Allelic imbalance at NBS1 is frequent in both proximal and distal colorectal carcinoma

Nijmegen breakage syndrome (NBS) is a hereditary disorder involving chromos omal instability, cancer risk and radiosensitivity. NBS carriers have an in creased risk of cancer, though the significance of mutations in the NBS1 ge ne in sporadic cancer has not yet been investigated. Because the loss of NB S1 is associated with increased chromosomal rearrangements, and tumors of t he colon are particularly prone to chromosomal anomalies, we have begun to study the NBS1 locus in colorectal cancer (CRC). DNA was isolated from 99 m icrodissected colorectal tumors, and micro-satellite markers flanking the N BS1 locus at 8q21.3 as well as elsewhere on 8q were analyzed. Normal lympho cyte DNA from each patient served to normalize the amplification of each al lele, and a reduction of at least 35% in the intensity of one allele was ta ken as evidence of allelic imbalance (AI). In proximal and distal CRCs we f ound 25.9 and 36.2% with AI at 8q21.3, respectively. AI in proximal CRC ten ded not to extend to marker D8S555 at 8q24.1, whereas in distal CRC the reg ion of AI frequently included all the informative markers. AI of 8q21.3 was not associated with any clinical variable. These results suggest that 8q21 .3 contains a tumor suppressor gene involved in proximal CRC, possibly NBS1 . The large regions of AI make it difficult to determine the importance of AI at the NBSI locus in distal CRC.