An Integrative Variant Scoring Function for Finding Novel Genes Associated with Ovarian and Thyroid Cancer

We devised a quantitative scoring function to assess the cumulative effects of somatic nonsynonymous single-nucleotide variants (SNVs) on protein-coding genes in patients with ovarian cancer (OvCa) and thyroid cancer (ThCa). The goal is to find novel candidate cancer-related genes for downstream bioinformatics analyses and wet-lab studies. With the Genomic Data Commons as primary data resource, SNV information was extracted from whole-exome sequencing data from patients with these cancers. A cumulative variant scoring function, Q(G), was developed to sum up the deleterious effects of the individual SNVs on gene G. While Q(G) can be computed using any popular functional effect analyzers such as FATHMM-XF, SIFT, PolyPhen, and CADD, we have also established an integrative scoring function iQ(G) that combines the deleterious assessments from different analyzers and demonstrated that iQ(G) is a more effective method for identifying likely cancer-related genes. Based on the iQ(G) rankings, the top three novel genes for OvCa are AHNAK2, UNC13A, and PCDHB4; and those for ThCa are PLEC, HECTD4, and CES1. Furthermore, the top 1% genes with highest iQ(G) scores for each cancer were submitted for KEGG pathway analysis. The results revealed that several genes of the CACNA1 family within the type II diabetes mellitus pathway are likely related to both OvCa and ThCa and suggested other molecular interactions that should be further studied in connection with OvCa prognosis and ThCa treatment.