Diagnostics of -Tumor Predisposition Syndrome by a Multitesting Approach: A Ten-Year-Long Experience.

Germline mutations in the tumor suppressor gene BRCA1-associated protein-1 () lead to tumor predisposition syndrome (-TPDS), characterized by high susceptibility to several tumor types, chiefly melanoma, mesothelioma, renal cell carcinoma, and basal cell carcinoma. Here, we present the results of our ten-year experience in the molecular diagnosis of -TPDS, along with a clinical update and cascade genetic testing of previously reported -TPDS patients and their relatives. Specifically, we sequenced germline DNA samples from 101 individuals with suspected -TPDS and validated pathogenic variants (PVs) by assessing somatic loss in matching tumor specimens. Overall, we identified seven patients (7/101, 6.9%) carrying six different germline PVs, including one novel variant. Consistently, cascade testing revealed a total of seven PV carriers. In addition, we explored the mutational burden of -TPDS tumors by targeted next-generation sequencing. Lastly, we found that certain tumors present in PV carriers retain a wild-type allele, suggesting a sporadic origin of these tumors or a functional role of heterozygous in neoplastic development. Altogether, our findings have important clinical implications for therapeutic response of -TPDS patients.