Module 3 readings

Question 1

illumina sequencing to measure TMB and detect variants as a cost-effective alternative - Pestinger et al. 2020

Answer 1

• Compared illumina sequencing to WGS
• Had similar results as WGS
• could detect low variant allele freq, long INDELS, MSI high and RNA fusions
• Identified actionable mutations allowing for clinical trials to be matched to all patients
• Cost-effective
• Limitation = complex to make library

Question 2

Use of a MTB - Kato et al. 2020

Answer 2

patients with MTB-recommended regimens had a significantly longer PFS and overall survival

Question 3

Pan cancer association of HLA gene expression with prognosis and immunotherapy efficacy - Schaafsma et al. 2021

Answer 3

• Looked at 33 cancer types
• Higher HLA expression was associated with increased immune cell infiltration, prolonged survival, increased response to immune checkpoint inhibitors
• many cancers associated with HLA mutations > chromosome loss, promoter methylation and mutants

Question 4

WGS, transcriptome and methylome profile for target discovery in high risk pediatric cancers - Wong et al. 2020

Answer 4

• 5.2% patients had a change in diagnosis as WGS identified missed driver mutations and methylome profiling reclassified tumours
• Identified therapeutic targets in 71.4% patients
• 31% who received recommended therapies had durable objective clinical benefit

Question 5

Using high and low TMB as a predictor for response in immunotherapy - Valero et al. 2021

Answer 5

• high TMB = 10 or more mt per mb in solid tumour patients
• TMB-high patients had a higher response rate to immunotherapy

Question 6

Viral associations with cancers - Zapatka et al. 2020

Answer 6

• analysed WGS data from PCAWG
• cancer type specific associations
• Most common = EBV, HPV and HBV
• HPV had increased expression of immune cells and APOBEC3B > different viruses had different outcomes = therapeutic potential
• ERV1 high expression in kidney cancers had worse prognosis

Question 7

Molecular determinants of immunotherapy response in glioblastoma patients - Zhao et al. 2019

Answer 7

• WES
• PTEN mutations were associated with non-responders
• MAPK pathway enrichment > PI3K-AKT increase in responders
• different neoantigen evolution in non vs responders
• non responders had greater T cell clonal diversity = more TCR

Question 8

TMB as a predictor in non-European ancestries - Nassar et al. 2022

Answer 8

• TMB inflation and misclassified germline variants in non-european populations
• in lung cancer TMB-high was a predictive of better outcomes in european not african and asian populations
• shows need for ancestry specific marker

Question 9

Lung adenocarcinoma promoted by air pollutants - Hill et al. 2023

Answer 9

• air pollutants might promote inflammatory changes in the microenviro to allow expansion of pre-existing mutant clones
• explanation for non-smoking mediated mutagenesis
• particle matter (PM) exposure in mice models induced expression of oncogenic EGFR and KRAS
• PM2.5 triggered macrophage infiltration into the lungs and production of IL-1B

Question 10

Genome wide identification and analysis of prognostic features in human cancers - Smith and Sheltzer 2022

Answer 10

• no single genome feature was prognostic across all cancer types
• overexpressed transcripts were typically gene associated with chromosome segregation, DNA replication and cell cycle
• strongest biomarkers tended to be housekeeping genes with roles in cell cycle
• most successful drugs dont target adverse prognostic genes.