Bioinformatics Seminar
Time:
Venue: Na
16 August 2016
NaLarge-scale chromosomal changes dominate the genomic landscape of end-stage melanoma
Ismael VergaraPeter Mac
Each year ; 13 ;000 people are diagnosed in Australia with melanoma ; an aggressive type of cancer characterized by low survival rates after metastasis is initiated. The CAncer tiSsue Collection After DEath (CASCADE) is a rapid autopsy program established at the Peter Mac that provides multi-site sampling of metastases from patients. In this talk ; I will present the genomic changes occurring in 13 melanoma patients through progression from primary cutaneous disease to metastases detected from whole exome and genome sequencing data. Gain of single nucleotide variants (SNV) and small insertions/deletions (indel) in metastases was generally limited ; although in some sites massive SNV/indel acquisition was associated with mutations in DNA repair genes. In contrast ; changes in chromosomal copy number and large allelic imbalances (AI) dominated the landscape of metastases ; with extensive loss of heterozygosity decreasing mutational load in some cases. In one case ; multicore sampling of a primary tumor revealed spatial heterogeneity in copy number. These findings were validated by fluorescence in situ hybridization. Increased ploidy and AI were identified in treatment-naïve metastases and primary tumour ; suggesting that this dominant pattern may emerge early and independently of therapy. Genes associated with chromosomal instability were mutated in most cases. We hypothesize that extensive acquired AI and ploidy change sculpt mutational profiles that are strongly selected for during melanoma progression in most patients.;