Abstract
Uncontrolled replication is a process common to all cancers facilitated by the summation of changes accumulated as tumors progress. The aim of this study was to examine small groups of genes with known biology in replication and repair at the transcriptional and genomic levels, correlating alterations with survival in Uveal Melanoma tumor progression. Selected components of Pre-Replication, Pre-Initiation, and Replisome Complexes, DNA Damage Response and Mismatch Repair have been observed. As is common in cancer we find evidence of replication stress and replication stress response, processes that have been suggested as targetable points of intervention. We have generated two groups for each gene examined “above” and “below” the average alteration level, and compared relative expression and survival across TCGA UVM subtypes based on somatic copy number alteration supported by DNA methylation and mRNA/miRNA/lncRNA expression. Specific genes with significant alteration include MCM2 MCM4 and MCM5 of the Minichromosome Maintenance helicase complex, CDC45, MCM10, CIZ1, PCNA, FEN1, LIG1, POLD1, POLE, HUS1, CHECK1, ATRIP, MLH3, and MSH6. We found evidence of Exon 4 skipping in CIZ1 previously identified as a cancer variant and reportedly used as an early serum biomarker in lung cancer, accompanied by evidence of instability of a mononucleotide repeat in Intron 3 that may be due to Mismatch Repair deficiency. Mismatch Repair protein MLH3 was found to have splicing variations with deletions to both Exon 5 and Exon 7 simultaneously. PCNA, FEN1, and LIG1 had increased relative expression levels not due to their mutation or to copy number variation.
Abbreviations
- TCGA
- The Cancer Genome Atlas
- UVM
- Uveal Melanoma
- WES
- Whole exome sequencing
- WGS
- Whole genome sequencing
- SCNA
- Somatic copy number alterations
- DDR
- DNA Damage Repair
- MMR
- Mismatch Repair
- BER
- Base excision repair
- MCM
- Mini-Chromosome Maintenance
- RPKM
- Reads per Kilobase of transcript per million mapped reads
- RSEM
- RNAseq by Expectation Maximization