Connecting molecular pathways to hereditary cancer risk syndromes

Abstract

An understanding of the genetic causes and molecular pathways of hereditary cancer syndromes has historically informed our knowledge and treatment of all types of cancers. For this review, we focus on three rare syndromes and their associated genetic mutations including BAP1, TP53, and SDHx (SDHA, SDHB, SDHC, SDHD, SDHAF2). BAP1 encodes an enzyme that catalyzes the removal of ubiquitin from protein substrates, and germline mutations of BAP1 cause a novel cancer syndrome characterized by high incidence of benign atypical melanocytic tumors, uveal melanomas, cutaneous melanomas, malignant mesotheliomas, and potentially other cancers. TP53 mutations cause Li-Fraumeni syndrome (LFS), a highly penetrant cancer syndrome associated with multiple tumors including but not limited to sarcomas, breast cancers, brain tumors, and adrenocortical carcinomas. Genomic modifiers for tumor risk and genotype-phenotype correlations in LFS are beginning to be identified. SDH is a mitochondrial enzyme complex involved in the tricarboxylic acid (TCA) cycle, and germline SDHx mutations lead to increased succinate with subsequent paragangliomas, pheochromocytomas, renal cell carcinomas (RCCs), gastrointestinal stromal tumors (GISTs), and other rarer cancers. In all of these syndromes, the molecular pathways have informed our understanding of tumor risk and successful early tumor surveillance and screening programs.

FIG 1. Distribution of BAP1 germline mutations in families with BAP1 cancer syndrome.^–,– Figure depicts BAP1 protein and various domains, with symbols indicating amino acids corresponding to frameshift, nonsense, and splice site mutation sites

Abbreviations: ASXL1/2, additional sex combs-like proteins 1 and 2 interaction domain: BARD1, BRCA1-associated RING finger domain protein 1 interaction motif; BRCA1, BRCA1 interaction domain; HBM, HCF1-binding motif; NLS, nuclear localization signal: UCH, ubiquitin C-terminal hydrolase: ULD, UCH37-like domain.