Review article
Genetic susceptibility to non-polyposis colorectal cancer
Henry T Lyncha, Albert de la Chapelleb
a Department
of Preventive Medicine and Public Health, Creighton University School
of Medicine, 2500 California Plaza, Omaha, Nebraska 68178, USA, b Human Cancer Genetics, The
Ohio State University, Columbus, Ohio 43210, USA
Correspondence to: Dr Lynch.
Familial colorectal cancer (CRC) is a major public health
problem by virtue of its relatively high frequency. Some 15-20% of all
CRCs are familial. Among these, familial adenomatous polyposis (FAP),
caused by germline mutations in the APC
gene, accounts for less than 1%. Hereditary non-polyposis colorectal
cancer (HNPCC), also called Lynch syndrome, accounts for approximately
5-8% of all CRC patients. Among these, some 3% are mutation positive, that is, caused by germline mutations in the DNA mismatch repair genes
that have so far been implicated (MLH1,
MSH2, MSH6,
PMS1, and PMS2).
Most of the remaining patients belonging to HNPCC or HNPCC-like
families are still molecularly unexplained. Among the remaining
familial CRCs, a large proportion is probably caused by gene mutations
and polymorphisms of low penetrance, of which the I1307K polymorphism
in the APC gene is a prime example.
Molecular genetic findings have enabled hereditary CRC to be divided
into two groups: (1) tumours that show microsatellite instability
(MSI), occur more frequently in the right colon, have diploid DNA,
harbour characteristic mutations such as transforming growth factor
type II receptor and BAX, and behave
indolently, of which HNPCC is an example; and (2) tumours with
chromosomal instability (CIN), which tend to be left sided, show
aneuploid DNA, harbour characteristic mutations such as
K-ras, APC, and p53, and behave aggressively, of which FAP
is an example.
This review focuses most heavily on the clinical features, pathology,
molecular genetics, surveillance, and management including prophylactic
surgery in HNPCC. Because of the difficulty in diagnosing HNPCC, a
detailed differential diagnosis of the several hereditary CRC variants
is provided. The extant genetic and phenotypic heterogeneity in CRC
leads to the conclusion that it is no longer appropriate to discuss the
genetics of CRC without defining the specific hereditary CRC syndrome
of concern. Therefore, it is important to ascertain cancer of all
anatomical sites, as well as non-cancer phenotypic stigmata (such as
the perioral and mucosal pigmentations in Peutz-Jeghers syndrome), when
taking a family cancer history.
Keywords: colorectal cancer; hereditary non-polyposis colorectal cancer; genetic susceptibility
© 1999 by J Med Genet
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Nakagawa, H., Nuovo, G. J., Zervos, E. E., Martin, E. W. Jr., Salovaara, R., Aaltonen, L. A., de la Chapelle, A.
(2001). Age-related Hypermethylation of the 5' Region of MLH1 in Normal Colonic Mucosa Is Associated with Microsatellite-unstable Colorectal Cancer Development. Cancer Res.
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(2001). Hereditary and somatic DNA mismatch repair gene mutations in sporadic endometrial carcinoma. J. Med. Genet.
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Marra, G., D'Atri, S., Corti, C., Bonmassar, L., Cattaruzza, M. S., Schweizer, P., Heinimann, K., Bartosova, Z., Nystrom-Lahti, M., Jiricny, J.
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(2001). Detecting Colorectal Cancer in Stool With the Use of Multiple Genetic Targets. JNCI J Natl Cancer Inst
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Wagner, A, Hendriks, Y, Meijers-Heijboer, E J, de Leeuw, W J F, Morreau, H, Hofstra, R, Tops, C, Bik, E, Bröcker-Vriends, A H J T, van der Meer, C, Lindhout, D, Vasen, H F A, Breuning, M H, Cornelisse, C J, van Krimpen, C, Niermeijer, M F, Zwinderman, A H, Wijnen, J, Fodde, R
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(2001). Deficient DNA mismatch repair: a common etiologic factor for colon cancer. Hum Mol Genet
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Zhang, L., Yu, J., Park, B. H., Kinzler, K. W., Vogelstein, B.
(2000). Role of BAX in the Apoptotic Response to Anticancer Agents. Science
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(2000). Lynch Syndrome: Genetics, Natural History, Genetic Counseling, and Prevention. JCO
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(2000). Clinical Diagnosis and Management of Hereditary Colorectal Cancer Syndromes. JCO
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Fleisher, A. S., Esteller, M., Harpaz, N., Leytin, A., Rashid, A., Xu, Y., Liang, J., Stine, O. C., Yin, J., Zou, T.-T., Abraham, J. M., Kong, D., Wilson, K. T., James, S. P., Herman, J. G., Meltzer, S. J.
(2000). Microsatellite Instability in Inflammatory Bowel Disease-associated Neoplastic Lesions Is Associated with Hypermethylation and Diminished Expression of the DNA Mismatch Repair Gene, hMLH1. Cancer Res.
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Desai, D. C, Lockman, J. C, Chadwick, R. B, Gao, X., Percesepe, A., Evans, D G. R, Miyaki, M., Yuen, S. T., Radice, P., Maher, E. R, Wright, F. A, de la Chapelle, A.
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MONTERA, M., RESTA, N., SIMONE, C., GUANTI, G., MARCHESE, C., CIVITELLI, S., MANCINI, A., POZZI, S., DE SALVO, L., BRUZZONE, D., DONADINI, A., ROMIO, L., MARENI, C.
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Salovaara, R., Loukola, A., Kristo, P., Kaariainen, H., Ahtola, H., Eskelinen, M., Harkonen, N., Julkunen, R., Kangas, E., Ojala, S., Tulikoura, J., Valkamo, E., Jarvinen, H., Mecklin, J.-P., Aaltonen, L. A., de la Chapelle, A.
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