen, Germany
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Jenny Chang-Claude
- Division of Cancer Epidemiology, German Cancer Research Center, Heidelberg, Germany
| | - Helga B. Salvesen
- Department of Clinical Science, Center for Cancer Biomarkers, University of Bergen, Norway
| | - Vessela Kristensen
- Department of Genetics, Institute for Cancer Research, The Norwegian Radium Hospital, Oslo, Norway; The K.G. Jebsen Center for Breast Cancer Research, Institute for Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway; Department of Clinical Molecular Oncology, Division of Medicine, Akershus University Hospital, Ahus, Norway
| | - Hatef Darabi
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Jingmei Li
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Tao Liu
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Annika Lindblom
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Per Hall
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Magdalena Echeverry de Polanco
- Grupo de investigación Citogenética, Filogenia y Evolución de Poblaciones, Universidad del Tolima, Ibagué, Tolima, Colombia
| | - Monica Sans
- Departamento de Antropologia Biologica, Facultad de Humanidades, UDELAR, Magallanes 1577, CP 11200, Montevideo, Uruguay
| | - Angel Carracedo
- Universidade de Santiago de Compostel, R/ San Francisco s/n 15782, Santiago de Compostela, Spain
| | - Sergi Castellvi-Bel
- Genetic Predisposition to Colorectal Cancer Group, Gastrointestinal & Pancreatic Oncology Team, IDIBAPS/CIBERehd/Hospital Clínic, Centre Esther Koplowitz (CEK), Rosselló 153 planta 4, 08036 Barcelona, Spain
| | - Augusto Rojas-Martinez
- Universidad Autónoma De Nuevo León, Pedro de Alba s/n, San Nicolás de Los Garza, Nuevo León, Mexico
| | | | - Manuel R. Teixeira
- Department of Genetics and IPO-Porto Research Center (CI-IPOP), Portuguese Oncology Institute of Porto (IPO-Porto), Porto, Portugal, and Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal
| | - Alison M Dunning
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Joe Dennis
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Geoffrey Otton
- School of Medicine and Public Health, University of Newcastle, NSW, Australia
| | - Tony Proietto
- School of Medicine and Public Health, University of Newcastle, NSW, Australia
| | - Elizabeth Holliday
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
| | - John Attia
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
| | - Katie Ashton
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
| | - Rodney J Scott
- Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW, Australia
| | - Mark McEvoy
- Centre for Clinical Epidemiology and Biostatistics, School of Medicine and Public Health, University of Newcastle, NSW, Australia
| | - Sean C Dowdy
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Mayo Clinic, Rochester, MN, USA
| | - Brooke L Fridley
- Department of Biostatistics, University of Kansas Medical Center, Kansas City, KS, USA
| | - Henrica MJ Werner
- Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, Norway
| | - Jone Trovik
- Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, Norway
| | - Tormund S Njolstad
- Centre for Cancer Biomarkers, Department of Clinical Science, The University of Bergen, Norway
| | - Emma Tham
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden
| | - Miriam Mints
- Department of Women’s and Children’s Health, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Ingo Runnebaum
- Department of Gynaecology, Jena University Hospital - Friedrich Schiller University, Jena, Germany
| | - Peter Hillemanns
- Hannover Medical School, Clinics of Gynaecology and Obstetrics, Hannover, Germany
| | - Thilo Dörk
- Hannover Medical School, Gynaecology Research Unit, Hannover, Germany
| | - Frederic Amant
- Division of Gynaecological Oncology, University Hospital Leuven, Leuven, Belgium
| | | | - Alexander Hein
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Matthias W Beckmann
- Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Arif Ekici
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany
| | - Kamila Czene
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Alfons Meindl
- Department of Obstetrics and Gynecology, Division of Tumor Genetics, Technical University of Munich, Munich, Germany
| | - Manjeet K Bolla
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Kyriaki Michailidou
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Jonathan P Tyrer
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Qin Wang
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
| | - Shahana Ahmed
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Catherine S Healey
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Mitul Shah
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Daniela Annibali
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven, University of Leuven, 3000, Belgium
| | - Jeroen Depreeuw
- Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University Hospitals, KU Leuven, University of Leuven, 3000, Belgium
| | - Nada A. Al-Tassan
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh11211, Saudi Arabia
| | - Rebecca Harris
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Brian F. Meyer
- Department of Genetics, King Faisal Specialist Hospital and Research Center, P.O.Box 3354, Riyadh11211, Saudi Arabia
| | - Nicola Whiffin
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Fay J Hosking
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Ben Kinnersley
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Susan M. Farrington
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Maria Timofeeva
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Albert Tenesa
- The Roslin Institute, University of Edinburgh, Easter Bush, Roslin, EH25 9RG, UK
| | - Harry Campbell
- Centre for Population Health Sciences, University of Edinburgh, Edinburgh, EH8 9AG, UK
| | - Robert W. Haile
- Stanford Cancer Institute, Lorry Lokey Building/SIM 1, 265 Campus Drive, Ste G2103, Stanford, CA 94305-5456, USA
| | - Shirley Hodgson
- Department of Cancer Genetics, St. George’s University of London, London SW17 0RE, UK
| | - Luis Carvajal-Carmona
- Genome Center and Department of Biochemistry and Molecular Medicine, School of Medicine, University of California, Davis, USA
| | - Jeremy P. Cheadle
- Institute of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff, CF14 4XN, UK
| | - Douglas Easton
- Centre for Cancer Genetic Epidemiology, Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK
| | - Malcolm Dunlop
- Colon Cancer Genetics Group, Institute of Genetics and Molecular Medicine, University of Edinburgh and MRC Human Genetics Unit, Western General Hospital Edinburgh, Crewe Road, Edinburgh, EH4 2XU, UK
| | - Richard Houlston
- Division of Genetics and Epidemiology, The Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
| | - Amanda Spurdle
- The Molecular Cancer Epidemiology Laboratory, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia
| | - Ian Tomlinson
- Molecular and Population Genetics Laboratory, Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
- Oxford NIHR Comprehensive Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, Roosevelt Drive, Oxford OX3 7BN, UK
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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
Women who report a history of endometrial cancer in a first-degree relative are at increased risk of endometrial cancer, with a hazard ratio of 1.5 to 2.0. Only a minority of patients with familial endometrial cancer have a recognized cancer syndrome. Lynch syndrome is the most common genetic syndrome associated with endometrial cancer and a marked increased risk of colon cancer. Cowden syndrome is a rare condition resulting from a mutation in the tumor suppressor gene phosphatase and tensin homolog. The risk for endometrial cancer is about five times higher in women with Cowden syndrome than in the general population. Recently, a novel germline mutation in the POLD1 gene that encodes the catalytic subunit of DNA polymerase δ was described in several families with multiple cases of endometrial cancer. This mutation is also associated with colorectal cancer. The association between BRCA1 mutations and endometrial cancer has been investigated in several studies; it appears that the risk of endometrial cancer is restricted to women with a history of tamoxifen exposure. In recent years, research has focused on genetic polymorphisms that are associated with endometrial cancer risk. Although many polymorphisms have been identified, their clinical significance is unclear and they have not been adapted for clinical practice.
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Hugen N, van Beek JJP, de Wilt JHW, Nagtegaal ID. Insight into mucinous colorectal carcinoma: clues from etiology. Ann Surg Oncol 2014; 21:2963-70. [PMID: 24728741 DOI: 10.1245/s10434-014-3706-6] [Citation(s) in RCA: 72] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2014] [Indexed: 12/17/2022]
Abstract
The prognostic impact of mucinous carcinoma (MC) in colorectal cancer (CRC) has been subject to debate ever since the introduction of the classification of tumors according to their histological differentiation. MC is a distinct clinical and pathological entity within the spectrum of CRC and accounts for approximately 10-15 % of cases. Factors involved in MC development have not been completely understood, but clinical observations may lead to a better insight into the etiology of MC. In this article, we provide an in-depth review of the literature regarding etiological aspects of MC. We show that there are worldwide differences in the prevalence of MC, with low rates in Asian countries and higher rates in the western world. Moreover, MC is more commonly diagnosed in patients suffering from inflammatory bowel diseases or Lynch syndrome and an increased rate of MC is observed in patients with radiotherapy-induced CRCs. These findings are suggestive of a different oncogenic development. Identification of conditions that are associated with MC generates insight into the etiological pathways leading to the development of this special subtype.
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Affiliation(s)
- Niek Hugen
- Department of Surgery, Radboud University Medical Center, HB, Nijmegen, The Netherlands,
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Wang Y, Wang Y, Li J, Cragun J, Hatch K, Chambers SK, Zheng W. Lynch syndrome related endometrial cancer: clinical significance beyond the endometrium. J Hematol Oncol 2013; 6:22. [PMID: 23531335 PMCID: PMC3623651 DOI: 10.1186/1756-8722-6-22] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2013] [Accepted: 03/17/2013] [Indexed: 12/20/2022] Open
Abstract
Lynch syndrome (LS), an autosomal dominant inherited cancer susceptibility syndrome, also known as hereditary non-polyposis colon cancer (HNPCC), is caused by a germline mutation in one of several DNA mismatch repair (MMR) genes. LS is the most common presentation of hereditary colorectal cancer (CRC), accounting for about 2–5% of all CRC cases. More recently, it is found that a similar number of endometrial cancers is also due to one of the MMR gene mutations. There has been significant progress in LS-related CRC in terms of molecular pathogenesis, risks, genetic basis, and cancer prevention. In contrast, the advance about LS-related endometrial cancer (EC) is very much limited. In this commentary, we summarize the main clinicopathologic features of LS-related EC and propose universal screening for LS in individuals with endometrial cancer.
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Affiliation(s)
- Yiying Wang
- Department of Obstetrics and Gynecology, Henan Province People’s Hospital Zhengzhou, Henan, China
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Abstract
In a fraction of families fulfilling the Amsterdam criteria for hereditary non-polyposis colorectal cancer, colorectal cancers are microsatellite stable and DNA mismatch repair gene (MMR) mutations are not found. These families were designated as familial colorectal cancer type X (FCCTX). We aimed to characterise a group of FCCTX families defined by the Amsterdam criteria and MSS tumours at clinical and molecular level. Twenty-four tumours from 15 FCCTX families were analysed for loss of known tumour suppressor gene (TSG) loci (APC, TP53, SMAD4 and DCC), MGMT and MMR genes promoter methylation, and also APC and KRAS somatic mutations. FCCTX families presented specific clinical features: absence of endometrial tumours, high adenoma/carcinoma ratio (1.91) and prevalence of rectal cancers (13/27, 48%). New molecular features were found: the majority of FCCTX tumours (13/18; 72%) presented TSG loss. TSG loss positive tumours presented frequent APC and KRAS somatic mutations and MGMT methylation [10/13 (77%), 7/13 (54%) and 6/11 (54%), respectively]. In TSG loss negative tumours (5/18; 28%), the same molecular events were found in 2/5 (40%), 2/5 (40%) and 1/3 (33%) tumours, respectively. Transition mutations in KRAS were more frequent among MGMT methylated tumours than in unmethylated [5/8 (63%) vs. 1/10 (10%), P = 0.03]. Although sharing similar clinical features, at least two different molecular entities should exist among FCCTX families, one whose tumours present frequent TSG loss, APC and KRAS somatic mutations, and MGMT promoter methylation, and a second, lesser predominant, with no evidence of TSG loss and rarely presenting promoter methylation.
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Katkoori VR, Shanmugam C, Jia X, Vitta SP, Sthanam M, Callens T, Messiaen L, Chen D, Zhang B, Bumpers HL, Samuel T, Manne U. Prognostic significance and gene expression profiles of p53 mutations in microsatellite-stable stage III colorectal adenocarcinomas. PLoS One 2012; 7:e30020. [PMID: 22276141 PMCID: PMC3261849 DOI: 10.1371/journal.pone.0030020] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2011] [Accepted: 12/12/2011] [Indexed: 12/15/2022] Open
Abstract
Although the prognostic value of p53 abnormalities in Stage III microsatellite stable (MSS) colorectal cancers (CRCs) is known, the gene expression profiles specific to the p53 status in the MSS background are not known. Therefore, the current investigation has focused on identification and validation of the gene expression profiles associated with p53 mutant phenotypes in MSS Stage III CRCs. Genomic DNA extracted from 135 formalin-fixed paraffin-embedded tissues, was analyzed for microsatellite instability (MSI) and p53 mutations. Further, mRNA samples extracted from five p53-mutant and five p53-wild-type MSS-CRC snap-frozen tissues were profiled for differential gene expression by Affymetrix Human Genome U133 Plus 2.0 arrays. Differentially expressed genes were further validated by the high-throughput quantitative nuclease protection assay (qNPA), and confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) and by immunohistochemistry (IHC). Survival rates were estimated by Kaplan-Meier and Cox regression analyses. A higher incidence of p53 mutations was found in MSS (58%) than in MSI (30%) phenotypes. Both univariate (log-rank, P = 0.025) and multivariate (hazard ratio, 2.52; 95% confidence interval, 1.25-5.08) analyses have demonstrated that patients with MSS-p53 mutant phenotypes had poor CRC-specific survival when compared to MSS-p53 wild-type phenotypes. Gene expression analyses identified 84 differentially expressed genes. Of 49 down-regulated genes, LPAR6, PDLIM3, and PLAT, and, of 35 up-regulated genes, TRIM29, FUT3, IQGAP3, and SLC6A8 were confirmed by qNPA, qRT-PCR, and IHC platforms. p53 mutations are associated with poor survival of patients with Stage III MSS CRCs and p53-mutant and wild-type phenotypes have distinct gene expression profiles that might be helpful in identifying aggressive subsets.
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Affiliation(s)
- Venkat R. Katkoori
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Chandrakumar Shanmugam
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Xu Jia
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Swaroop P. Vitta
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Meenakshi Sthanam
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Tom Callens
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Ludwine Messiaen
- Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Dongquan Chen
- Division of Preventive Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Bin Zhang
- Department of Biostatistics, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
| | - Harvey L. Bumpers
- Department of Surgery, Morehouse School of Medicine, Atlanta, Georgia, United States of America
| | - Temesgen Samuel
- Department of Pathology, Tuskegee University, Tuskegee, Alabama, United States of America
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
- UAB Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America
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10
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Kovac M, Laczko E, Haider R, Jiricny J, Mueller H, Heinimann K, Marra G. Familial colorectal cancer: eleven years of data from a registry program in Switzerland. Fam Cancer 2012; 10:605-16. [PMID: 21671081 DOI: 10.1007/s10689-011-9458-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
Deleterious germ-line variants involving the DNA mismatch repair (MMR) genes have been identified as the cause of the hereditary nonpolyposis colorectal cancer syndrome known as the Lynch syndrome, but in numerous familial clusters of colon cancer, the cause remains obscure. We analyzed data for 235 German-speaking Swiss families with nonpolyposis forms of colorectal cancer (one of the largest and most ethnically homogeneous cohorts of its kind) to identify the phenotypic features of forms that cannot be explained by MMR deficiency. Based on the results of microsatellite instability analysis and immunostaining of proband tumor samples, the kindreds were classified as MMR-proficient (n = 134, 57%) or MMR-deficient (n = 101, 43%). In 81 of the latter kindreds, deleterious germ-line MMR-gene variants have already been found (62 different variants, including 13 that have not been previously reported), confirming the diagnosis of Lynch syndrome. Compared with MMR-deficient kindreds, the 134 who were MMR proficient were less likely to meet the Amsterdam Criteria II regarding autosomal dominant transmission. They also had primary cancers with later onset and colon-segment distribution patterns resembling those of sporadic colorectal cancers, and they had lower frequencies of metachronous colorectal cancers and extracolonic cancers in general. Although the predisposition to colorectal cancer in these kindreds is probably etiologically heterogeneous, we were unable to identify distinct phenotypic subgroups solely on the basis of the clinical data collected in this study. Further insight, however, is expected to emerge from the molecular characterization of their tumors.
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Affiliation(s)
- Michal Kovac
- Research Group Human Genetics, Department of Biomedicine, University of Basel, Mattenstrasse 28, 4058, Basel, Switzerland
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11
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Walsh TJ, Schembri M, Turek PJ, Chan JM, Carroll PR, Smith JF, Eisenberg ML, Van Den Eeden SK, Croughan MS. Increased risk of high-grade prostate cancer among infertile men. Cancer 2010; 116:2140-7. [PMID: 20309846 PMCID: PMC2893877 DOI: 10.1002/cncr.25075] [Citation(s) in RCA: 61] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND It has been reported that fatherhood status may be a risk factor for prostate cancer. In the current study, the authors examined the subsequent occurrence of prostate cancer in a cohort of men evaluated for infertility to determine whether male infertility is a risk factor for prostate cancer. METHODS A total of 22,562 men who were evaluated for infertility from 1967 to 1998 were identified from 15 California infertility centers and linked to the California Cancer Registry. The incidence of prostate cancer was compared with the incidence in an age-matched and geography-matched sample of men from the general population. The risk of prostate cancer in men with and those without male factor infertility was modeled using a Cox proportional hazards regression model. RESULTS A total of 168 cases of prostate cancer that developed after infertility were identified. Men evaluated for infertility but not necessarily with male factors were not found to have an increased risk of cancer compared with the general population (standardized incidence ratio [SIR], 0.9; 95% confidence interval [95% CI], 0.8-1.1). This risk was found to be highest for men with male factor infertility who developed high-grade prostate cancer (SIR, 2.0; 95% CI, 1.2-3.0). On multivariate analyses, men with male factor infertility were found to be 2.6 times more likely to be diagnosed with high-grade prostate cancer (hazard ratio, 2.6; 95% CI, 1.4-4.8). CONCLUSIONS Men with male factor infertility were found to have an increased risk of subsequently developing high-grade prostate cancer. Male infertility may be an early and identifiable risk factor for the development of clinically significant prostate cancer.
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Affiliation(s)
- Thomas J Walsh
- Department of Urology, University of Washington School of Medicine, Seattle, Washington 98195-6510, USA.
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12
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Buchanan DD, Roberts A, Walsh MD, Parry S, Young JP. Lessons from Lynch syndrome: a tumor biology-based approach to familial colorectal cancer. Future Oncol 2010; 6:539-49. [PMID: 20373868 PMCID: PMC2896690 DOI: 10.2217/fon.10.16] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Colorectal cancer (CRC) develops within precursor lesions in the single-celled epithelial lining of the gut. The two most common epithelial lesions are the adenoma and the serrated polyp. CRC is also one of the most familial of the common cancers, and just as there are syndromes associated with increased risk of CRC arising in adenomas, there are also syndromes with increased CRC risk associated with serrated polyps. In this article, we describe the features of such a syndrome, familial serrated neoplasia, which distinguish it from the well-characterized condition Lynch syndrome (or hereditary nonpolyposis CRC), and show that the molecular pathology of tumors forms the basis for this distinction. Lynch syndrome CRC arises almost exclusively within adenomatous precursor lesions, in contrast with familial serrated neoplasia where at least half of the cancers develop in serrated polyps. Finally, rare families exist in which both conditions segregate independently, producing a difficult diagnostic picture.
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Affiliation(s)
- Daniel D Buchanan
- Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 733 620 498
| | - Aedan Roberts
- Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 733 620 493
| | - Michael D Walsh
- Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 738 453 775
| | - Susan Parry
- Genetic Services, Auckland City Hospital, & Department of Gastroenterology & Hepatology, Middlemore Hospital, Auckland, New Zealand, Tel.: +64 930 749 49
| | - Joanne P Young
- Associate Professor, Familial Cancer Laboratory, QIMR, Herston Q 4006, Australia, Tel.: +61 733 620 490, Fax: +61 733 620 108
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13
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Søreide K, Nedrebø BS, Knapp JC, Glomsaker TB, Søreide JA, Kørner H. Evolving molecular classification by genomic and proteomic biomarkers in colorectal cancer: Potential implications for the surgical oncologist. Surg Oncol 2009; 18:31-50. [DOI: 10.1016/j.suronc.2008.06.006] [Citation(s) in RCA: 47] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2008] [Revised: 06/13/2008] [Accepted: 06/16/2008] [Indexed: 02/07/2023]
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14
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Walsh TJ, Croughan MS, Schembri M, Chan JM, Turek PJ. Increased risk of testicular germ cell cancer among infertile men. ARCHIVES OF INTERNAL MEDICINE 2009; 169:351-6. [PMID: 19237718 PMCID: PMC2881689 DOI: 10.1001/archinternmed.2008.562] [Citation(s) in RCA: 174] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/14/2022]
Abstract
BACKGROUND The risk of testicular cancer is thought to be higher among men seeking infertility treatment compared with the general population. Confirmation of this risk in a large US cohort of at-risk patients is lacking. This study explored the association between male infertility and subsequent development of testicular cancer in a US-based cohort. METHODS A total of 51 461 couples evaluated for infertility from 1967 to 1998 were recruited from 15 California infertility centers. We linked data on 22 562 identified male partners to the California Cancer Registry. The incidence of testicular cancer in this cohort was compared with the incidence in an age-matched sample of men from the general population using the Surveillance Epidemiology and End Results program. We analyzed the risk for testicular cancer in men with and without male factor infertility using a Cox proportional hazards regression model. RESULTS Thirty-four post-infertility-diagnosis cases of histologically confirmed testicular cancer were identified. Men seeking infertility treatment had an increased risk of subsequently developing testicular cancer (standardized incidence ratio, 1.3; 95% confidence interval, 0.9-1.9), with a markedly higher risk among those with known male factor infertility (2.8; 1.5-4.8). In multivariable analysis, men with male factor infertility were nearly 3 times more likely to develop testicular cancer compared with those without (hazard ratio, 2.8; 95% confidence interval, 1.3-6.0). CONCLUSION Men with male factor infertility have an increased risk of subsequently developing testicular cancer, suggesting the existence of common etiologic factors for infertility and testicular cancer.
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Affiliation(s)
- Thomas J Walsh
- Department of Urology, University of Washington, School of Medicine, 1959 NE Pacific Street, Seattle, WA 98195-6510.
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15
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Case AS, Zighelboim I, Mutch DG, Babb SA, Schmidt AP, Whelan AJ, Thibodeau SN, Goodfellow PJ. Clustering of Lynch syndrome malignancies with no evidence for a role of DNA mismatch repair. Gynecol Oncol 2008; 108:438-44. [PMID: 18022218 PMCID: PMC3023170 DOI: 10.1016/j.ygyno.2007.09.036] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2007] [Revised: 09/23/2007] [Accepted: 09/26/2007] [Indexed: 11/24/2022]
Abstract
OBJECTIVES We ascertained a large kindred with an excess of Lynch syndrome-associated cancers. Our objective was to determine if a defect in one of the DNA mismatch repair (DMMR) genes was the probable cause of cancer susceptibility as microsatellite instability (MSI) and immunohistochemical (IHC) analysis of the probands' tumors did not provide a clear indication. METHODS A detailed history and review of medical records was undertaken to construct a four-generation pedigree. Blood samples were obtained for analysis of germline DNA. Polymorphic repeats from the MLH1, MSH2, MSH6, and PMS2 loci were genotyped and the co-segregation of markers and disease was assessed. DMMR gene expression for all available tumors was evaluated by IHC. Combined bisulfite restriction analysis (COBRA) of MLH1 was utilized to test for germline epimutation. RESULTS Four gynecologic carcinomas, 3 colon carcinomas, and 13 cases of adenomatous polyps were identified. The family met Amsterdam II criteria. The mean age of cancer diagnosis in the kindred was 63 years (range 44-82 years). DNA marker analyses excluded linkage to MLH1, MSH2, MSH6, and PMS2. Furthermore, MSI and IHC analysis of tumors did not suggest a role for DMMR. Methylation of the MLH1 promoter was identified in the peripheral blood leukocytes (PBLs) of a family member with an early onset colon cancer. CONCLUSIONS We identified a large family with multiple Lynch malignancies and no evidence for an inherited defect in DMMR. This family represents an important but poorly understood form of autosomal dominant inherited cancer susceptibility. Aberrant MLH1 promoter methylation in normal tissues may be a marker for cancer susceptibility in families such as this.
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Affiliation(s)
- Ashley S Case
- Divison of Gynecologic Oncology, Department of Obstetrics and Gynecology, Washington University School of Medicine, 4911 Barnes-Jewish Hospital Plaza, 3rd Floor Maternity, St. Louis, MO 63110, USA.
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16
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Differences between familial and sporadic forms of colorectal cancer with DNA microsatellite instability. Surg Oncol 2007; 16 Suppl 1:S37-42. [PMID: 18023569 DOI: 10.1016/j.suronc.2007.10.018] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Microsatellite instability (MSI) is observed in approximately 13% of colorectal cancers. Genes containing a mononucleotide microsatellite in the coding sequence are particularly prone to inactivation in MSI tumourigenesis, and much work has been conducted to identify genes with high repetitive tract mutation rates in these tumours. MSI caused by deficient DNA mismatch-repair functions is a hallmark of cancers associated with the hereditary non-polyposis colorectal cancer syndrome but is also found in about 15% of all sporadic tumours.
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17
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Abstract
In recent decades there have been significant advances in our understanding of the genes that underlie hereditary susceptibility to colorectal cancer (CRC). In 2007 it is well established that mutations in DNA repair genes (MLH1, MSH2, MSH6, MYH) and Wnt pathway signal transduction inhibitors (APC) underlie a significant percentage of hereditary CRC susceptibility. However, it also is clear that the known CRC susceptibility genes do not explain fully the inherited risk seen even in families meeting the revised Bethesda guidelines. Furthermore, the optimal medical management of these syndromes is still being defined. What underlies CRC susceptibility in these highly unusual families that do not have identifiable mutations in the known genes, often referred to as syndrome X? This review addresses this important question that is relevant to our current understanding of the management of individuals with hereditary predisposition to CRC.
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Affiliation(s)
- Steven M Lipkin
- Cancer Genetics Clinic, Chao Family NCI Designated Comprehensive Cancer Center, University of California, Irvine, CA 92697-4038, USA.
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18
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Perez RO, Habr-Gama A, dos Santos RMN, Proscurshim I, Campos FG, Rawet V, Kiss D, Cecconello I. Peritumoral inflammatory infiltrate is not a prognostic factor in distal rectal cancer following neoadjuvant chemoradiation therapy. J Gastrointest Surg 2007; 11:1534-40. [PMID: 17786526 DOI: 10.1007/s11605-007-0287-8] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2007] [Accepted: 07/29/2007] [Indexed: 01/31/2023]
Abstract
BACKGROUND Peritumoral inflammatory response has been considered a good prognostic factor for colorectal cancer. However, this has not been evaluated in patients submitted to neoadjuvant therapy for distal rectal cancer. For this reason, we decided to study the effect of the presence of this pathological finding on disease recurrence and survival. METHODS The peritumoral inflammatory infiltrate from recovered pathological specimens of patients operated after neoadjuvant therapy for distal rectal cancer was graded (positive or negative). Patients were compared according to the presence of peritumoral inflammatory response. RESULTS Of the 168 patients, 63 (37%) patients had a peritumoral inflammatory response. The lack of peritumoral inflammatory response was significantly associated with the presence of mucinous component (13 vs 3%; p = 0.02). Five-year overall survival (91 vs 81%) and disease-free survival (57 vs 48%) were not significantly different between patients with and without peritumoral inflammatory response (p = 0.5 and 0.3, respectively). CONCLUSIONS Peritumoral inflammatory response is not a favorable prognostic factor in patients with distal rectal cancer after neoadjuvant chemoradiation therapy. Possibly, the immunosuppressive action of chemoradiation therapy may lead to a loss of function of the immunological response, which may represent a disadvantage of the neoadjuvant approach for the management of distal rectal cancer.
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Affiliation(s)
- Rodrigo O Perez
- Department of Gastroenterology, School of Medicine, University of São Paulo, Rua Manuel da Nóbrega, 1564, São Paulo, SP, 04001-005, Brazil.
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19
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Valle L, Perea J, Carbonell P, Fernandez V, Dotor AM, Benitez J, Urioste M. Clinicopathologic and pedigree differences in amsterdam I-positive hereditary nonpolyposis colorectal cancer families according to tumor microsatellite instability status. J Clin Oncol 2007; 25:781-786. [PMID: 17228022 DOI: 10.1200/jco.2006.06.9781] [Citation(s) in RCA: 58] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
PURPOSE To establish the clinicopathologic and familial differences within Amsterdam I-positive families, showing either tumor microsatellite instability (MSI) or microsatellite stability (MSS) in order to confirm or deny the existence of hereditary nonpolyposis colorectal cancer (HNPCC) without defects in the mismatch repair system. PATIENTS AND METHODS Sixty-four Amsterdam I-positive families were included in the study for which full, three-generation, family medical histories and colorectal paraffin-embedded tumors were obtained. Both personal and clinicopathologic information of patients were collected. In all cases, both the MSI status and the mismatch repair (MMR) protein expression were analyzed. MMR genetic testing was performed on the MSI families. RESULTS Of the Amsterdam I-positive families, 59.4% were tumor MSI, and 40.6% were tumor MSS. When comparing both groups, the statistical differences were observed in the age of onset (MSI, 41 years; MSS, 53 years); in the colorectal tumor location, more frequently proximal in MSI cases; in fewer mucinous tumors in MSS; and loss of MMR protein expression in the MSI tumors. Regarding the individual and familial cancer history, we observed a predominance of individuals with multiple primary tumors in MSI pedigrees, as well as differences in the type of tumors developed within the family. CONCLUSION Our findings support the suspicion of another hereditary colorectal syndrome different from HNPCC and characterized by MSS, the normal MMR immunohistochemical expression, the presence of only colorectal tumors, and the absence of individuals with multiple primary tumors. All these circumstances suggest the existence of a non-MMR gene being responsible for this new syndrome.
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Affiliation(s)
- Laura Valle
- Familial Cancer Unit, Spanish National Cancer Centre, Melchor Fernández Almagro, Madrid, Spain.
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20
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Abstract
The term Hereditary Non-Polyposis Colorectal Cancer (HNPCC) is a poor descriptor of the syndrome described by Lynch. Over the last decade, the term has been applied to heterogeneous groups of families meeting limited clinical criteria, for example the Amsterdam criteria. It is now apparent that not all Amsterdam criteria-positive families have the Lynch syndrome. The term HNPCC has also been applied to clinical scenarios in which CRCs with DNA microsatellite instability are diagnosed but in which there is no vertical transmission of an altered DNA mismatch repair (MMR) gene. A term that has multiple, mutually incompatible meanings is highly problematic, particularly when it may influence the management of an individual family. The Lynch syndrome is best understood as a hereditary predisposition to malignancy that is explained by a germline mutation in a DNA MMR gene. The diagnosis does not depend in an absolute sense on any particular family pedigree structure or age of onset of malignancy. Families with a strong family history of colorectal cancer that do not have Lynch syndrome have been grouped as ‘Familial Colorectal Cancer Type-X’. The first step in characterizing these cancer families is to distinguish them from Lynch syndrome. The term HNPCC no longer serves any useful purpose and should be phased out.
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Affiliation(s)
- Jeremy R Jass
- Department of Pathology, McGill University, Montreal, Quebec H3A 2B4, Canada.
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21
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Söreide K, Janssen EAM, Söiland H, Körner H, Baak JPA. Microsatellite instability in colorectal cancer. Br J Surg 2006; 93:395-406. [PMID: 16555243 DOI: 10.1002/bjs.5328] [Citation(s) in RCA: 174] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND Microsatellite instability (MSI) causes hereditary non-polyposis colorectal cancer (HNPCC), and occurs in about 15 per cent of sporadic colorectal cancers. Although the basic mechanisms are not clear, there is increased understanding of the clinicopathological consequences of MSI. METHODS Medline was searched for articles with a combination of keywords relating to MSI in colorectal cancer, focusing on molecular mechanisms, clinicopathological implications, and prognostic and predictive value. Emphasis was placed on articles from the past 5 years. RESULTS The genetic mechanisms differ in hereditary (germline mutation) and sporadic (epigenetic silencing) colorectal cancer. The MSI pathway frequently has altered transforming growth factor beta receptor II and BAX genes, often beta-catenin, and occasionally p16INK4A and PTEN. Changes in K-ras, adenomatous polyposis coli and p53 are rare. Polymerase chain reaction testing for MSI is superior to immunohistochemistry, but complicated by the number and types of nucleotide markers. The Bethesda panel guides HNPCC testing, but guidelines are lacking for general screening. The presence and role of low-frequency MSI remains controversial. Tumours with MSI tend to occur in the proximal colon and be large, but they have a good prognosis. Their reduced response to adjuvant chemotherapy requires confirmation. CONCLUSION Research on colorectal cancer needs to be stratified according to microsatellite status in order further to explore the molecular mechanisms and clinicopathological consequences of MSI.
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Affiliation(s)
- K Söreide
- Departments of Pathology, Stavanger University Hospital, Stavanger, Norway.
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22
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Llor X, Pons E, Xicola RM, Castells A, Alenda C, Piñol V, Andreu M, Castellví-Bel S, Payá A, Jover R, Bessa X, Girós A, Roca A, Gassull MA. Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res 2006; 11:7304-10. [PMID: 16243801 DOI: 10.1158/1078-0432.ccr-05-0965] [Citation(s) in RCA: 88] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023]
Abstract
PURPOSE Hereditary nonpolyposis colorectal cancer (HNPCC) is the commonest form of inherited colorectal cancer. Whereas it has been known that mismatch repair gene mutations are the underlying cause of HNPCC, an undetermined number of patients do not have these alterations. The main objectives of this study were to assess the relevance of clinically defined HNPCC patients without characteristic mutator pathway alterations and to identify their specific features. EXPERIMENTAL DESIGN This was a prospective, population-based, cohort that included 1,309 newly diagnosed colorectal cancer patients. Demographic, clinical, pathologic data and tumor DNA from probands as well as a detailed family history were collected. Microsatellite analysis and MLH1, MSH2, and MSH6 immunohistochemistry were done. Germ line MLH1 and MSH2 mutational analysis was done in all patients with evidence of MMR alterations. RESULTS Twenty-five patients (1.9%) fulfilled Amsterdam criteria of HNPCC but 15 (60%) of them did not have microsatellite instability and showed normal expression of MMR proteins. These patients presented mostly left-sided tumors without lymphocytic infiltrate; they were older, had fewer family members affected with colorectal or endometrial cancers, and more often fulfilled Amsterdam II criteria than HNPCC patients with microsatellite instability. Like unstable HNPCC patients, this group without mutator pathway alterations had a significant percentage of synchronous and metachronous adenomatous polyps and cancers. CONCLUSIONS We define an important group of HNPCC families with specific features, no evidence of mismatch repair deficiency, and an autosomal dominant trait with a lesser penetrance than HNPCC with deficiency.
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Affiliation(s)
- Xavier Llor
- Gastroenterology Department, Germans Trias i Pujol Hospital, Universitat Autonòma de Barcelona, Spain.
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23
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Abstract
Precancerous polyposes other than classic familial adenomatous polyposis and the condition hereditary nonpolyposis colorectal cancer, or Lynch syndrome, continue to present major diagnostic challenges for the anatomic pathologist. This editorial highlights the practical significance of novel insights and clinical guidelines in the recent literature, as well as in 4 contributions to this edition of the Archives of Pathology & Laboratory Medicine. The first section will address attenuated familial adenomatous polyposis and a newly recognized type of autosomal-recessive adenomatous polyposis associated with the DNA repair gene MYH. The remainder of the editorial discusses the role of the revised Bethesda guidelines in the diagnosis of hereditary nonpolyposis colorectal cancer and concludes with the recently identified serrated pathway syndrome.
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Affiliation(s)
- Jeremy R Jass
- Department of Pathology, McGill University, Montreal, Quebec, Canada.
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Broaddus RR, Lynch HT, Chen LM, Daniels MS, Conrad P, Munsell MF, White KG, Luthra R, Lu KH. Pathologic features of endometrial carcinoma associated with HNPCC. Cancer 2006; 106:87-94. [PMID: 16323174 DOI: 10.1002/cncr.21560] [Citation(s) in RCA: 201] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
BACKGROUND Endometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas. METHODS Fifty women with HNPCC and endometrial carcinoma were analyzed from four different hereditary cancer registries. H&E stained slides and pathology reports were reviewed for clinically important pathologic features of endometrial carcinoma. These results were compared with those for two different groups of sporadic endometrial carcinoma--women younger than age 50 years (n = 42) and women of all ages with tumors demonstrating microsatellite instability (MSI-high) secondary to methylation of MLH1 (n = 26). RESULTS Nearly one-fourth of HNPCC patients in this study had endometrial tumors with pathologic features that would require adjuvant therapy after hysterectomy. There was a trend toward the HNPCC patients having more nonendometrioid tumors; all of these patients were carriers of MSH2 mutations. Such nonendometrioid tumors were extremely rare in the MLH1 methylated group. A subset of MLH1 methylated sporadic tumors demonstrated a unique, 'undifferentiated' histology that was not observed in HNPCC or the young group. CONCLUSION Data suggest a genotype-phenotype relation in which microsatellite instability resulting from MLH1 methylation is almost exclusively associated with classical or 'undifferentiated' endometrioid tumors, whereas microsatellite instability secondary to MSH2 mutation can result in a more variable histologic spectrum of endometrial carcinoma.
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MESH Headings
- Adaptor Proteins, Signal Transducing
- Adult
- Carcinoma, Endometrioid/genetics
- Carcinoma, Endometrioid/pathology
- Carcinoma, Papillary/genetics
- Carcinoma, Papillary/pathology
- Carrier Proteins/genetics
- Colorectal Neoplasms, Hereditary Nonpolyposis/genetics
- Colorectal Neoplasms, Hereditary Nonpolyposis/pathology
- DNA Methylation
- Endometrial Neoplasms/genetics
- Endometrial Neoplasms/pathology
- Female
- Humans
- Microsatellite Repeats
- Middle Aged
- Mixed Tumor, Mullerian/genetics
- Mixed Tumor, Mullerian/pathology
- MutL Protein Homolog 1
- MutS Homolog 2 Protein/genetics
- Mutation
- Neoplasms, Multiple Primary/genetics
- Neoplasms, Multiple Primary/pathology
- Nuclear Proteins/genetics
- Promoter Regions, Genetic
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Affiliation(s)
- Russell R Broaddus
- Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
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Evans DGR, Walsh S, Jeacock J, Robinson C, Hadfield L, Davies DR, Kingston R. Incidence of hereditary non-polyposis colorectal cancer in a population-based study of 1137 consecutive cases of colorectal cancer. Br J Surg 2005. [DOI: 10.1046/j.1365-2168.1997.02781.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
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Beck NE, Tomlinson IPM, Homfray T, Hodgson SV, Harocopos CJ, Bodmer WF. Genetic testing is important in families with a history suggestive of hereditary non-polyposis colorectal cancer even if the Amsterdam criteria are not fulfilled. Br J Surg 2005. [DOI: 10.1046/j.1365-2168.1997.02700.x] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Lindor NM, Rabe K, Petersen GM, Haile R, Casey G, Baron J, Gallinger S, Bapat B, Aronson M, Hopper J, Jass J, LeMarchand L, Grove J, Potter J, Newcomb P, Terdiman JP, Conrad P, Moslein G, Goldberg R, Ziogas A, Anton-Culver H, de Andrade M, Siegmund K, Thibodeau SN, Boardman LA, Seminara D. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293:1979-85. [PMID: 15855431 PMCID: PMC2933042 DOI: 10.1001/jama.293.16.1979] [Citation(s) in RCA: 394] [Impact Index Per Article: 19.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
CONTEXT Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown. OBJECTIVE To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities. DESIGN, SETTING, AND PARTICIPANTS Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses. MAIN OUTCOME MEASURES Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data. RESULTS Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001). CONCLUSIONS Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.
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Castells A, Marzo M, Bellas B, Amador FJ, Lanas A, Mascort JJ, Ferrándiz J, Alonso P, Piñol V, Fernández M, Bonfill X, Piqué JM. [Clinical guidelines for the prevention of colorectal cancer]. GASTROENTEROLOGIA Y HEPATOLOGIA 2005; 27:573-634. [PMID: 15574281 DOI: 10.1016/s0210-5705(03)70535-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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29
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Chiba T, Ohtani H, Mizoi T, Naito Y, Sato E, Nagura H, Ohuchi A, Ohuchi K, Shiiba K, Kurokawa Y, Satomi S. Intraepithelial CD8+ T-cell-count becomes a prognostic factor after a longer follow-up period in human colorectal carcinoma: possible association with suppression of micrometastasis. Br J Cancer 2004; 91:1711-7. [PMID: 15494715 PMCID: PMC2410024 DOI: 10.1038/sj.bjc.6602201] [Citation(s) in RCA: 159] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
T-cell infiltration into human cancer tissues can be a manifestation of host immune responses to cancer cells. The present study was undertaken to explore the clinicopathological significance of intraepithelial CD8+ T cells using 371 consecutively sampled human colorectal carcinomas. By univariate analysis, we noted that the survival curves by intraepithelial CD8+ T cells became separated only after 1 to 2 years postoperation. Multivariate analyses revealed that the beneficial effect of this factor becomes significant only after a longer (more than 2 year), but not after a shorter (less than 2 year) follow-up period. Furthermore, the number of intraepithelial CD8+ T cells was significantly higher in patients alive for more than 5 years than in patients who either died of cancer after a curative operation or patients who underwent a noncurative operation. Patients' cancer-specific death long after a curative operation is thought to be caused by the growth of micrometastases in other organs or near the primary sites. The effects of intraepithelial CD8+ T cells, therefore, may be mediated by suppression of micrometastasis, rather than suppression of growth in the primary tumour. In conclusion, our data support a hypothesis on the presence of systemic immunosurveillance against micrometastasis of cancer cells.
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Affiliation(s)
- T Chiba
- Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - H Ohtani
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
- Department of Pathology, Mito Medical Center, Ibaraki, Japan
- Department of Pathology, Mito Medical Center, 280 Sakurano-sato, Ibaraki, Ibaraki 311-3193, Japan. E-mail:
| | - T Mizoi
- Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Y Naito
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - E Sato
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - H Nagura
- Department of Pathology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - A Ohuchi
- Department of Surgery, Tohoku Rosai Hospital, Sendai, Japan
| | - K Ohuchi
- Department of Surgery, Miyagi Cancer Center, Natori, Japan
| | - K Shiiba
- Division of Biological Regulation and Oncology, Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Y Kurokawa
- Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - S Satomi
- Division of Advanced Surgical Science and Technology, Tohoku University Graduate School of Medicine, Sendai, Japan
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Jass JR. HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam Cancer 2004; 3:93-100. [PMID: 15340259 DOI: 10.1023/b:fame.0000039849.86008.b7] [Citation(s) in RCA: 108] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Morphological features may serve as diagnostically useful markers of colorectal cancer (CRC) with the microsatellite instability-high (MSI-H) phenotype. The most important of these are lymphocytic infiltration, mucin secretion and poor differentiation. These features are apparent in both sporadic MSI-H CRC and CRC occurring in the context of hereditary non-polyposis colorectal cancer (HNPCC). There is now strong evidence that that the two principal subtypes of MSI-H CRC evolve through different pathways. Sporadic MSI-H CRC orginate within serrated polyps with BRAF mutation and DNA methylation while CRC in HNPCC arise within conventional adenomas in which there is frequent mutation of APC or beta -catenin and/or K- ras. These early differences in pathogenesis translate into multiple morphological distinctions in the cancers developing through the two pathways. Lymphocytic infiltration, tumour budding (de-differentiation), and co-existing adenomas are more evident in HNPCC while mucin secretion, poor differentiation, tumour heterogeneity and glandular serration, and co-existing serrated polyps are more evident in sporadic MSI-H CRC. Sporadic MSI-H CRC are also characterized by cytoplasmic eosinophilia and nuclei that are large, round, vesicular and contain a prominent nucleolus while in HNPCC the cytological features recapitulate the basophilia and nuclear characteristics of conventional adenomas. In practice, lymphocytic infiltration is the most sensitive marker of MSI-H status in both sporadic CRC and HNPCC. The crucial distinction between HNPCC and sporadic MSI-H CRC should be achieved by means of all available data including family history, age at onset of malignancy and molecular features. There is increasing evidence that genetic factors may predispose to DNA methylation. This can result in familial clustering of MSI-H CRC in which the underlying mechanism is methylation of hMLH1 rather than germline mutation. Morphological features can assist is distinguishing such families from bona fide HNPCC families which they closely mimic.
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Affiliation(s)
- Jeremy R Jass
- Department of Pathology, McGill University, Montreal, Quebec, Canada.
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Abstract
Colorectal cancer is the third leading cause of cancer-related deaths in both men and women in the United States and is estimated to have affected 148,000 people in 2002. The cumulative lifetime risk for colon cancer is approximately 5%-6%, and this risk is influenced by hereditary and lifestyle factors. In fact, 20%-30% of all colon cancer cases have a potentially definable inherited cause, and 3%-5% of colon cancers occur in genetically defined high-risk colon cancer family syndromes. Although the genes responsible for the cases of moderate-risk colon cancer remain to be characterized, many of the genes responsible for the high-risk colon cancer cases have already been determined. These genetic discoveries have been translated into clinical practice and have led to improved risk assessment through the use of genetic testing. The introduction into clinical practice of genetic testing for the assessment of colon cancer risk has led to more effective management strategies for patients with potentially high-risk colon cancer and has presented new challenges to the clinician because of the unique issues involved with genetic testing. In this review, an overview of the colon cancer high-risk syndromes, with a focus on the availability and indications for genetic testing, is presented.
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Affiliation(s)
- William M Grady
- Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2279, USA.
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33
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Sarroca C, Peltomäki P, Alfano N, Tedesco G, Della Valle A, Dominguez A, Lynch HT. Three new mutations in hereditary nonpolyposis colorectal cancer (Lynch syndrome II) in Uruguay. CANCER GENETICS AND CYTOGENETICS 2003; 142:13-20. [PMID: 12660027 DOI: 10.1016/s0165-4608(02)00766-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Hereditary nonpolyposis colorectal cancer (HNPCC) is the most common hereditary form of colorectal cancer (CRC). Our purpose is to describe three extended HNPCC families, each of which manifests novel germline mutations in Uruguay, a small country that is a study model for cancer investigation given its high cancer incidence and mortality rate. This is a study of three extended HNPCC families in which extensive genealogic information, medical history, and pathology findings are critically reviewed. DNA testing was performed for evidence of HNPCC mutations. The findings reveal three novel germline mutations, namely MLH1, with a deletion resulting in a frameshift and a premature stop codon (codon 228) in one of the families; in the second family, MSH2 exon 1, codon 61 at nucleotide 181, which results in immediate stop of translation; and in the third family, a mutation in MSH2 at exon 3: the amino acid at nucleotide 530, codon 117, causing a frameshift and a premature stop codon eight base pairs later. We conclude that it is important to study HNPCC mismatch repair genes because of emerging evidence for genotypic and phenotypic heterogeneity, which will harbor the potential to eventually translate this knowledge into specific screening and management protocols. Future projections for such mutations could even contribute to the emergence of molecular-based designer drugs developed through advances in genomics, proteomics, high-throughput screening, and bioinformatics, which would be effective therapeutically for these high-cancer risk patients.
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Affiliation(s)
- Carlos Sarroca
- Uruguayan Collaborative Group: Survey of Hereditary Oncologic Disorders, Hospital Central de las Fuerzas Armadas, 11600 Montevideo, Uruguay
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34
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Gumbs AA, Moore PS, Falconi M, Bassi C, Beghelli S, Modlin I, Scarpa A. Review of the clinical, histological, and molecular aspects of pancreatic endocrine neoplasms. J Surg Oncol 2002; 81:45-54. [PMID: 12210027 DOI: 10.1002/jso.10142] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic endocrine neoplasms (PENs) are rare tumors, and little is known about their genetic and chromosomal alterations. Elucidation of the molecular events involved in PEN carcinogenesis has been hindered by the fact that PENs have been considered a single disease entity. The emergence of novel molecular characterization strategies has, however, made it apparent that these lesions exhibit diverse molecular fingerprints, which will facilitate the precise delineation of PEN prognosis, histopathology, and carcinogenesis.
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Affiliation(s)
- A A Gumbs
- Department of Surgery, University of Verona, Verona, Italy
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35
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Jass JR, Walsh MD, Barker M, Simms LA, Young J, Leggett BA. Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability. Eur J Cancer 2002; 38:858-66. [PMID: 11978509 DOI: 10.1016/s0959-8049(02)00041-2] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Attempts to classify colorectal cancer into subtypes based upon molecular characterisation are overshadowed by the classical stepwise model in which the adenoma-carcinoma sequence serves as the morphological counterpart. Clarity is achieved when cancers showing DNA microsatellite instability (MSI) are distinguished as sporadic MSI-low (MSI-L), sporadic MSI-high (MSI-H) and hereditary non-polyposis colorectal cancer (HNPCC). Divergence of the 'methylator' pathway into MSI-L and MSI-H is at least partly determined by the respective silencing of MGMT and hMLH1. Multiple differences can be demonstrated between sporadic and familial (HNPCC) MSI-H colorectal cancer with respect to early mechanisms, evolution, molecular characterisation, demographics and morphology. By acknowledging the existence of multiple pathways, rapid advances in the fields of basic and translational research will occur and this will lead to improved strategies for the prevention, early detection and treatment of colorectal cancer.
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Affiliation(s)
- J R Jass
- Department of Pathology, University of Queensland, Herston, Queensland 4006, Australia.
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36
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Ponz de Leon M. The Causes of Colorectal Cancer. COLORECTAL CANCER 2002. [DOI: 10.1007/978-3-642-56008-8_1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Church J, Lowry A, Simmang C. Practice parameters for the identification and testing of patients at risk for dominantly inherited colorectal cancer--supporting documentation. Dis Colon Rectum 2001; 44:1404-12. [PMID: 11598466 DOI: 10.1007/bf02234589] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
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Abstract
OBJECTIVE To determine the present state of colonoscopic screening practice for patients at a high risk of developing colorectal cancer. METHODS We assessed colonoscopic screening practice in nine colorectal surgery or gastroenterology units referring patients to the regional genetics centre in the North-west of England. The validity of the pedigree was confirmed by inspection of Hospital records, use of cancer registries and records of general practitioners across the United Kingdom. The screening activity at the participating centres was investigated by means of a questionnaire, site visit and study of case notes. RESULTS One hundred and eight high risk families were identified. Outside the genetics unit, family history was not taken in a structured manner and family pedigree was not confirmed. In four units screening was offered directly by the consultant surgeon. Differing protocols for screening were in place in six units, but were frequently not adhered to. Colonoscopy completion rates were known in only four units (range 83-97%). Frequency of screening varied from 2 to 5 years. Recording of information was minimal outside the patients' records and there were no dedicated databases. Facilities for families to be screened together existed in three units and the psychological effect of screening was not determined outside the genetics centre. CONCLUSIONS Screening practice should be standardized and specific criteria met before regular screening is initiated. A dedicated database should be established to record information from units screening patients at high risk of colorectal cancer.
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Affiliation(s)
- J Hill
- Department of Colorectal Surgery, Manchester Royal Infirmary, Manchester, UK.
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Saletti P, Edwin ID, Pack K, Cavalli F, Atkin WS. Microsatellite instability: application in hereditary non-polyposis colorectal cancer. Ann Oncol 2001; 12:151-60. [PMID: 11300317 DOI: 10.1023/a:1008342420825] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Colorectal cancer (CRC) is a significant cause of mortality in Western populations. About 15% of CRC patients report a family history of the disease. Studies on individuals with a genetic predisposition to CRC have been responsible for significant advances in the understanding of this disease. Thus, although developments in molecular biology have been mainly restricted to a minority of individuals with a hereditary background, information obtained from this group may affect the diagnosis and therapy of sporadic CRCs as well. Deficiency in the DNA mismatch repair (MMR) system results in microsatellite instability (MSI). Individuals from hereditary non-polyposis colorectal cancer (HNPCC) kindreds with germline mutations in genes involved in MMR may benefit from clinical screening programs. The higher frequency of MSI in HNPCC than in sporadic tumours suggests that involvement of MMR genes in sporadic adenomas may be uncommon. Consequently
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Affiliation(s)
- P Saletti
- Istituto Oncologico della Svizzera Italiana, Oncologia medica, Ospedale S. Giovanni, Bellinzona, Switzerland.
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40
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Schünemann HJ, Stanulla M, Trevisan M, Aplan PD, Freudenheim JL, Muti P. Short-term storage of blood samples and DNA isolation in serum separator tubes for application in epidemiological studies and clinical research. Ann Epidemiol 2000; 10:538-44. [PMID: 11118934 DOI: 10.1016/s1047-2797(00)00076-4] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
PURPOSE To investigate the use of a simple DNA isolation technique for application in epidemiologic studies. To analyze systematically the potential impact of lag time between blood drawing and DNA isolation and the condition of storage of blood samples on the quantity and quality of isolated DNA in large-scale epidemiologic studies. METHODS A modified single tube DNA isolation technique was used. DNA was isolated from samples collected from six participants and processed in triplicate: a) without delay after blood drawing; b) after blood cells were stored at 4 degrees C for 7 days; c) after blood cells were stored at -70 degrees C for 7 days; and d) after storage for 7 days at -70 degrees C with addition of lysis/digestion buffer. Polymerase chain reaction (PCR) and Southern blot analysis were performed to analyze the quality of the isolated DNA. RESULTS The average amount of DNA isolated ranged from 27.0 to 71.1 microg/4.5 ml whole blood. Storage at 4 degrees C yielded, on the average, 20% less DNA than the samples processed without delay or after storage at -70 degrees C, although this difference was not statistically significant. All four conditions studied allowed isolation of highly pure DNA suitable for genetic analyses by Southern blot analysis and polymerase chain reaction. CONCLUSIONS This pilot study suggests that storage for 7 days and at different temperatures allows isolation of high quality DNA. Using the described technique, storage of up to 7 days permits processing of large numbers of samples (50-70) in a single day, allowing for a reliable and cost-efficient way of processing in various settings. Further studies are needed to investigate the influence of long-term storage of biological specimens on DNA isolation and quality.
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Affiliation(s)
- H J Schünemann
- Department of Medicine, State University of New York, Buffalo, NY 14214, USA
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41
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Anwar S, Hall C, White J, Deakin M, Farrell W, Elder JB. Hereditary non-polyposis colorectal cancer: an updated review. EUROPEAN JOURNAL OF SURGICAL ONCOLOGY 2000; 26:635-45. [PMID: 11078609 DOI: 10.1053/ejso.2000.0974] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
INTRODUCTION Colorectal cancer is the commonest cause of death due to malignancy in non-smokers in the western countries. The two main hereditary types of colorectal cancer are familial adenomatous polyposis (FAP) and hereditary non-polyposis colorectal cancer (HNPCC), constituting approximately 10% of all cases of colorectal cancer. The main aim of this review is to reappraise the current advances in the genetics and diagnosis of HNPCC. METHODS A Medline search was carried out to identify papers published from 1970 to 1999 on HNPCC. Embase and Cochrane databases were also searched. Reference lists of retrieved articles were carefully searched for additional articles. RESULTS AND CONCLUSIONS Recent technological advances in the genetics of HNPCC have refined the criteria for diagnosis and management of HNPCC, however current policies regarding the testing of pedigrees are not clearly established. We believe that with the rapid development in this area definitive clinical guidelines will need to be available in future for the management of HNPCC.
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Affiliation(s)
- S Anwar
- Department of Surgery, North Manchester General Hospital, Manchester, UK.
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43
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de Leon MP, Benatti P, Pedroni M, Viel A, Genuardi M, Percesepe A, Roncucci L. Problems in the identification of hereditary nonpolyposis colorectal cancer in two families with late development of full-blown clinical spectrum. Am J Gastroenterol 2000; 95:2110-5. [PMID: 10950068 DOI: 10.1111/j.1572-0241.2000.02163.x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The recognition of Hereditary Nonpolyposis Colorectal Cancer (HNPCC) remains difficult despite the most recent advancements of molecular biology and technology. We describe two families with early onset of cancer but no suspicion of hereditary tumors; during follow-up, both families developed a tumor spectrum highly suggestive of HNPCC, thus emphasizing the importance of family history for a proper identification of hereditary tumors or cancer aggregation. Microsatellite instability was negative in tumors from both families and, as expected, no germline mutations of the major DNA mismatch repair genes (MSH2 and MLH1) could be detected. Suspicion of the disease at the time of proband's lesion might have led to prevention, or early diagnosis, of at least three malignant tumors. We conclude that a possible genetic origin should always be suspected in individuals with early-onset neoplasms of the large bowel and probably of other organs such as the endometrium, small bowel, and urothelium, even when the initial pedigree does not show marked aggregation of cancers or vertical transmission.
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Affiliation(s)
- M P de Leon
- Dipartimento di Medicina Interna, Università di Modena, Italy
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44
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Affiliation(s)
- M Ponz de Leon
- Department of Internal Medicine, University of Modena, Italy.
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45
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Stone JG, Tomlinson IP, Houlston RS. Optimising methods for determining RER status in colorectal cancers. Cancer Lett 2000; 149:15-20. [PMID: 10737703 DOI: 10.1016/s0304-3835(99)00324-9] [Citation(s) in RCA: 19] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
Approximately 13% of colorectal cancers display microsatellite instability (MSI), a form of replication error repair. Colorectal cancers developing in individuals with constitutional defects in the mismatch repair (MMR) genes hMLH1, hMSH2, hPMS1 and hPMS2 consistently show evidence of this phenomenon. Since MSI is indicative of MMR deficiency, testing colorectal cancers for MSI provides a method of refining the identification of carriers of germline MMR mutations. To assess which microsatellites represent the best reporters of replication error (RER) status we have examined 116 early onset colorectal cancers for MSI. MSI was assessed using eight dinucleotide- and two mononucleotide-repeat fluorescently labelled polymerase chain reaction (PCR) markers. The two mononucleotide repeat markers (BAT25 and BAT26) were highly sensitive and typing of either represents an efficient strategy for defining RER status of colorectal cancers and obviates the requirement of typing numerous microsatellite markers.
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Affiliation(s)
- J G Stone
- Section of Cancer Genetics, Institute of Cancer Research, Sutton, UK
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46
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Calistri D, Presciuttini S, Buonsanti G, Radice P, Gazzoli I, Pensotti V, Sala P, Eboli M, Andreola S, Russo A, Pierotti M, Bertario L, Ranzani GN. Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition. Int J Cancer 2000; 89:87-91. [PMID: 10719736 DOI: 10.1002/(sici)1097-0215(20000120)89:1<87::aid-ijc14>3.0.co;2-9] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA-mismatch-repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC). Aim of this work was to assess MSI in colorectal-cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG-HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI-H (high frequency of instability, i.e., in > or =30% of the markers) in 85% of the HNPCC patients and in 16% of the non-HNPCC subjects. The 5 NCI/ICG-HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2- and hMLH1 gene mutations and MSI. Our results indicate that AC are highly predictive both of tumour instability and of MMR-gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non-HNPCC patients and to further investigate MMR genes in MSI-H cases, appears to be a cost-effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing.
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Affiliation(s)
- D Calistri
- Dipartimento di Genetica e Microbiologia, University of Pavia, Italy
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47
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Abstract
The molecular genetics of colorectal cancer is presented in an order that ascends from the basic to the applied: molecular mechanisms, morphogenesis, classification and diagnosis. Major consideration is given to the nature of genetic instability and the role of this mechanism in driving neoplastic progression. It is shown how the fundamental principle of genetic instability cuts across applied research, tissue diagnosis and clinical management with respect to both sporadic and inherited forms of colorectal cancer.
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Affiliation(s)
- J R Jass
- Department of Pathology, University of Queensland Medical School, Brisbane, Australia.
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48
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Terdiman JP, Conrad PG, Sleisenger MH. Genetic testing in hereditary colorectal cancer: indications and procedures. Am J Gastroenterol 1999; 94:2344-56. [PMID: 10483990 DOI: 10.1111/j.1572-0241.1999.01356.x] [Citation(s) in RCA: 44] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Approximately 25% of colorectal cancers occur in younger individuals or those with a personal or family history of the disease, suggesting a heritable susceptibility. The minority of these cases are accounted for by one of the well-described hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and hereditary nonpolyposis colorectal cancer (HNPCC). The recent identification and cloning of the genes responsible for FAP and HNPCC, along with other colon cancer susceptibility genes, has led to the wide-spread availability of genetic testing for hereditary colorectal cancer. Genetic testing raises clinical, ethical, legal, and psychosocial questions that must urgently be discussed. This review highlights areas of knowledge and uncertainty about genetic predisposition testing for colorectal cancer and provides clinicians with practical recommendations regarding the proper indications and procedures for this testing.
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Affiliation(s)
- J P Terdiman
- Department of Medicine, University of California, San Francisco, USA
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49
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Kobayashi K, Sagae S, Takeda T, Sugimura M, Nishioka Y, Kudo R. Genetic analysis of familial and multiple malignancies of endometrial cancer. Int J Gynaecol Obstet 1999; 66:149-53. [PMID: 10468338 DOI: 10.1016/s0020-7292(99)00066-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
The presence of the positive replication errors (RER) phenotype in familial and multiple primary malignancies of endometrial cancer, and its association with a poor prognosis was examined. We analyzed 40 endometrial cancers for RER. Eight endometrial cancers with the RER(+) phenotype at multiple microsatellite loci were detected. The presence of the RER(+) phenotype was higher than in non-familial malignancies. None of the eight cases with the RER(+) phenotype involved multiple primary malignancies; however these patients had shorter survival times. In this study, we suggest that RER examination in endometrial cancer may be useful for establishing a diagnosis of a familial malignancy, and for predicting a poor prognosis.
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Affiliation(s)
- K Kobayashi
- Department of Obstetrics and Gynecology, Sapporo Medical University, School of Medicine, Hokkaido, Japan
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50
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Nakajima K, Fukuzawa M, Kusafuka T, Tsuji H, Oue T, Inoue M, Komoto Y, Okada A. Brief report. Metachronous multiple colorectal cancer with genomic instability in a child. MEDICAL AND PEDIATRIC ONCOLOGY 1998; 31:549-50. [PMID: 9835917 DOI: 10.1002/(sici)1096-911x(199812)31:6<549::aid-mpo22>3.0.co;2-c] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Affiliation(s)
- K Nakajima
- Department of Pediatric Surgery, Osaka University Medical School, Japan.
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