High frequency of germline TP53 mutations in a prospective adult-onset sarcoma cohort

Abstract

Sarcomas are a key feature of Li-Fraumeni and related syndromes (LFS/LFL), associated with germline TP53 mutations. Current penetrance estimates for TP53 mutations are subject to significant ascertainment bias. The International Sarcoma Kindred Study is a clinic-based, prospective cohort of adult-onset sarcoma cases, without regard to family history. The entire cohort was screened for mutations in TP53 using high-resolution melting analysis and Sanger sequencing, and multiplex-ligation-dependent probe amplification and targeted massively parallel sequencing for copy number changes. Pathogenic TP53 mutations were detected in blood DNA of 20/559 sarcoma probands (3.6%); 17 were germline and 3 appeared to be somatically acquired. Of the germline carriers, one appeared to be mosaic, detectable in the tumor and blood, but not epithelial tissues. Germline mutation carriers were more likely to have multiple cancers (47% vs 15% for non-carriers, P = 3.0×10(-3)), and earlier cancer onset (33 vs 48 years, P = 1.19×10(-3)). The median survival of mutation carriers following first cancer diagnosis was not significantly different from non-carriers. Only 10/17 (59%) pedigrees met classical or Chompret criteria for LFS. In summary, germline TP53 mutations are not rare in adult patients with sarcoma, with implications for screening, surveillance, treatment and genetic counselling of carriers and family members.

Figure 1. Somatic mosaicism demonstrated in an ISKS proband.

Case 14 presented with an osteosarcoma of the mandible at age 19yrs. HRM analysis of the peripheral blood DNA estimated that 20–25% of alleles were mutant. The mutation was detected in tumour DNA and found to be heterozygous, but was absent in multiple other non-tumour tissues of the mouth.

Figure 2. Kaplan-Meier overall survival analysis comparing TP53 mutation carriers to non-carriers.

To correct for survival bias, this analysis was limited to ISKS participants prospectively recruited from 2007 onwards (TP53 mutation carriers, n = 11; Non-carriers, n = 420).