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.

Using a Family History Questionnaire to Identify Adult Patients with Increased Genetic Risk for Sarcoma

“…As a result, the questionnaire identified one family with lfs and other families that harboured mutations in genes which are usually more relevant to susceptibility to other cancers. The distribution of sarcoma subtypes observed in our clinical sample was consistent with those reported in the literature 20 .…”

GermlineTP53Mutations in Patients With Early-Onset Colorectal Cancer in the Colon Cancer Family Registry

“…Her family history included a mother and maternal uncle with gastric cancer (ages unknown), a sister with leukemia (age 17 years), and another sister with liver carcinoma (age 34 years), none of whom had been tested for the TP53 p.Arg283Cys alteration. 31 Other reports of germline p.Arg283Cys TP53 alteration carriers include a woman 32 with HER2/neu -negative breast cancer (age unknown), for whom family history data were unknown, and a 25-year-old proband 33 with a desmoplastic small round cell tumor and no family history of cancer.…”

Surveillance recommendations for patients with germline TP53 mutations

“…In such settings, 49% of women and 21% of men will develop cancer by the age of 30 years [23], increasing to almost 100% of women and 73% of men over a lifetime [24,25]. There is also an increased risk of second and subsequent cancers [12,26,27]. Sarcomaaffected TP53 mutation carriers are more likely to have multiple primary cancers than noncarriers [27].…”

“…There is also an increased risk of second and subsequent cancers [12,26,27]. Sarcomaaffected TP53 mutation carriers are more likely to have multiple primary cancers than noncarriers [27]. Given the current cure rates in many cancers, there is clearly a need for adequate secondary surveillance in this population.…”

“…Individuals and families ascertained via approaches blinded to family history may have a reduced lifetime cancer risk compared with those ascertained on family history [17,27]. Indeed, as more TP53 mutation carriers are identified, the range of associated phenotypes will continue to expand and contribute to further understanding…”