71. Integrated genomic analysis of hepatocellular carcinoma using WES and aCGH

Aly Abdelkareem

Mei Ling Chong

Mei Ling Chong received her PhD from the Cancer Research Institute of National University of Singapore in 2014. With a passion for genetic diagnostics, she has gained extensive experience in developing NGS tests for clinical use. Her contributions include developing WES for rare diseases, WES hematology assay, and a patented NGS cancer panel, and she has over 5 years of experience in providing clinical-grade data analysis and interpretation based on NGS data. Currently, Mei Ling is an Associate Research Scientist at Yale Cytogenetics Laboratory, which provides chromosome, fluorescence in situ hybridization (FISH), and microarray tests for prenatal, pediatric, and cancer patients. Combining her past experience in molecular genetic testing with the current cytogenetic testing, Mei Ling’s research interests lie in identifying disease-causing genes or biomarkers of diagnostic and prognostic values and dissecting underlying molecular mechanisms for hematologic malignancies and inherited diseases.

Abstract

Mei Ling Chonga, Hongyan Chaia, Qiping Hub, Peining Lia

aYale University Cytogenetics Lab, New Haven, CT, United States; bGuangxi Medical University, Nanning, Guangxi, China

A retrospective study was conducted on a case series of hepatocellular carcinoma (HCC) using whole exome sequencing (WES) and array comparative genomic hybridization (aCGH) to evaluate genetic defects for underlying mechanisms and clinicopathologic associations. Paired DNA samples from tumor and adjacent nontumor tissues of 36 HCC cases and their clinicopathologic findings based on Edmondson-Steiner (E-S) grading, Barcelona-Clinic Liver Cancer (BCLC) stages, recurrence, and survival status were collected. Somatic variants and copy number alterations (CNAs) in a panel of key genes related to HCC were identified, and the tumor mutation burden (TMB) and CNA burden (CNAB) were calculated. An integrated genomic analysis was performed to evaluate the underlying pathways and clinicopathologic associations for HCC. The WES of the cases revealed variants in the TP53, AXIN1, CTNNB1, and SMARCA4 genes, amplifications of the AKT3, MYC, and TERT genes, and deletions of the CDH1, TP53, IRF2, RB1, RPL5, and PTEN genes. These genetic defects affecting the p53/cell cycle control, PI3K/Ras, and β-catenin pathways were observed in approximately 80% of the cases. A germline variant in the ALDH2 gene was detected in 52% of the cases. Significantly higher CNAB in patients with poor prognosis by E-S grade III, BCLC stage C, and recurrence than patients with good prognosis by grade III, stage A, grade III and nonrecurrence was noted. Further analysis on a large case series to correlate genomic profiling with clinicopathologic classifications could provide evidence for diagnostic interpretation, prognostic prediction, and target intervention on involved genes and pathways.