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

Area of Science:

• Genomics
• Cancer Biology
• Bioinformatics

Background:

• Somatic nonsynonymous single-nucleotide variants (SNVs) accumulate in protein-coding genes and can influence cancer development.
• Identifying novel cancer-related genes is crucial for advancing cancer research and therapeutic strategies.
• Existing methods for assessing variant effects may not fully capture the cumulative impact on cancer gene identification.

Purpose of the Study:

• To develop and validate a quantitative scoring function to assess the cumulative effects of SNVs on protein-coding genes.
• To identify novel candidate cancer-related genes in ovarian cancer (OvCa) and thyroid cancer (ThCa) for further investigation.
• To compare the effectiveness of an integrative scoring function against individual variant effect analyzers.

Main Methods:

• Utilized whole-exome sequencing data from the Genomic Data Commons for OvCa and ThCa patients.
• Developed a cumulative variant scoring function, Q(G), to aggregate deleterious SNV effects on genes.
• Established an integrative scoring function, iQ(G), combining multiple functional effect analyzers (e.g., FATHMM-XF, SIFT, PolyPhen, CADD).

Main Results:

• The integrative scoring function, iQ(G), proved more effective than individual analyzers in identifying likely cancer-related genes.
• Top novel candidate genes for OvCa were AHNAK2, UNC13A, and PCDHB4; for ThCa, they were PLEC, HECTD4, and CES1.
• KEGG pathway analysis of top-ranked genes revealed the CACNA1 family within the type II diabetes mellitus pathway associated with both cancers.

Conclusions:

• The iQ(G) scoring function is a powerful tool for discovering novel cancer-related genes.
• Identified specific novel genes (AHNAK2, UNC13A, PCDHB4 for OvCa; PLEC, HECTD4, CES1 for ThCa) warranting further study.
• Suggests potential molecular links between type II diabetes mellitus pathway genes and OvCa/ThCa, offering new avenues for research and treatment.