p53 mutations and microsatellite instability in ovarian cancer: Yin and Yang

OBJECTIVE: We tested the hypothesis that p53 frameshift mutations in ovaria n cancer occur as a result of genomic instability rather than as a proximal cause of this process. STUDY DESIGN: Sequencing of the p53 tumor suppressor gene has been carried out on 305 ovarian, fallopian tube, and peritoneal cancers. Two groups of p 53 null mutations were identified: (1) those caused by frameshift insertion or deletion mutations (n = 31) and (2) those caused by nonsense mutations (n = 28). As a control group 59 tumors with p53 missense mutations were sel ected by matching with the p53 null tumors on the basis of patient age at d iagnosis, stage and grade of cancer, cancer site, and year of diagnosis. Mi crosatellite instability was determined from paired normal and tumor tissue deoxyribonucleic acid by means of the following different markers: D2S123, D5S346, D17S250, BAT25, and BAT26. Amplimers from polymerase chain reactio ns were evaluated on 7% polyacrylamide gels. RESULTS: The p53 null tumors were more likely to be of higher stage and gra de. Fallopian tube cancers were more common (P =.02) in the p53 frameshift group. The overall incidence of microsatellite instability was 39%, 36%, an d 25% for tumors with p53 frameshift nonsense and missense mutations (P =.3 0). Microsatellite instability was seen almost exclusively with ovarian can cer (P=.04). CONCLUSIONS: Microsatellite instability is a relatively common event in ova rian cancer and is dependent on marker selection. The p53 frameshift mutati ons do not appear to occur as a consequence of genomic instability.