PURPOSE: Multiple primary cancers are a feature of hereditary nonpolyposis colorectal cancer in which defects in DNA repair mechanisms result in accumulation of replication errors within tumor DNA. We assessed replication error incidence in multiple primary cancer patients who may have similar genetic defects. METHODS: DNA was obtained from 69 patients from the Yorkshire region who had developed colorectal cancer and one other primary tumor from the hereditary nonpolyposis colorectal cancer tumor spectrum (28 colorectal, 12 stomach, 15 ovary, and 14 uterus). DNA was also obtained from 86 sporadic, single primary cancer patients attending a colorectal cancer clinic. Replication error status was assessed at five microsatellite loci using fluorescent polymerase chain reaction and computer-assisted analysis. RESULTS: The replication error phenotype was observed in 7 of 86 (8 percent) of the sporadic single primary patients. This compared with 23 of 69 (33 percent) of the multiple primary group (P<0.001). Replication error was also observed more frequently in each subgroup. Even excluding patients from families meeting the Amsterdam criteria (likely to be hereditary nonpolyposis colorectal cancer and have the replication error phenotype), this increased frequency remained in both the multiple primary group (P<0.005) and multiple colorectal and colorectal/uterine subgroups (P<0.001). CONCLUSIONS: Results suggest that genetic instability plays an important role in development of multiple primary cancers, particularly from certain cancer subsets. Testing for replication errors may be an appropriate way of identifying individuals at risk of multiple primary cancers.
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Tsukuma H, Fujimoto I, Hanai A, Hiyama T, Kitagawa T, Kinoshita N. Incidence of second primary cancers in Osaka residents, Japan, with special reference to cumulative and relative risks. Jpn J Cancer Res 1994;85:339–45.
Bulow S, Svendsen LB, Mellemgaard A. Metachronous colorectal carcinoma. Br J Surg 1990;77:502–5.
Lynch H, Smyrk T. Hereditary nonpolyposis colorectal cancer: an updated review. Cancer 1996;78:1149–67.
Peltomaki P, Aaltonen LA, Sistonen P,et al. Genetic mapping of a locus predisposing to human colorectal cancer. Science 1993;260:810–2.
Lindblom A, Tannergard P, Werelius B. Genetic mapping of a second locus predisposing to hereditary onopolyposis colorectal cancer. Nat Genet 1993;2:279–82.
Papadopoulos N, Nicolaides NC, Wei Y-F,et al. Mutation of amutL homolog in hereditary colon cancer. Science 1994;263:1625–9.
Aaltonen LA, Peltomaki P, Leach FS,et al. Clues to the pathogenesis of familial colorectal cancer. Science 1993;260:812–6.
Markowitz S, Wang J, Myeroff L,et al. Inactivation of the type II TGF-beta receptor in colon cancer cells with microsatellite instability. Science 1995;268:1336–8.
Fishel R, Lescoe MK, Rao MR,et al. The human mutator gene homologMSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993;75:1027–38.
Liu B, Parsons R, Papadopoulos N,et al. Analysis of mismatch repair genes in hereditary nonpolyposis colorectal cancer patients. Nat Med 1996;2:169–74.
Aaltonen LA, Peltomaki P, Mecklin J-P,et al. Replication errors in benign and malignant tumours from hereditary nonpolyposis colorectal cancer patients. Cancer Res 1994;54:1645–8.
Vasen HF, Mecklin J-P, Meerakhan P, Lynch HT. The international collaborative group on hereditary nonpolyposis colorectal cancer. Dis Colon Rectum 1991;34:424–5.
Liu B, Farrington S, Peterson G,et al. Genetic instability occurs in the majority of young patients with colorectal cancer. Nat Med 1995;1:348–52.
Cawkwell L, Bell S, Lewis F, Dixon M, Taylor G, Quirke P. Rapid detection of allele loss in colorectal tumours using microsatellites and fluorescent DNA technology. Br J Cancer 1993;67:1262–7.
Lothe RA, Peltomäki P, Meling GI,et al. Genomic instability in colorectal cancer: relationship to clinicopathological variables and family history. Cancer Res 1993;53:5849–52.
Watson P, Lynch HT. Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer 1993;71:677–85.
Bronner CE, Baker SM, Morrison PT,et al. Mutation in the DNA mismatch repair gene homologuehMLH1 is associated with hereditary non-polyposis colon cancer. Nature 1994;368:258–61.
Vasen HF, Wijnen JT, Menko FH,et al. Cancer risk in families with hereditary nonpolyposis colorectal cancer diagnosed by mutation analysis. Gastroenterology 1996;110:1020–7.
Supported by the Imperial Cancer Research Fund.
Read at the meeting of The American Society of Colon and Rectal Surgeons, Philadelphia, Pennsylvania, June 22 to 26, 1997.
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Brown, S.R., Finan, P.J., Hall, N.R. et al. Incidence of DNA replication errors in patients with multiple primary cancers. Dis Colon Rectum 41, 765–769 (1998). https://doi.org/10.1007/BF02236266
- Multiple primary cancers
- Hereditary nonpolyposis colorectal cancer
- Replication errors