A Comprehensive Assessment of Genetic and Epigenetic Alterations Identifies Frequent Variations Impacting Six Prototypic SCF Complex Members

Abstract

The SKP1, CUL1, F-box protein (SCF) complex represents a family of 69 E3 ubiquitin ligases that poly-ubiquitinate protein substrates marking them for proteolytic degradation via the 26S proteasome. Established SCF complex targets include transcription factors, oncoproteins and tumor suppressors that modulate cell cycle activity and mitotic fidelity. Accordingly, genetic and epigenetic alterations involving SCF complex member genes are expected to adversely impact target regulation and contribute to disease etiology. To gain novel insight into cancer pathogenesis, we determined the prevalence of genetic and epigenetic alterations in six prototypic SCF complex member genes (SKP1, CUL1, RBX1, SKP2, FBXW7 and FBXO5) from patient datasets extracted from The Cancer Genome Atlas (TCGA). Collectively, ~45% of observed SCF complex member mutations are predicted to impact complex structure and/or function in 10 solid tumor types. In addition, the distribution of encoded alterations suggest SCF complex members may exhibit either tumor suppressor or oncogenic mutational profiles in a cancer type dependent manner. Further bioinformatic analyses reveal the potential functional implications of encoded alterations arising from missense mutations by examining predicted deleterious mutations with available crystal structures. The SCF complex also exhibits frequent copy number alterations in a variety of cancer types that generally correspond with mRNA expression levels. Finally, we note that SCF complex member genes are differentially methylated across cancer types, which may effectively phenocopy gene copy number alterations. Collectively, these data show that SCF complex member genes are frequently altered at the genetic and epigenetic levels in many cancer types, which will adversely impact the normal targeting and timely destruction of protein substrates, which may contribute to the development and progression of an extensive array of cancer types.

Genetics and Epigenetics in Complex Diseases

“…While Schedel et al identified a germline variant in RAD21 that can predispose to childhood lymphoblastic leukemia or lymphoma without displaying a Cornelia-de-Lange syndrome phenotype [1], Michler et al identified a germline variant in POT1 in a child with acute myeloid leukemia and showed a connection between this variant and POT expression and telomeric dysregulation [2]. Regarding adult malignancies, Pacholewska et al identified local decreases in methylation levels in chronic lymphocytic leukemia patients harboring mutations at SF3B1, mostly in proximity to telomeric regions, enriched in cancer-related signaling genes [3], and Campos Gudiño et al observed that SKP1, CUL1, and F-box protein complex member genes were frequently altered at the genetic and epigenetic levels in many cancer types, which might contribute to the development and progression of these malignancies [4].…”