Extracolonic Manifestations of Lynch Syndrome

Abstract

Lynch syndrome has classically been defined by several predominant malignancies. Initial clinical criteria for diagnosis of Lynch syndrome would miss 40% of affected individuals. As time has passed, our understanding of Lynch syndrome has evolved and will continue to do so. The number of cancer types that are included in the Lynch phenotype is growing. This has allowed clinicians to redefine Lynch syndrome, at risk populations, screening needs, and diagnostic criteria. Inclusion of extracolonic malignancies and alternative genetic pathways gives new insight into the true prevalence and penetrance of Lynch syndrome.

Keywords

Lynch syndrome - extracolonic malignancies - mismatch repair genes - atypical phenotype

• References

• 1 Ponz de Leon M, Bertario L, Genuardi M , et al; Report from the Italian Association for the Study of Hereditary Colorectal Tumors Consensus Group. Identification and classification of hereditary nonpolyposis colorectal cancer (Lynch syndrome): adapting old concepts to recent advancements. Report from the Italian Association for the study of Hereditary Colorectal Tumors Consensus Group. Dis Colon Rectum 2007; 50 (12) 2126-2134
• 2 Lin KM, Shashidharan M, Ternent CA , et al. Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary nonpolyposis colorectal cancer kindreds and the general population. Dis Colon Rectum 1998; 41 (4) 428-433
• 3 Vasen HFA, Offerhaus GJ, den Hartog Jager FC , et al. The tumor spectrum in HNPCC: a study of 24 kindred in the Netherlands. Int J Cancer 1990; 46: 31-34
• 4 da Silva FC, de Oliveira LP, Santos EM , et al. Frequency of extracolonic tumors in Brazilian families with Lynch syndrome: analysis of a hereditary colorectal cancer institutional registry. Fam Cancer 2010; 9 (4) 563-570
• 5 Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993; 71 (3) 677-685
• 6 Akiyama Y, Sato H, Yamada T , et al. Germline mutation of the hMSH6 gene in an atypical hereditary non-polyposis colorectal cancer kindred. Clin Cancer Res 1997; 57: 3920-3923
• 7 Park YJ, Shin KH, Park JG. Risk of gastric cancer in hereditary nonpolyposis colorectal cancer in Korea. Clin Cancer Res 2000; 6 (8) 2994-2998
• 8 Suchy J, Cybulski C, Wokołorczyk D , et al. CHEK2 mutations and HNPCC-related colorectal cancer. Int J Cancer 2010; 126 (12) 3005-3009
• 9 Risinger JI, Barrett JC, Watson P, Lynch HT, Boyd J. Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 1996; 77 (9) 1836-1843
• 10 Jensen UB, Sunde L, Timshel S , et al. Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 2010; 120 (3) 777-782
• 11 Boyd J, Rhei E, Federici MG , et al. Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 1999; 53 (1) 87-91
• 12 Scott RJ, McPhillips M, Meldrum CJ , et al. Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 2001; 68 (1) 118-127
• 13 Vasen HFA, Morreau H, Nortier JWR. Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer?. Am J Hum Genet 2001; 68 (6) 1533-1535
• 14 Cybulski C, Górski B, Huzarski T , et al. CHEK2 is a multiorgan cancer susceptibility gene. Am J Hum Genet 2004; 75 (6) 1131-1135
• 15 Meijers-Heijboer H, Wijnen J, Vasen H , et al. The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 2003; 72 (5) 1308-1314
• 16 Wasielewski M, Vasen H, Wijnen J , et al. CHEK2 1100delC is a susceptibility allele for HNPCC-related colorectal cancer. Clin Cancer Res 2008; 14 (15) 4989-4994
• 17 Lenz DL, Harpster LE. Urothelial carcinoma in a man with hereditary nonpolyposis colon cancer. Rev Urol 2003; 5 (1) 49-53
• 18 Valenzuela CD, Moore HG, Huang WC , et al. Three synchronous primary carcinomas in a patient with HNPCC associated with a novel germline mutation in MLH1: case report. World J Surg Oncol 2009; 7: 94 . Available at http://www.wjso.com/content/7/1/97
• 19 Goecke T, Schulmann K, Engel C , et al; German HNPCC Consortium. Genotype-phenotype comparison of German MLH1 and MSH2 mutation carriers clinically affected with Lynch syndrome: a report by the German HNPCC Consortium. J Clin Oncol 2006; 24 (26) 4285-4292
• 20 Watson P, Vasen HFA, Mecklin JP , et al. The risk of extra-colonic, extra-endometrial cancer in the Lynch syndrome. Int J Cancer 2008; 123 (2) 444-449
• 21 Wagner A, Hendriks Y, Meijers-Heijboer EJ , et al. Atypical HNPCC owing to MSH6 germline mutations: analysis of a large Dutch pedigree. J Med Genet 2001; 38 (5) 318-322
• 22 Kastrinos F, Stoffel EM, Balmaña J, Steyerberg EW, Mercado R, Syngal S. Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States. Cancer Epidemiol Biomarkers Prev 2008; 17 (8) 2044-2051
• 23 Gylling AHS, Nieminen TT, Abdel-Rahman WM , et al. Differential cancer predisposition in Lynch syndrome: insights from molecular analysis of brain and urinary tract tumors. Carcinogenesis 2008; 29 (7) 1351-1359
• 24 Rouprêt M, Yates DR, Comperat E, Cussenot O. Upper urinary tract urothelial cell carcinomas and other urological malignancies involved in the hereditary nonpolyposis colorectal cancer (Lynch syndrome) tumor spectrum. Eur Urol 2008; 54 (6) 1226-1236
• 25 Grindedal EM, Møller P, Eeles R , et al. Germ-line mutations in mismatch repair genes associated with prostate cancer. Cancer Epidemiol Biomarkers Prev 2009; 18 (9) 2460-2467
• 26 Kilpivaara AP, Vahteristo P , et al. CHEK2 I157T Associates with familial and sporadic colorectal cancer. J Med Genet 2006; 43: e34
• 27 Kohlmann W, Gruber SB. Lynch syndrome. Gene reviews. Bethesda, MD: National Center Biotechnology Information; 2011
• 28 Kastrinos F, Mukherjee B, Tayob N , et al. Risk of pancreatic cancer in families with Lynch syndrome. JAMA 2009; 302 (16) 1790-1795
• 29 Wolff BG, Fleshman JW, Beck DE , et al. The ASCRS Textbook of Colon and Rectal Surgery. New York, NY: Springer; 2007: 525-542
• 30 Song YM, Zheng S. Analysis for phenotype of HNPCC in China. World J Gastroenterol 2002; 8 (5) 837-840
• 31 Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M, Järvinen HJ. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995; 64 (6) 430-433
• 32 Barrow E, Robinson L, Alduaij W , et al. Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009; 75 (2) 141-149
• 33 Roa JC, Roa I, Correa P , et al. Microsatellite instability in preneoplastic and neoplastic lesions of the gallbladder. J Gastroenterol 2005; 40 (1) 79-86
• 34 ten Kate GL, Kleibeuker JH, Nagengast FM , et al. Is surveillance of the small bowel indicated for Lynch syndrome families?. Gut 2007; 56 (9) 1198-1201
• 35 Schulmann K, Brasch FE, Kunstmann E , et al; German HNPCC Consortium. HNPCC-associated small bowel cancer: clinical and molecular characteristics. Gastroenterology 2005; 128 (3) 590-599
• 36 Aarnio M, Sankila R, Pukkala E , et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81 (2) 214-218
• 37 Vasen HFA, Stormorken A, Menko FH , et al. MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 2001; 19 (20) 4074-4080
• 38 Murphy HR, Armstrong R, Cairns D, Greenhalgh KL. Muir-Torre syndrome: expanding the genotype and phenotype—a further family with a MSH6 mutation. Fam Cancer 2008; 7 (3) 255-257
• 39 Lynch HT, Lynch PM, Pester J, Fusaro RM. The cancer family syndrome. Rare cutaneous phenotypic linkage of Torre's syndrome. Arch Intern Med 1981; 141 (5) 607-611
• 40 Czakó L, Tiszlavicz L, Takács R , et al. [The first molecular analysis of a Hungarian HNPCC family: a novel MSH2 germline mutation]. Orv Hetil 2005; 146 (20) 1009-1016
• 41 Hitchins MP, Ward RL. Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet 2009; 46 (12) 793-802
• 42 Hangaishi A, Ogawa S, Mitani K , et al. Mutations and loss of expression of a mismatch repair gene, hMLH1, in leukemia and lymphoma cell lines. Blood 1997; 89 (5) 1740-1747
• 43 Pineda M, Castellsagué E, Musulén E , et al. Non-Hodgkin lymphoma related to hereditary nonpolyposis colorectal cancer in a patient with a novel heterozygous complex deletion in the MSH2 gene. Genes Chromosomes Cancer 2008; 47 (4) (Issue 4) 326-332
• 44 Hirano K, Yamashita K, Yamashita N , et al. Non-Hodgkin's lymphoma in a patient with probable hereditary nonpolyposis colon cancer: report of a case and review of the literature. Dis Colon Rectum 2002; 45 (2) 273-279
• 45 Peled JU, Sellers RS, Iglesias-Ussel MD , et al. Msh6 protects mature B cells from lymphoma by preserving genomic stability. Am J Pathol 2010; 177 (5) 2597-2608
• 46 Lucci-Cordisco E, Rovella V, Carrara S , et al. Mutations of the 'minor' mismatch repair gene MSH6 in typical and atypical hereditary nonpolyposis colorectal cancer. Fam Cancer 2001; 1 (2) 93-99
• 47 Edelmann W, Yang K, Umar A , et al. Mutation in the mismatch repair gene Msh6 causes cancer susceptibility. Cell 1997; 91 (4) 467-477
• 48 Nilbert M, Therkildsen C, Nissen A, Akerman M, Bernstein I. Sarcomas associated with hereditary nonpolyposis colorectal cancer: broad anatomical and morphological spectrum. Fam Cancer 2009; 8 (3) 209-213
• 49 Brieger A, Engels K, Schaefer D , et al. Malignant fibrous histiocytoma is a rare Lynch syndrome-associated tumor in two German families. Familial Cancer 2011; 10 (3) 591-595
• 50 Medina Arana V, Barrios del Pino Y, García-Castro C, González-Aguilera JJ, Fernández-Peralta A, González Hermoso F. Highly aggressive leiomyosarcoma associated with Lynch II syndrome: increasing the range of extracolonic cancers related with hereditary non-polyposis colonic cancer. Ann Oncol 2002; 13 (5) 807-808