INCIDENCE OF DNA-REPLICATION ERRORS IN PATIENTS WITH MULTIPLE PRIMARYCANCERS

PURPOSE: Multiple primary cancers are a feature of hereditary nonpolyp osis colorectal cancer in which defects in DNA repair mechanisms resul t in accumulation of replication errors within tumor DNA. We assessed replication error incidence in multiple primary cancer patients who ma y have similar genetic defects. METHODS: DNA was obtained from 69 pati ents from the Yorkshire region who had developed colorectal cancer and one other primary tumor from the hereditary nonpolyposis colorectal c ancer tumor spectrum (28 colorectal, 12 stomach, 15 ovary, and 14 uter us). DNA was also obtained from 86 sporadic, single primary cancer pat ients attending a colorectal cancer clinic. Replication error status w as assessed at five microsatellite loci using fluorescent polymerase c hain reaction and computer-assisted analysis. RESULTS: The replication error phenotype was observed in 7 of 86 (8 percent) of the sporadic s ingle primary patients. This compared with 23 of 69 (33 percent) of th e multiple primary group (P < 0.001). Replication error was also obser ved more frequently in each subgroup. Even excluding patients from fam ilies meeting the Amsterdam criteria (likely to be hereditary nonpolyp osis 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, particularl y from certain cancer subsets. Testing for replication errors may be a n appropriate way of identifying individuals at risk of multiple prima ry cancers.