Advertisement

Familial Cancer

, 8:519 | Cite as

Cancer risk in a cohort of subjects carrying a single mismatch repair gene mutation

  • D. A. StupartEmail author
  • P. A. Goldberg
  • U. Algar
  • R. Ramesar
Article

Abstract

Hereditary non-polyposis colon cancer (HNPCC) is an autosomal dominant condition, caused by germline mutations in the mismatch repair genes, that presents with colorectal cancers at a young age, as well as extracolonic tumours. One of the causative mutations is the C1528T (Exon 13) mutation of the MLH1 gene. The purpose of this study is to document the cancer risk for subjects who carry this mutation. This is a prospective cohort study of 200 subjects who carry this mutation. We calculated the risk of developing colorectal cancer only in those subjects who had not undergone surveillance colonoscopy. The incidence of extracolonic cancers (for which surveillance is not routinely offered) was determined for the entire cohort. The results of the study are among the 71 subjects who did not undergo surveillance colonoscopy, colorectal cancers occurred in 36 (51%). They occurred at a median age of 44 years (range 17–73). Using Kaplan–Meier estimates, the risk of developing a colorectal cancer by age 65 was 92%. Eighteen subjects in the cohort of 200 were diagnosed with extracolonic tumours. The most common extracolonic malignancies were breast (6/98 women) and endometrial (3/98 women). Thus this mutation has a high penetrance for colorectal cancer, but is not associated with a high risk of developing extracolonic malignancies.

Keywords

Hereditary nonpolyposis colorectal cancer Screening MLH1 Mismatch repair gene Colorectal cancer 

References

  1. 1.
    Watson P, Riley B (2005) The tumor spectrum in the Lynch syndrome. Fam Cancer 4(3):245–248CrossRefPubMedGoogle Scholar
  2. 2.
    Ramesar RS, Madden MV, Felix R, Harocopos CJ, Westbrook CA, Jones G, Cruse JP, Goldberg PA (2000) Molecular genetics improves the management of hereditary non-polyposis colorectal cancer. S Afr Med J 90(7):709–714PubMedGoogle Scholar
  3. 3.
    Goldberg PA, Madden MV, Harocopos C, Felix R, Westbrook C, Ramesar RS (1998) In a resource-poor country, mutation identification has the potential to reduce the cost of family management for hereditary nonpolyposis colorectal cancer. Dis Colon Rectum 41(10):1250–1253CrossRefPubMedGoogle Scholar
  4. 4.
    Anderson DW, Goldberg PA, Algar U, Felix R, Ramesar RS (2007) Mobile colonoscopic surveillance provides quality care for hereditary nonpolyposis colorectal carcinoma families in South Africa. Colorectal Dis 9(6):509–514CrossRefPubMedGoogle Scholar
  5. 5.
    Aarnio M, Mecklin JP, Aaltonen LA, Nyström-Lahti M, Järvinen HJ (1995) Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 64(6):430–433CrossRefPubMedGoogle Scholar
  6. 6.
    Vasen HF, Wijnen JT, Menko FH, Kleibeuker JH, Taal BG, Griffioen G, Nagengast FM, Meijers-Heijboer EH, Bertario L, Varesco L, Bisgaard ML, Mohr J, Fodde R, Khan PM (1996) Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 110(4):1020–1027CrossRefPubMedGoogle Scholar
  7. 7.
    Dunlop MG, Farrington SM, Carothers AD, Wyllie AH, Sharp L, Burn J, Liu B, Kinzler KW, Vogelstein B (1997) Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 6(1):105–110CrossRefPubMedGoogle Scholar
  8. 8.
    Jäger AC, Bisgaard ML, Myrhøj T, Bernstein I, Rehfeld JF, Nielsen FC (1997) Reduced frequency of extracolonic cancers in hereditary nonpolyposis colorectal cancer families with monoallelic hMLH1 expression. Am J Hum Genet 61(1):129–138CrossRefPubMedGoogle Scholar
  9. 9.
    Aarnio M, Sankila R, Pukkala E, Salovaara R, Aaltonen LA, de la Chapelle A, Peltomäki P, Mecklin JP, Järvinen HJ (1999) Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 81(2):214–218CrossRefPubMedGoogle Scholar
  10. 10.
    Vasen HF, Stormorken A, Menko FH, Nagengast FM, Kleibeuker JH, Griffioen G, Taal BG, Moller P, Wijnen JT (2001) MSH2 mutation carriers are at higher risk of cancer than MLH1 mutation carriers: a study of hereditary nonpolyposis colorectal cancer families. J Clin Oncol 19(20):4074–4080PubMedGoogle Scholar
  11. 11.
    Parc Y, Boisson C, Thomas G, Olschwang SJ (2003) Cancer risk in 348 French MSH2 or MLH1 gene carriers. Med Genet 40(3):208–213CrossRefGoogle Scholar
  12. 12.
    Barrow E, Robinson L, Alduaij W, Shenton A, Clancy T, Lalloo F, Hill J, Evans DG (2009) Cumulative lifetime incidence of extracolonic cancers in Lynch Syndrome: a report of 121 families with proven mutations. Clin Genet 75:141–149CrossRefPubMedGoogle Scholar
  13. 13.
    Stupart DA, Goldberg PA, Algar U, Ramesar R (2009) Surveillance colonoscopy improves survival in a cohort of subjects with a single mismatch repair gene mutation. Colorectal Dis 11(2):126–130CrossRefPubMedGoogle Scholar
  14. 14.
    Quehenberger F, Vasen HF, van Houwelingen HC (2005) Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 42(6):491–496CrossRefPubMedGoogle Scholar
  15. 15.
    Watson P, Lynch HT (2001) Cancer risk in mismatch repair gene mutation carriers. Fam Cancer 1(1):57–60CrossRefPubMedGoogle Scholar
  16. 16.
    Lynch HT, Lynch J (2000) Lynch syndrome: genetics, natural history, genetic counseling, and prevention. J Clin Oncol 18(21 suppl):19S–31SPubMedGoogle Scholar
  17. 17.
    Mitchell RJ, Farrington SM, Dunlop MG, Campbell H (2002) Mismatch repair genes hMLH1 and hMSH2 and colorectal cancer: a HuGEreview. Am J Epidemiol 156(10):885–902CrossRefPubMedGoogle Scholar
  18. 18.
    Vasen HF, Möslein G, Alonso A, Bernstein I, Bertario L, Blanco I, Burn J, Capella G, Engel C, Frayling I, Friedl W, Hes FJ, Hodgson S, Mecklin JP, Møller P, Nagengast F, Parc Y, Renkonen-Sinisalo L, Sampson JR, Stormorken A, Wijnen J (2007) Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet 44(6):353–362CrossRefPubMedGoogle Scholar
  19. 19.
    Renkonen-Sinisalo L, Bützow R, Leminen A, Lehtovirta P, Mecklin JP, Järvinen HJ (2007) Surveillance for endometrial cancer in hereditary nonpolyposis colorectal cancer syndrome. Int J Cancer 120(4):821–824CrossRefPubMedGoogle Scholar
  20. 20.
    Dove-Edwin I, Boks D, Goff S, Kenter GG, Carpenter R, Vasen HF, Thomas HJ (2002) The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 94(6):1708–1712CrossRefPubMedGoogle Scholar
  21. 21.
    Boilesen AE, Bisgaard ML, Bernstein I (2008) Risk of gynecologic cancers in Danish hereditary non-polyposis colorectal cancer families. Acta Obstet Gynecol Scand 87(11):1129–1135CrossRefPubMedGoogle Scholar
  22. 22.
    Blokhuis MM, Goldberg PA, Pietersen GE, Algar U, Vorster AA, Govender D, Ramesar RS (2008) The extracolonic cancer spectrum in females with the common ‘South African’ hMLH1 c. C1528T mutation. Fam Cancer 7(3):191–198 (Epub 2007)CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • D. A. Stupart
    • 1
    • 2
    Email author
  • P. A. Goldberg
    • 1
    • 2
  • U. Algar
    • 1
    • 2
  • R. Ramesar
    • 3
    • 4
  1. 1.Colorectal Unit, Department of SurgeryUniversity of Cape TownCape TownSouth Africa
  2. 2.E22 Colorectal UnitGroote Schuur HospitalObservatory, Cape TownSouth Africa
  3. 3.MRC/UCT Human Genetics Research Unit, Division of Human Genetics, Institute for Infectious Diseases and Molecular MedicineUniversity of Cape TownCape TownSouth Africa
  4. 4.Faculty of Health SciencesUniversity of Cape TownObservatory, Cape TownSouth Africa

Personalised recommendations