30. Clinical utility of NGS in the understanding of crosstalk between nuclear cancer genes and mitochondrial genome in tumorigenesis

Abstract

Reprogramming of energy metabolism is one of the hallmarks of cancers. Dynamic bioenergetics changes can be evidenced by the detection of deleterious mutations in nuclear or mitochondrial genes related to energy metabolism and cancer during tumorigenesis. In order to identify these molecular changes, we developed a comprehensive next-generation sequencing (NGS) approach by target capture-sequencing of 183 cancer-related genes with an average read depth of approximately 1000X. The deep coverage facilitates simultaneous detection of exonic copy number variants (CNVs) and single nucleotide variants (SNVs) at low somatic mosaicism in one comprehensive assessment. Additionally, the circular mitochondrial genome is analyzed as a single amplicon using one pair of back to back primers for the long-range PCR-based enrichment coupled with massively parallel sequencing at an average coverage of ∼20,000X. Thirty Trio (tumor, adjacent tissue, and blood) of colon cancers (20 carcinomas and 10 polyps) were studied. Variants detected are classified according to ACMG guidelines. Out of 30 Trio samples, germline variants were found in 11 patients, 4 of which have pathogenic mutations. Somatic nuclear driver mutations are present in all tumors at >15%. As for mtDNA variants, 1 out of 30 carries deleterious germline mtDNA mutations and 5 harbor somatic pathogenic mtDNA variants. Upon completion of data analysis of 30 Trio samples, it demonstrates energy reprogramming is the pathway intimately correlated with tumorigenesis even though every tumor develops its unique mechanism leading to tumorigenesis.