Deficient DNA repair capacity: A predisposing factor and high risk predictive marker in familial colorectal cancer

Even though colorectal cancer tends to aggregate in families, there is pauc ity of information on the genetic determinism for familial colorectal cance r (FCRC) predisposition. Therefore, we investigated constitutional chromoso me abnormalities and bleomycin induced chromosome sensitivity of 26 familia l and 30 sporadic colorectal cancer (SCRC) patients, 60 unaffected family m embers (first/second degree relatives) and 30 normal healthy controls to de termine whether these parameters could give any clues on genetic predisposi ng factors by which high risk members in CRC families could be identified. The test assay used bleomycin-induced chromatid breaks in short term microc ultures of peripheral blood lymphocytes of the subjects. The CRC patients, the unaffected family members and the controls did not show any constitutio nal chromosomal abnomalities. However, with regard to bleomycin sensitivity , there was significant difference between the CRC patients, unaffected rel atives and controls. The mean b/c values of 1.64 +/- 0.42 for the FCRC pati ents and 1.08 +/- 0.34 for the SCRC patients were significantly higher than the mean b/c values of 0.62 +/- 0.18 for the unaffected relatives and 0.52 +/- 0.12 for the controls (P < 0.001). A noteworthy observation was that 6 unaffected members from 6 CRC families also showed bleomycin hypersensitiv ity, at the initiation of the study. Since they expressed mean b/c values g reater than 1.0, which was as high a value as those of the patients, they w ere regularly followed up. Out of these 6 members, 2 developed CRC later. T his clearly demonstrates that mutagen hypersensitivity among unaffected rel atives in CRC families may be related to cancer predisposition. Hence, this cytogenetic assay could be utilised to identify the genetically high risk individuals in CRC families.