Abstract
Lynch syndrome (LS) is caused by inherited germline mutations in mismatch repair (MMR) genes. It is one of the commonest forms of inherited predisposition to colorectal cancer (CRC), accounting for 2–5% of all CRC. LS is characterized by early age of onset, with a tendency for multiplicity and an increased risk for extra-colonic tumors at particular sites. In this study we have evaluated the frequency of extra-colonic tumors in 60 unrelated LS families fulfilling the Amsterdam criteria (ACI. ACII) from the Oncotree database of the Hereditary Colorectal Cancer Registry of the AC Camargo Hospital. All families’ pedigree was extensively analyzed, varying from 2 to 6 generations with a total of 2,095 individuals evaluated. As expected, colorectal cancer was the most frequent tumor in the families (334 cases). We found 200 extracolonic tumors among all individuals with a higher ratio in women (123 cases) than men (77 cases). By far, breast cancer (32 cases) was the most frequent extracolonic manifestation in women followed by endometrial (20 cases) and uterine cervix cancer (20 cases). For man, prostate (16 cases) and stomach (12 cases) cancer were the most frequent extracolonic tumors. It is well know that establishing the diagnosis is challenging and requires knowledge and surveillance. Thus, recognition of individuals and families with hereditary predisposition to cancer according to clinical and molecular features, combined with intensive surveillance and management programs, can contribute substantially to improve results related to the diagnosis and characterization of LS.
Similar content being viewed by others
Abbreviations
- HNPCC:
-
Hereditary non-polyposis colorectal cancer
- CRC:
-
Colorectal cancer
- MMR:
-
Mismatch repair gene
- LS:
-
Lynch syndrome
- ACI:
-
Amsterdam criteria I
- ACII:
-
Amsterdam criteria II
References
Woolf CM (1958) A genetic study of carcinoma of the large intestine. Am J Hum Genet 10(1):42–47
Lovett E (1976) Family studies in cancer of the colon and rectum. Br J Surg 63(1):13–18
Macklin MT (1960) Inheritance of cancer of the stomach and large intestine in man. J Natl Cancer Inst 24:551–571
Duncan JL, Kyle J (1982) Family incidence of carcinoma of the colon and rectum in north-east Scotland. Gut 23(2):169–171
Potter JD (1999) Colorectal cancer: molecules and populations. J Natl Cancer Inst 91(11):916–932
Warthin AS (1913) Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan. Arch Int Med 12:546–555
Savage D (1956) A family history of uterine and gastro-intestinal cancer. Br Med J 2(4988):341–343
Kluge T (1964) Familial cancer of the colon. Acta Chir Scand 127:392–398
Lynch HT, Krush AJ (1971) Cancer family “G” revisited: 1895–1970. Cancer 27(6):1505–1511
Boland CR, Troncale FJ (1984) Familial colonic cancer without antecedent polyposis. Ann Intern Med 100(5):700–701
Ministry of Health/National Institute of Cancer-Inca (2010) Available from: http://www1.inca.gov.br/estimativa/2010/index.asp?link=tabelaestados.asp&UF=BR. Cited 1 May 2010
Geary J, Sasieni P, Houlston R et al (2008) Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer 7(2):163–172
Lynch HT, Ens J, Lynch JF, Watson P (1988) Tumor variation in three extended Lynch syndrome II kindreds. Am J Gastroenterol 83(7):741–747
Lynch HT, Lynch JF (1993) The Lynch syndromes. Curr Opin Oncol 5(4):687–696
Lin KM, Shashidharan M, Ternent CA et al (1998) Colorectal and extracolonic cancer variations in MLH1/MSH2 hereditary non-polyposis colorectal cancer kindreds and the general population. Dis Colon Rectum 41(4):428–433
Watson P, Riley B (2005) The tumor spectrum in the Lynch syndrome. Fam Cancer 4(3):245–248
Vasen HF, Mecklin JP, Khan PM, Lynch HT (1991) The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 34(5):424–425
Vasen HF, Watson P, Mecklin JP, Lynch HT (1999) New clinical criteria for hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 116(6):1453–1456
Lynch HT, Smyrk TC, Watson P et al (1993) Genetics, natural history, tumor spectrum, and pathology of hereditary non-polyposis colorectal cancer: an updated review. Gastroenterology 104(5):1535–1549
Marra G, Boland CR (1995) Hereditary non-polyposis colorectal cancer: the syndrome, the genes, and historical perspectives. J Natl Cancer Inst 87(15):1114–1125
Lynch HT, Smyrk T (1996) Hereditary non-polyposis colorectal cancer (Lynch syndrome): an updated review. Cancer 78(6):1149–1167
Lynch HT, Smyrk T, Lynch J (1997) An update of HNPCC (Lynch syndrome). Cancer Genet Cytogenet 93(1):84–99
Peltomäki P, Vasen HF (1997) Mutations predisposing to hereditary non-polyposis colorectal cancer: database and results of a collaborative study. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer. Gastroenterology 113(4):1146–1158
Giardiello FM (1997) Genetic testing in hereditary colorectal cancer. JAMA 278(15):1278–1281
Bai YQ, Akiyama Y, Nagasaki H et al (1999) Predominant germ-line mutation of the hMSH2 gene in Japanese hereditary non-polyposis colorectal cancer kindreds. Int J Cancer 82(4):512–515
Kim JC, Kim HC, Roh SA et al (2001) hMLH1 and hMSH2 mutations in families with familial clustering of gastric cancer and hereditary non-polyposis colorectal cancer. Cancer Detect Prev 25(6):503–510
Rossi BM, Lopes A, Oliveira Ferreira F et al (2002) hMLH1 and hMSH2 gene mutation in Brazilian families with suspected hereditary non-polyposis colorectal cancer. Ann Surg Oncol 9(6):555–561
Oliveira Ferreira F, Napoli Ferreira CC, Rossi BM et al (2004) Frequency of extracolonic tumors in hereditary non-polyposis colorectal cancer (HNPCC) and familial colorectal cancer (FCC) Brazilian families: An analysis by a Brazilian Hereditary Colorectal Cancer Institutional Registry. Fam Cancer 3(1):41–47
Henderson TO, Amsterdam A, Bhatia S et al (2010) Systematic review: surveillance for breast cancer in women treated with chest radiation for childhood, adolescent, or young adult cancer. Ann Intern Med 152(7):444–455
Vasen HF, Morreau H, Nortier JW (2001) Is breast cancer part of the tumor spectrum of hereditary non-polyposis colorectal cancer? Am J Hum Genet 68(6):1533–1535
Westenend PJ, Schütte R, Hoogmans MM et al (2005) Breast cancer in an MSH2 gene mutation carrier. Hum Pathol 36(12):1322–1326
Risinger JI, Barrett JC, Watson P et al (1996) Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary non-polyposis colorectal carcinoma syndrome. Cancer 77(9):1836–1843
Nelson CL, Sellers TA, Rich SS et al (1993) Familial clustering of colon, breast, uterine, and ovarian cancers as assessed by family history. Genet Epidemiol 10(4):235–244
de Leeuw WJ, van Puijenbroek M, Tollenaar RA et al (2003) Correspondence re: A. Müller et al., Exclusion of breast cancer as an integral tumor of hereditary non-polyposis colorectal cancer. Cancer Res., 62: 1014–1019, 2002. Cancer Res 63(5):1148–1149
Boyd J, Rhei E, Federici MG et al (1999) Male breast cancer in the hereditary non-polyposis colorectal cancer syndrome. Breast Cancer Res Treat 53(1):87–91
Scott RJ, McPhillips M, Meldrum CJ et al (2001) Hereditary non-polyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 68(1):118–127
Müller A, Edmonston TB, Corao DA et al (2002) Exclusion of breast cancer as an integral tumor of hereditary non-polyposis colorectal cancer. Cancer Res 62(4):1014–1019
Itoh H, Houlston RS, Harocopos C, Slack J (1990) Risk of cancer death in first-degree relatives of patients with hereditary non-polyposis cancer syndrome (Lynch type II): a study of 130 kindreds in the United Kingdom. Br J Surg 77(12):1367–1370
Watson P, Lynch HT (1993) Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 71(3):677–685
Aarnio M, Sankila R, Pukkala E et al (1999) Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81(2):214–218
Jass JR (2000) Pathology of hereditary non-polyposis colorectal cancer. Ann NY Acad Sci 910:62–73
Jensen UB, Sunde L, Timshel S et al (2010) Mismatch repair defective breast cancer in the hereditary non-polyposis colorectal cancer syndrome. Breast Cancer Res Treat 120:777–782
Meijers-Heijboer H, Wijnen J, Vasen H et al (2003) The CHEK2 1100delC mutation identifies families with a hereditary breast and colorectal cancer phenotype. Am J Hum Genet 72(5):1308–1314
Parc Y, Boisson C, Thomas G et al (2003) Cancer risk in 348 French MSH2 or MLH1 gene carriers. J Med Genet 40(3):208–213
Aarnio M, Mecklin JP, Aaltonen LA et al (1995) Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64(6):430–433
Vasen HF, Stormorken A, Menko FH et al (2001) MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary non-polyposis colorectal cancer families. J Clin Oncol 19(20):4074–4080
Watson P, Lynch HT (2001) Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1(1):57–60
Goodfellow PJ, Buttin BM, Herzog TJ et al (2003) Prevalence of defective DNA mismatch repair and MSH6 mutation in an unselected series of endometrial cancers. Proc Natl Acad Sci USA 100(10):5908–5913
Wagner A, Barrows A, Wijnen JT et al (2003) Molecular analysis of hereditary non-polyposis colorectal cancer in the United States: high mutation detection rate among clinically selected families and characterization of an American founder genomic deletion of the MSH2 gene. Am J Hum Genet 72(5):1088–1100
Franco EL, Villa LL, Ruiz A et al (1995) Transmission of cervical human papillomavirus infection by sexual activity: differences between low and high oncogenic risk types. J Infect Dis 172(3):756–763
Kjaer SK, Chackerian B, van den Brule AJ et al (2001) High-risk human papillomavirus is sexually transmitted: evidence from a follow-up study of virgins starting sexual activity (intercourse). Cancer Epidemiol Biomark Prev 10(2):101–106
Peyton CL, Gravitt PE, Hunt WC et al (2001) Determinants of genital human papillomavirus detection in a US population. J Infect Dis 183(11):1554–1564
Burchell AN, Winer RL, de Sanjosé S et al (2006) Chapter 6: epidemiology and transmission dynamics of genital HPV infection. Vaccine 24(Suppl 3):S52–S61
Goecke T, Schulmann K, Engel C et al (2006) 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 24(26):4285–4292
Park YJ, Shin KH, Park JG (2000) Risk of gastric cancer in hereditary non-polyposis colorectal cancer in Korea. Clin Cancer Res 6(8):2994–2998
Zhang Y, Sheng J, Li S et al (2005) Clinical phenotype and prevalence of hereditary non-polyposis colorectal cancer syndrome in Chinese population. World J Gastroenterol 11(10):1481–1488
Lynch HT, Grady W, Suriano G et al (2005) Gastric cancer: new genetic developments. J Surg Oncol 90(3):114–133 (discussion 133)
Gayther SA, Gorringe KL, Ramus SJ et al (1998) Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 58(18):4086–4089
Guilford P, Hopkins J, Harraway J et al (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392(6674):402–405
Bevan S, Houlston RS (1999) Genetic predisposition to gastric cancer. QJM 92(1):5–10
Gylling A, Abdel-Rahman WM, Juhola M et al (2007) Is gastric cancer part of the tumour spectrum of hereditary non-polyposis colorectal cancer? A molecular genetic study. Gut 56(7):926–933
Mueller-Koch Y, Vogelsang H, Kopp R et al (2005) Hereditary non-polyposis colorectal cancer: clinical and molecular evidence for a new entity of hereditary colorectal cancer. Gut 54(12):1733–1740
Wijnen J, Khan PM, Vasen H et al (1997) Hereditary nonpolyposis colorectal cancer families not complying with the Amsterdam criteria show extremely low frequency of mismatch-repair-gene mutations. Am J Hum Genet 61(2):329–335
Nyström-Lahti M, Wu Y, Moisio AL et al (1996) DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 5(6):763–769
Katballe N, Juul S, Christensen M et al (2001) Patient accuracy of reporting on hereditary non-polyposis colorectal cancer-related malignancy in family members. Br J Surg 88(9):1228–1233
Murff HJ, Spigel DR, Syngal S (2004) Does this patient have a family history of cancer? An evidence-based analysis of the accuracy of family cancer history. JAMA 292(12):1480–1489
Liu B, Parsons R, Papadopoulos N et al (1996) Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients. Nat Med 2(2):169–174
Renkonen E, Zhang Y, Lohi H et al (2003) Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol 21(19):3629–3637
Lindor NM, Rabe K, Petersen GM et al (2005) Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 293(16):1979–1985
Lynch HT, Lynch PM, Lanspa SJ et al (2009) Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet 76(1):1–18
Roy HK, Lynch HT (2003) Diagnosing Lynch syndrome: is the answer in the mouth? Gut 52(12):1665–1667
de la Chapelle A (2005) The incidence of Lynch syndrome. Fam Cancer 4(3):233–237
Acknowledgment
Supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
da Silva, F.C., de Oliveira, L.P., Santos, É.M. et al. Frequency of extracolonic tumors in Brazilian families with Lynch syndrome: analysis of a hereditary colorectal cancer institutional registry. Familial Cancer 9, 563–570 (2010). https://doi.org/10.1007/s10689-010-9373-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s10689-010-9373-2