Replication errors (RER) associated with genetic instability have been found in cancers of several different types and particularly in the tumours of patients with hereditary non-polyposis colorectal cancer (HNPCC). We have here determined the prevalence of such instability in relation to age among patients without HNPCC. Colorectal cancers (CRCs) in the majority of patients 35 years of age or younger exhibited instability (58% of 31 patients), whereas CRCs from patients older than 35 uncommonly did (12% of 158, P < 0.0001). Twelve of the patients under 35 with instability were evaluated for alterations of mismatch repair genes, and five were found to harbour germline mutations. These data suggest that the mechanisms underlying tumour development in young CRC patients differ from those in most older patients, regardless of HNPCC status. The results have important implications for genetic testing and management of young CRC patients and their families.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $18.75 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Loeb, L.A., Springgate, C.F. & Battula, N. Errors in DNA replication as a basis of malignant changes. Can. Res. 34, 2311–2321 (1974).
Hartwell, L. & Weinert, T. Genetic control of mitotic fidelity in yeast and its relation to cancer, in Origins of Human Cancer, (eds. Brugge, J., Curran, T., Harlow, E. & McCormick, F.) 45–9 (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, New York, 1991).
Cairns, J. Mutation selection and the natural history of cancer. Nature 255, 197–200 (1975).
Cleaver, J.E. Defective repair replication of DNA in xeroderma pigmentosum. Nature 218, 652–656 (1968).
lonov, Y.M., Peinado, A., Malkhosyan, S., Shibata, D., Perucho, M. Ubiquitous somatic mutations in simple repeated sequences reveal a new mechanism for colonic carcinogenesis. Nature 363, 558–561 (1993).
Thibodeau, S.N., Bren, G. & Schaid, D. Microsatellite instability in cancer of the proximal colon. Science 260, 816–819 (1993).
Aaltonen, L.A. et al. Clues to the pathogenesis of familial colorectal cancer. Science 260, 812–816 (1993).
Peltomaki, P. et al. Microsatellite instability is associated with tumours that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res. 53, 5853–5855 (1993).
Han, H-J., Yanagisawa, A., Kato, Y., Park, J.-G., Nakamura, Y. Genetic instability in pancreatic cancer and poorly differentiated type of gastric cancer. Cancer Res. 53, 5087–5089 (1993).
Risinger, I. et al. Genetic instability of microsatellites in endometrial carcinoma. Cancer Res. 53, 5100–5103 (1993).
Burks, R.T., Kessis, T.D., Cho, K.R. & Hedrick, L. Microsatellite instability in endometrial carcinoma. Oncogene 9, 1163–1166 (1994).
Wooster, R. et al. Instability of short tandem repeats (microsatellites) in human cancers. Nature Genet. 6, 152–156 (1994).
Merlo, A. et al. Frequent microsatellite instability in primary small cell lung cancer. Cancer Res. 54, 2098–2101 (1994).
Orth, K. et al. Genetic instability in human ovarian cancer cell lines. Prvc. natn. Acad. Sci. U.S.A. 91, 9495–9499 (1994).
Parsons, R. et al. Hypermutability and mismatch repair deficiency in RER+ tumour cells. Cell 75, 1227–1236 (1993).
Shibata, D., Peinado, M.A., Ionov, Y., Malkhosyan, S. & Perucho, M. Genomic instability in repeated sequences is an early somatic event in colorectal tumori-genesis that persists after transformation. Nature Genet. 6, 273–281 (1994).
Umar, A. et al. Defective mismatch repair in extracts of colorectal and endometrial cancer cell lines exhibiting microsatellite instability. J. Biol. Chem. 269, 14367–14370 (1994).
Kim, H., Jen, J., Vogelstein, B. & Hamilton, S.R. Clinical and pathological characteristics of sporadic colorectal carcinomas with DNA replication errors in microsatellite sequences. Am. J. Pathol. 145, 1–8 (1994).
Lothe, R.A. et al. Genomic instability in colorectal cancer: Relationship to clinicopathological variables and family history. Cancer Res. 53, 5849–5852, (1993).
Liu, B. et al. Mismatch repair gene defects in sporadic colorectal cancers with microsatellite instability. Nature Genet. 9, 48–54 (1995).
Lindblom, A., Tannergard, P., Werelius, B. & Nordenskjold, M. Genetic mapping of a second locus predisposing to hereditary non-polyposis colon cancer. Nature Genet. 5, 279–282 (1993).
Aaltonen, L.A. et al. Replication errors in benign and malignant tumours from hereditary nonpolyposis colorectal cancer patients. Cancer Res. 54, 1645–1648 (1994).
Lynch, H.T. et al. Genetics, natural history, tumour spectrum, and pathology of hereditary nonpolyposis colorectal cancer: An updated review. Gastroenterology 104, 1535–1549 (1993).
Fishel, R. et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75, 1027–1038 (1993).
Leach, F.S. et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75, 1215–1225 (1993).
Bronner, C.E. et al. Mutation in the DNA mismatch repair gene homologue hMLHl is associated with hereditary non-polyposis colon cancer. Nature 368, 258–261 (1994).
Papadopoulos, N. et al. Mutation of a mutL homolog in hereditary colon cancer. Science 263, 1625–1629 (1994).
Nicolaides, N.C. et al. Mutations of two PMS homologues in hereditary nonpolyposis colon cancer. Nature 371, 75–80 (1994).
Palombo, F., Hughes, M., Jiricny, J., Truong, O. & Hsuan, J. Mismatch repair and cancer. Nature 367, 417–418 (1994).
Liu, B. et al. hMSH2 mutations in hereditary nonpolyposis colorectal cancer kindreds. Cancer Res. 54, 4590–4594 (1994).
Hemminki, A. et al. Loss of the wild type MLH1 gene is a feature of hereditary nonpolyposis colorectal cancer. Nature Genet. 8, 405–410 (1994).
Powell, S.M. et al. Molecular diagnosis of familial adenomatous polyposis. New Engl. J. Med. 329, 1982–1987 (1993).
Dietz, H.C. et al. The skipping of constitutive exons in vivo induced by nonsense mutations. Science 259, 680–683 (1993).
Jen, J. et al. Allelic loss of chromosome 18q and prognosis in colorectal cancer. New Engl J. Med. 331, 213–221 (1994).
Costa, L.T. et al. DNA polymerase mutations in colorectal cancers with microsatellite instability. Nature Genet. 9, 9–10 (1995).
Cancer Registration Statistics, Scotland 1978–1987, ISD Publications, Edinburgh (1990).
Miller, B.A. et al. SEER Cancer Statistics Review 1973–1990, National Cancer Institute, NIH Pub.No. 93–2789 (1993).
Vasen, H.F., Mecklin, J.P., Meera Khan, P. & Lynch, H.T. The international collaborative group on hereditary nonpolyposis colorectal cancer (ICG-HNPCC). Dis. Colon. Rectum. 34, 424–425 (1991).
Sidransky, D. et al. Identification of p53 gene mutations in bladder cancers and urine samples. Science 252, 706–709 (1991)
About this article
A Summary of the Fight Colorectal Cancer Working Meeting: Exploring Risk Factors and Etiology of Sporadic Early-Age Onset Colorectal Cancer
Unique profiles of targetable genomic alterations and prognosis in young Chinese patients with lung adenocarcinoma
Pathology - Research and Practice (2019)
The Cancer Journal (2018)