Germline Mutations in the CDKN2B Tumor Suppressor Gene Predispose to Renal Cell Carcinoma

Abstract

Familial renal cell carcinoma (RCC) is genetically heterogeneous and may be caused by mutations in multiple genes, including VHL , MET , SDHB , FH , FLCN , PTEN , and BAP1 . However, most individuals with inherited RCC do not have a detectable germline mutation. To identify novel inherited RCC genes, we undertook exome resequencing studies in a familial RCC kindred and identifi ed a CDKN2B nonsense mutation that segregated with familial RCC status. Targeted resequencing of CDKN2B in individuals ( n = 82) with features of inherited RCC then revealed three candidate CDKN2B missense mutations (p.Pro40Thr, p.Ala23Glu, and p.Asp86Asn). In silico analysis of the threedimensional structures indicated that each missense substitution was likely pathogenic through reduced stability of the mutant or reduced affi nity for cyclin-dependent kinases 4 and 6, and in vitro studies demonstrated that each of the mutations impaired CDKN2B-induced suppression of proliferation in an RCC cell line. These fi ndings identify germline CDKN2B mutations as a novel cause of familial RCC. SIGNIFICANCE:Germline loss-of-function CDKN2B mutations were identifi ed in a subset of patients with features of inherited RCC. Detection of germline CDKN2B mutations will have an impact on familial cancer screening and might prove to infl uence the management of disseminated disease. Cancer Discov; 5(7);

The Presence, Persistence and Functional Properties of Plasmodium vivax Duffy Binding Protein II Antibodies Are Influenced by HLA Class II Allelic Variants

“…The quality of the models was confirmed with Verify3D. The models of the HLA II complex of the alpha and beta chains were built using X-ray crystal structures of the complex (PDB ID: 1IEB, 3LQZ, 1SEB, 2Q6W, 4AEN) to guide protein docking [31]. Two representative DBPII antigenic peptides (H1: FHRDITFRKLYLKRKL; H3: DEKAQQRRKQWWNESK) were modelled into each HLA II complex variant using the available crystal structures of the HLA II complexes to guide docking.…”

Genetic and metabolic hallmarks of clear cell renal cell carcinoma

“…However, the functional relationship between intronic EPAS1 SNPs and its mRNA expression was not determined. A study of familial renal cell carcinoma identified mutations in the CDKN2B gene through exon sequencing as predisposing individuals to tumor development [35]. CDKN2B encodes the p15 INK4B protein, which normally functions as a tumor suppressor by binding and inhibiting cyclin-dependent kinases 4 and 6 to prevent cell cycle progression [36].…”

The epigenetic landscape of renal cancer

“…The heterogeneity of mutations within tumours, which results in different subclones that evolve differently, is a major obstacle to clinical translation 235,236,238,239 . Intratumour heterogeneity of DNA methylation might, however, not be as pronounced as intratumour heterogeneity of genomic changes.…”