The Genetics of Hereditary Non-Polyposis Colorectal Cancer

Authors: Stephen B. Gruber MD, PhD * and Wendy Kohlmann MD *
View More View Less
  • * From the Division of Molecular Medicine and Genetics, Departments of Internal Medicine and Epidemiology, University of Michigan, Ann Arbor, Michigan.

Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 3% to 5% of all colorectal cancer. HNPCC is caused by germline mutations in the mismatch repair system and is recognized by a characteristic clinical phenotype as well as a hallmark of the tumors termed “microsatellite instability.” Microsatellite instability serves as a molecular fingerprint for defective mismatch repair and has proven to be useful in the molecular diagnostic workup for HNPCC. The crystal structure of the DNA mismatch repair protein MutS has been solved, providing insight into the molecular basis of defective mismatch repair. Genetic testing has become a key component of the treatment of patients and families with HNPCC, and enhanced surveillance for HNPCC has been shown to reduce the rate of colorectal cancer by more than half and improve 10-year survival from 68% to 93%.

If the inline PDF is not rendering correctly, you can download the PDF file here.

Correspondence: Stephen B. Gruber, MD, PhD, 4301 MSRBIII, 1150 W Medical Center Drive, Ann Arbor, MI 48109-0638; e-mail: sgruber@umich.edu.
  • 1

    Lynch HT, Shaw MW, Magnuson CW. Hereditary factors in cancer: Study of two large midwestern kindreds. Arch Intern Med 1966;117:206212.

  • 2

    Boland CR, Troncale FJ. Familial colonic cancer without antecedent polyposis. Ann Intern Med 1984;100:700701.

  • 3

    Warthin AS. Heredity with reference to carcinoma as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895–1913. Arch Intern Med 1913;12:546555.

    • Search Google Scholar
    • Export Citation
  • 4

    Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary NonPolyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991;34:424425.

    • Search Google Scholar
    • Export Citation
  • 5

    Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology 1999;116:14531456.

    • Search Google Scholar
    • Export Citation
  • 6

    Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998;58:52485257.

    • Search Google Scholar
    • Export Citation
  • 7

    Giardiello FM, Brensinger JD, Petersen GM. AGA technical review on hereditary colorectal cancer and genetic testing. Gastroenterology 2001;121:198213.

    • Search Google Scholar
    • Export Citation
  • 8

    Watson P, Lynch HT. The tumor spectrum in HNPCC. Anticancer Res 1994;14:16351639.

  • 9

    Gruber SB. Cancer genetics: Lessons from colorectal cancer. In: Kelsen DP, Daly JM, Kern SE, eds. Gastrointestinal Oncology: Principles and Practice. Philadelphia: Lippincott Williams & Wilkins; 2002:3953.

    • Search Google Scholar
    • Export Citation
  • 10

    Hamilton SR, Liu B, Parsons RE. The molecular basis of Turcot's syndrome [see comments]. N Engl J Med 1995;332: 839847.

  • 11

    Schwartz RA, Torre DP. The Muir-Torre syndrome: A 25-year retrospect. J Am Acad Dermatol 1995;33:90104.

  • 12

    Spitz JL. Genodermatoses: A Full Color Clinical Guide to Genetic Skin Disorders. Baltimore: Williams & Wilkins; 1996.

  • 13

    Lynch HT, Smyrk T. Hereditary nonpolyposis colorectal cancer (Lynch syndrome). An updated review. Cancer 1996; 78:11491167.

  • 14

    Watson P, Vasen HF, Mecklin JP. The risk of endometrial cancer in hereditary nonpolyposis colorectal cancer. Am J Med 1994;96:516520.

  • 15

    Aarnio M, Sankila R, Pukkala E. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999;81:214218.

  • 16

    Aarnio M, Mecklin JP, Aaltonen LA. Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer 1995;64:430433.

    • Search Google Scholar
    • Export Citation
  • 17

    Lamers MH, Perrakis A, Enzlin JH. The crystal structure of DNA mismatch repair protein MutS binding to a G X T mismatch. Nature 2000;407:711717.

    • Search Google Scholar
    • Export Citation
  • 18

    Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon [see comments]. Science 1993;260:816819.

  • 19

    Aaltonen LA, Peltomaki P, Leach FS. Clues to the pathogenesis of familial colorectal cancer [see comments]. Science 1993;260:812816.

  • 20

    Peltomaki P, Lothe RA, Aaltonen LA. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993;53:58535855.

    • Search Google Scholar
    • Export Citation
  • 21

    Fishel R, Lescoe MK, Rao MR. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer [published erratum appears in Cell 1994;8:77]. Cell 1993;75:10271038.

    • Search Google Scholar
    • Export Citation
  • 22

    Leach FS, Nicolaides NC, Papadopoulos N. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993;75:12151225.

  • 23

    Bronner CE, Baker SM, Morrison PT. Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994;368:258261.

    • Search Google Scholar
    • Export Citation
  • 24

    Papadopoulos N, Nicolaides NC, Wei YF. Mutation of a mutL homolog in hereditary colon cancer [see comments]. Science 1994;263:16251629.

  • 25

    Fishel R. The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. Cancer Res 2001;61:73697374.

    • Search Google Scholar
    • Export Citation
  • 26

    Liu B, Parsons R, Papadopoulos N. Analysis of mismatch repair genes in hereditary non-polyposis colorectal cancer patients [see comments]. Nat Med 1996;2:169174.

    • Search Google Scholar
    • Export Citation
  • 27

    Peltomaki P, Vasen HF. Mutations predisposing to hereditary nonpolyposis colorectal cancer: Database and results of a collaborative study. The International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Gastroenterology 1997;113:11461158.

    • Search Google Scholar
    • Export Citation
  • 28

    Miyaki M, Konishi M, Tanaka K. Germline mutation of MSH6 as the cause of hereditary nonpolyposis colorectal cancer [letter]. Nat Genet 1997;17:271272.

    • Search Google Scholar
    • Export Citation
  • 29

    Berends MJ, Wu Y, Sijmons RH. Molecular and clinical characteristics of MSH6 variants: An analysis of 25 index carriers of a germline variant. Am J Hum Genet 2002;70:2637.

    • Search Google Scholar
    • Export Citation
  • 30

    Liu T, Yan H, Kuismanen S. The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res 2001;61:77987802.

  • 31

    Syngal S, Fox EA, Eng C. Sensitivity and specificity of clinical criteria for hereditary non-polyposis colorectal cancer associated mutations in MSH2 and MLH1. J Med Genet 2000;37:641645.

    • Search Google Scholar
    • Export Citation
  • 32

    Katballe N, Juul S, Christensen M. Patient accuracy of reporting on hereditary non-polyposis colorectal cancer-related malignancy in family members. Br J Surg 2001; 88:12281233.

    • Search Google Scholar
    • Export Citation
  • 33

    Cunningham JM, Kim CY, Christensen ER. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet 2001;69:780790.

    • Search Google Scholar
    • Export Citation
  • 34

    Solomon CH, Pho LN, Burt RW. Current status of genetic testing for colorectal cancer susceptibility. Oncology (Huntingt) 2002;16:161171.

  • 35

    Wijnen J, Vanderklift H, Vasen H. MSH2 Genomic deletions are a frequent cause of HNPCC. Nat Genet 1998; 20:326328.

  • 36

    Charbonnier F, Raux G, Wang Q. Detection of exon deletions and duplications of the mismatch repair genes in hereditary nonpolyposis colorectal cancer families using multiplex polymerase chain reaction of short fluorescent fragments. Cancer Res 2000;60:27602763.

    • Search Google Scholar
    • Export Citation
  • 37

    Yan H, Papadopoulos N, Marra G. Conversion of diploidy to haploidy. Nature 2000;403:723724.

  • 38

    Statement of the American Society of Clinical Oncology: genetic testing for cancer susceptibility, Adopted on February 20, 1996. J Clin Oncol 1996;14:17301736.

    • Search Google Scholar
    • Export Citation
  • 39

    Petersen GM, Brensinger JD, Johnson KA, Giardiello FM. Genetic testing and counseling for hereditary forms of colorectal cancer. Cancer 1999;86:25402550.

    • Search Google Scholar
    • Export Citation
  • 40

    Terdiman JP, Conrad PG, Sleisenger MH. Genetic testing in hereditary colorectal cancer: Indications and procedures. Am J Gastroenterol 1999;94:23442356.

    • Search Google Scholar
    • Export Citation
  • 41

    Lerman C, Narod S, Schulman K. BRCA1 testing in families with hereditary breast-ovarian cancer. A prospective study of patient decision making and outcomes. JAMA 1996;275:18851892.

    • Search Google Scholar
    • Export Citation
  • 42

    Croyle RT, Smith KR, Botkin JR. Psychological responses to BRCA1 mutation testing: preliminary findings. Health Psychol 1997;16:6372.

  • 43

    Lodder L, Frets PG, Trijsburg RW. Psychological impact of receiving a BRCA1/BRCA2 test result. Am J Med Genet 2001;98:1524.

  • 44

    Vernon SW, Gritz ER, Peterson SK. Correlates of psychologic distress in colorectal cancer patients undergoing genetic testing for hereditary colon cancer. Health Psychol 1997;16:7386.

    • Search Google Scholar
    • Export Citation
  • 45

    Gritz ER, Vernon SW, Peterson SK. Distress in the cancer patient and its association with genetic testing and counseling for hereditary non-polyposis colon cancer. Cancer Res Ther Control 1999;8:3549.

    • Search Google Scholar
    • Export Citation
  • 46

    DudokdeWit AC, Tibben A, Duivenvoorden HJ. Predicting adaptation to presymptomatic DNA testing for late onset disorders: who will experience distress? Rotterdam Leiden Genetics Workgroup. J Med Genet 1998;35: 745754.

    • Search Google Scholar
    • Export Citation
  • 47

    Watson P, Lin KM, Rodriguez-Bigas MA. Colorectal carcinoma survival among hereditary nonpolyposis colorectal carcinoma family members. Cancer 1998;83:259266.

    • Search Google Scholar
    • Export Citation
  • 48

    Elsaleh H, Joseph D, Grieu F. Association of tumour site and sex with survival benefit from adjuvant chemotherapy in colorectal cancer. Lancet 2000;355:17451750.

    • Search Google Scholar
    • Export Citation
  • 49

    Watanabe T, Wu TT, Catalano PJ. Molecular predictors of survival after adjuvant chemotherapy for colon cancer. N Engl J Med 2001;344:11961206.

    • Search Google Scholar
    • Export Citation
  • 50

    Maxwell GL, Risinger JI, Alvarez AA. Favorable survival associated with microsatellite instability in endometrioid endometrial cancers. Obstet Gynecol 2001;97:417422.

    • Search Google Scholar
    • Export Citation
  • 51

    Jarvinen HJ, Aarnio M, Mustonen H. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology 2000;118:829834.

    • Search Google Scholar
    • Export Citation
  • 52

    Lynch HT, Watson P, Kriegler M. Differential diagnosis of hereditary nonpolyposis colorectal cancer (Lynch syndrome I and Lynch syndrome II). Dis Colon Rectum 1988;31:372377.

    • Search Google Scholar
    • Export Citation
  • 53

    Burke W, Petersen G, Lynch P. Recommendations for follow-up care of individuals with an inherited predisposition to cancer: I. Hereditary nonpolyposis colon cancer. Cancer Genetics Studies Consortium. JAMA 1997;277:915919.

    • Search Google Scholar
    • Export Citation
  • 54

    Dove-Edwin I, Boks D, Goff S. The outcome of endometrial carcinoma surveillance by ultrasound scan in women at risk of hereditary nonpolyposis colorectal carcinoma and familial colorectal carcinoma. Cancer 2002; 94:17081712.

    • Search Google Scholar
    • Export Citation
  • 55

    Combination oral contraceptive use and the risk of endometrial cancer. JAMA 1987;257:796800.

  • 56

    Renkonen-Sinisalo L, Sipponen P, Aarnio M. No support for endoscopic surveillance for gastric cancer in hereditary non-polyposis colorectal cancer. Scand J Gastroenterol 2002;37:574577.

    • Search Google Scholar
    • Export Citation
  • 57

    Codori AM, Petersen GM, Miglioretti DL. Attitudes toward colon cancer gene testing: Factors predicting test uptake. Cancer Epidemiol Biomarkers Prev 1999;8:345351.

    • Search Google Scholar
    • Export Citation
  • 58

    Lerman C, Hughes C, Trock BJ. Genetic testing in families with hereditary nonpolyposis colon cancer. JAMA 1999;281:16181622.

  • 59

    Lynch HT, Lemon SJ, Karr B. Etiology, natural history, management and molecular genetics of hereditary nonpolyposis colorectal cancer (Lynch syndromes): Genetic counseling implications. Cancer Epidemiol Biomarkers Prev 1997;6:987991.

    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 2 0 0
Full Text Views 184 134 3
PDF Downloads 106 84 4
EPUB Downloads 0 0 0