ABSTRACT
Background Chronic inflammation and chromosome aneuploidy are major traits of primary liver cancer (PLC), which represent the second most common cause of cancer related death worldwide. Increased cancer fitness and aggressiveness of PLC may be achieved by enhancing tumoral genomic complexity that alters tumor biology.
Method Here, we developed a scoring method, namely functional genomic complexity (FGC), to determine the degree of molecular heterogeneity among 580 liver tumors with diverse ethnicities and etiologies by assessing integrated genomic and transcriptomic data.
Results We found that tumors with higher FGC scores are associated with chromosome instability and TP53 mutations, and a worse prognosis, while tumors with lower FGC scores have elevated infiltrating lymphocytes and a better prognosis. These results indicate that FGC scores may serve as a surrogate to define genomic heterogeneity of PLC linked to chromosomal instability and evasion of immune surveillance.
Conclusion Our findings demonstrate an ability to define genomic heterogeneity and corresponding tumor biology of liver cancer based only on bulk genomic and transcriptomic data. Our data also provide a rationale for applying this approach to survey liver tumor immunity and to stratify patients for immune-based therapy.
STATEMENT OF SIGNIFICANCE Genomic heterogeneity contributes to therapeutic failure and poor outcome in patients with liver cancer and poses a challenge in defining targeted therapy. Our findings demonstrate an ability to define genomic heterogeneity and corresponding tumor biology of liver cancer based only on bulk genomic and transcriptomic data. Our data also provide a rationale for applying this approach to survey liver tumor immunity and to stratify patients for immune-based therapy. \body
Abbreviations
- PLC
- primary liver cancer;
- FGC
- functional genomic complexity;
- HCC
- Hepatocellular carcinoma;
- iCCA
- intrahepatic cholangiocarcinoma;
- ITH
- intra-tumor heterogeneities;
- SCNA
- somatic copy number alteration;
- T
- tumor;
- NT
- non-tumor;
- PCC
- patient correlation coefficient;
- GO
- Gene Ontology;
- DDR
- DNA damage response;
- CIN
- chromosomal instability;
- tFA
- total functional aneuploidy;
- TILs
- tumor infiltrating lymphocytes;
- GIN
- genomic instability;
- HFGC
- high functional genomic complexity group;
- LFGC
- low functional genomic complexity group;
- TCGA
- the Cancer Genome Atlas;
- LOH
- loss of heterozygosity;
- DEL W/LOH
- deleted segments with LOH;
- AMP W/LOH
- amplified segments with LOH;
- CN LOH
- copy neutral LOH;
- GSEA
- gene set enrichment analysis;
- DBD
- DNA binding domain;
- Tregs
- regulatory T cell;
- NK
- natural killer cell;
- DC
- dendritic cell;
- KM
- Kaplan-Meier (KM);
- CTLA-4
- cytotoxic T-lymphocyte associated antigen 4;
- PD-1
- programmed cell death protein 1.