Abstract
Individuals harboring a germline TP53 mutation have a high lifetime risk of a broad spectrum of cancers, but the age of onset, tumor types and penetrance vary among carriers. The TP53-R337H variant is common in South and Southeastern Brazil due to founder effect and detected in 0.3% of the general population. TP53-R337H predisposes children to adrenocortical tumors (ACTs) and adults to various other Li-Fraumeni syndrome (LFS)-associated core cancers. Assessment of the family history of cancer in TP53-R337H carriers has revealed families fulfilling the classic criteria for LFS as well as those showing an apparently sporadic pattern of cancer presentation, suggesting that genetic and/or environmental factors modulate cancer penetrance in TP53-R337H carriers. Given the incomplete penetrance and heterogeneous familial cancer pattern in TP53-R337H carriers, we hypothesized that additional allelic variants in cis could act as modifiers of TP53-R337H activity and contribute to cancer risk. We used whole genome sequencing for fine mapping analysis of 2-Mb region flanking TP53 locus in ACT samples. Selected common and rare variants were genotyped in 204 unrelated TP53-R337H cancer patients and a control group of 67,359 newborns. Segregation analysis was performed by analyzing 682 family members. Cancer risk was ascertained, and in-vitro functional analysis was performed. We identified a common shared haplotype containing the E134* variant in the XAF1 gene in a subset (42%) of ACT patients harboring the TP53-R337H mutation. This rare variant (minor allele frequency worldwide= 0.004) was identified in 70% of TP53-R337H carrying chromosomes. Co-segregation of both variants was observed in 79% of cancer patients, however, it was significantly enriched in individuals with sarcoma (odds ratio, 5.6; 95% CI, 1.3 to 50.8; P=0.010) and multiple primary malignancies (odds ratio, 3.1; 95% CI, 1.0 to 12.9; P=0.033). Breast cancer patients harboring the extended haplotype developed multiple primary tumors three times more frequently than patients with the TP53-R337H-only haplotype. In vitro studies demonstrated that wild-type XAF1 enhances wild-type and p53-R337H transactivation whereas XAF1-E134* markedly attenuated this activity, thereby establishing a functional interaction between p53 and XAF1. These findings demonstrate that a tolerated and common polymorphism (XAF1-E134*) cooperates with the low-penetrance TP53-R337H variant to modulate cancer phenotype and highlights the potential biological contribution of additional variants that act in cis to influence the cancer phenotype conferred by low-penetrance TP53 alleles. Understanding the nature of the germline TP53 mutation and the contribution of other modifiers that influence its function, such as XAF1-E134*, will have implications for genetic counseling, surveillance and clinical management of these patients. Unless otherwise noted, all abstracts presented at ENDO are embargoed until the date and time of presentation. For oral presentations, the abstracts are embargoed until the session begins. Abstracts presented at a news conference are embargoed until the date and time of the news conference. The Endocrine Society reserves the right to lift the embargo on specific abstracts that are selected for promotion prior to or during ENDO.