Hereditary Nonpolyposis Colorectal Cancer


An inherited cancer predisposition syndrome characterized clinically by a propensity to colorectal, endometrial and other tumors, and molecularly by germline mutations in DNA mismatch repair genes.

Keywords: colon; rectum; endometrium; Lynch syndrome; microsatellite instability; mismatch repair

Figure 1.

Immunohistochemistry of DNA mismatch repair proteins in a colorectal cancer from an HNPCC patient with a germ‐line mutation in MLH1. The top panels (a,c) show low‐power views, the lower panels (b,d) show high‐power views. Antibodies specific to either MSH2 (a,b) or MLH1 (c,d), which have bound to the tissues, are stained red‐brown; nonspecific blue counterstaining is used to show tissue not expressing MSH2 or MLH1. Note that normal tissue (gc) expresses both proteins, as do normal lymphocytes in the stroma surrounding the cancer (n). However, while the cancer cells (Ca) stain strongly for MSH2 (a,b), they lack MLH1 (c,d). Ca: cancer cells; gc: lymphoid germinal centers; n: normal lymphocytes. (Photographs courtesy of Dr Mark Arends, University of Cambridge.)

Figure 2.

DNA mismatch repair in humans. A complex of MSH2–MSH6 binds to point mismatches (a), whereas a complex of MSH2–MSH3 binds to insertion–deletion loops (b). These complexes, bound to mismatched DNA, then bind complexes of MLH1 with either PMS2 or PMS1. The mismatches are then resolved, and repair is achieved.



Aaltonen LA, Peltomaki P, Leach FS, et al. (1993) Clues to the pathogenesis of familial colorectal cancer. Science 260: 812–816.

Boland CR, Thibodeau SN, Hamilton SR, et al. (1998) 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 Research 58: 5248–5257.

Bronner CE, Baker SM, Morrison PT, et al. (1994) Mutation in the DNA mismatch repair gene homologue hMLH1 is associated with hereditary non‐polyposis colon cancer. Nature 368: 258–261.

Fishel R (2001) The selection for mismatch repair defects in hereditary nonpolyposis colorectal cancer: revising the mutator hypothesis. Cancer Research 61: 7369–7374.

Fishel R, Lescoe MK, Rao MR, et al. (1993) The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 75: 1027–1038; erratum (1994) Cell 77: 167.

Halford S, Sasieni P, Rowan A, et al. (2002) Low‐level microsatellite instability occurs in most colorectal cancers and is a nonrandomly distributed quantitative trait. Cancer Research 62: 53–57.

Leach FS, Nicolaides NC, Papadopoulos N, et al. (1993) Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 75: 1215–1225.

Peltomaki P, Aaltonen LA, Sistonen P, et al. (1993a) Genetic mapping of a locus predisposing to human colorectal cancer. Science 260: 810–812.

Peltomaki P, Lothe RA, Aaltonen LA, et al. (1993b) Microsatellite instability is associated with tumors that characterize the hereditary non‐polyposis colorectal carcinoma syndrome. Cancer Research 53: 5853–5855.

Wijnen JT, Vasen HF, Khan PM, et al. (1998) Clinical findings with implications for genetic testing in families with clustering of colorectal cancer. New England Journal of Medicine 339: 511–518.

Further Reading

Jass JR (1998) Diagnosis of hereditary non‐polyposis colorectal cancer. Histopathology 32: 491–497. Review.

Jass JR, Walsh MD, Barker M, et al. (2002) Distinction between familial and sporadic forms of colorectal cancer showing DNA microsatellite instability. European Journal of Cancer 38: 858–866 (review).

Kolodner RD and Marsischky GT (1999) Eukaryotic DNA mismatch repair. Current Opinion in Genetics and Development 9: 89–96 (review).

Lynch HT and de la Chapelle A (1999) Genetic susceptibility to non‐polyposis colorectal cancer. Journal of Medical Genetics 36: 801–818 (review).

Lynch HT, Smyrk T and Lynch JF (1998) Molecular genetics and clinical‐pathology features of HNPCC (Lynch Syndrome): historical journey from pedigree anecdote to molecular genetic confirmation. Oncology 55: 103–108.

Muller A and Fishel R (2002) Mismatch repair and the hereditary non‐polyposis colorectal cancer syndrome (HNPCC). Cancer Investigation 20: 102–109 (review).

Peltomaki P (2001) DNA mismatch repair and cancer. Mutation Research 488: 77–85 (review).

Tomlinson I and Bodmer W (1999) Selection, the mutation rate and cancer: ensuring that the tail does not wag the dog. Nature Medicine 5: 11–12. (review).

Tomlinson IP, Novelli MR and Bodmer WF (1996) The mutation rate and cancer. Proceedings of the National Academy of Sciences of the United States of America 93: 14800–14803.

Warthin A (1913) Heredity with reference to carcinoma. Archives of Internal Medicine 12: 546–555.

Web Links

MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); Locus ID: 4292. LocusLink:

MutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); Locus ID: 4436. LocusLink:

MutS homolog 6 (E. coli) (MSH6); Locus ID: 2956. LocusLink:

PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2); Locus ID: 5395. LocusLink:

MutL homolog 1, colon cancer, nonpolyposis type 2 (E. coli) (MLH1); MIM number: 120436. OMIM:‐post/Omim/dispmim?120436

MutS homolog 2, colon cancer, nonpolyposis type 1 (E. coli) (MSH2); MIM number: 120435. OMIM:‐post/Omim/dispmim?120435

MutS homolog 6 (E. coli) (MSH6); MIM number: 600678. OMIM:‐post/Omim/dispmim?600678

PMS2 postmeiotic segregation increased 2 (S. cerevisiae) (PMS2); MIM number: 600259. OMIM:‐post/Omim/dispmim?600259

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Frayling, Ian(Jan 2006) Hereditary Nonpolyposis Colorectal Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1038/npg.els.0005965]