Award Title: Cancer genomics
Funder: The Francis Crick Institute

Abstract: Cancer is caused by somatic changes to the genome. Breakthrough sequencing technologies now enable us to compare the genomes of cancer cells to those of normal cells to base-pair resolution. This in theory allows us to identify all point mutations, small insertions and deletions, genomic rearrangements and copy number changes in a cancer cell, providing a unique opportunity to look at the genes and processes involved in cancer. As genomic changes occur throughout a tumour's lifetime, a cancer's genome is also an archaeological record of its past, allowing a unique view of the tumour's evolutionary history. The Cancer Genomics Group focuses on integrating cancer genomics data across tumour types to gain insight into the genes involved in cancer and into tumour evolution. Contributing to the landscape of cancer genes, we use pan-cancer approaches integrating copy-number data with other mutation classes to identify novel rare tumour suppressor genes. Our analyses are based on leveraging recurrent biallelic inactivation of genes by either homozygous deletions, or by germline deleterious variants combined with loss-of-heterozygosity events. We are developing "molecular archaeology of cancer" approaches that use cancer genomes to obtain detailed timelines of cancer development across thousands of cancers and to dissect the subclonal architecture and life history of cancer across cancer types. These analyses are performed within the context of the International Cancer Genome Consortium (ICGC) and its Pan-Cancer Analysis of Whole Genomes (PCAWG) initiative, which enables us to study intra-tumour heterogeneity and the life history of cancers using whole-genome sequences of thousands of tumours. Complementary to these large-scale pan-cancer efforts, we are performing smaller-scale collaborative studies of tumour bulk sequencing, in combination with single-cell and multi-sample sequencing of primary tumours, metastases and circulating and disseminated tumour cells, aiming to characterize intra-tumour heterogeneity in minute detail and to gain insight into tumour evolution and metastasis. As the cancer genome gradually reveals its secrets, we also focus on the next challenge: to understand how genomic changes lead to transcriptomic (and proteomic, interactomic, etc) changes to finally cause cancer. Deep understanding of the cancer transcriptome is confounded by expression signals originating from admixed normal cells. Gene expression analysis by massively parallel sequencing (RNAseq) allows allele-specific expression measurements. It can be shown that, given the fraction of tumour cells, the allele-specific copy number profiles of the tumour cells, and under a few reasonable hypotheses, the expression in tumour cells can be separated from that in normal cells. We are currently developing such bioinformatics approaches to deconvolute the tumour cell transcriptomes from transcriptomes of admixed normal cells, leveraging our experience in deconvoluting genomic signals from different cell populations. In the longer term, we aim to develop integrative ‘omics approaches that study the influence of point mutations, copy number changes and structural variants on transcription at the gene or transcript level and at the transcriptome level, and to apply these approaches in a large-scale pan-cancer setting, to understand the basic principles of cancer development and cancer evolution within and across tumour types.


Research Activity Codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health Categories: CANCER AND NEOPLASMS