Relative frequency and morphology of cancers in carriers of germline TP53 mutations

The spectrum and frequency of cancers associated with germline TP53 mutatio ns are uncertain. To address this issue a cohort of individuals from 28 fam ilies with Li-Fraumeni syndrome, segregating germline TP53 mutations was es tablished. Predicted cancers were estimated by applying age, morphology, si te and sex-specific UK cancer statistics to person-years at risk. Observed and predicted cancers were compared and two-sided P-values calculated. Canc er types occurring to excess and showing P-values <0.02, were designated st rongly associated with germline TP53 mutations. These were removed from the data and a second round of analyses performed. Cancer types with P-values <0.02 and 0.02-0.05 in the second round analyses were considered moderately and weakly associated respectively. Strongly associated cancers were: brea st carcinoma, soft tissue sarcomas, osteosarcoma, brain tumours, adrenocort ical carcinoma, Wilms' tumour and phyllodes tumour. Carcinoma of pancreas w as moderately associated. Leukaemia and neuroblastoma were weakly associate d. Other common carcinomas including lung, colon, bladder, prostate, cervix and ovary did not occur to excess. Although breast carcinoma and sarcomas were numerically most frequent, the greatest increases relative to general population rates were in adrenocortical carcinoma and phyllodes tumour. We conclude that germline TP53 mutations do not simply increase general cancer risk. There are tissue-specific effects.