Genetic variation in South African breast cancer patients using genome sequencing – Prof Fourie Joubert
Prof Fourie Joubert
- Dept Bioinformatics and Computational Biology Unit, University of Pretoria
An investigation into genetic variation in South African breast cancer patients using genome sequencing.
Breast cancer is the second most prevalent form of cancer in South Africa. As commonly identified mutations such as BRCA1 and BRCA2 mutations are often not observed, complete exome sequencing will be used to sequence genomes from selected breast cancer patients for the discovery of novel mutations. There are two work packages, the first entailing the sequencing of family members with breast cancer. Exome sequencing will yield around 30x coverage of approximately 200,000 exomes from these patients.
The second work package compares tumour-normal samples in matched black South African patients. Directed sequencing of the tumours will be performed using the Ion Torrent Comprehensive Cancer Panel, followed by complete exome sequencing of the normal tissue. Data will be mapped to the hg19 reference human genome assembly for variant identification and analysis. Selected variants will be further studied in larger sample groups using directed sequencing. Identified variants are of high significance for use in early detection and epidemiology studies, as well as in understanding the functional mechanisms of transformation in these cancers.
In work package 1, patients with family-related breast cancer were investigated. The parts of the genome that code for proteins were analyzed for changes that could potentially be related to their development of cancer. A few genes were identified that had changes which could potentially be interesting with relation to the development of cancer. Three genes (TCHP, EME2, HELQ) were then analyzed in a wider set of persons. It was decided that TCHP was not of further interest, but the EME2 and HELQ genes hold changes of interest that were are reporting in publications, and would like to further investigate.
In work package 2, the cancer DNA of four patients was compared to their normal DNA to understand what changes took place in the tumours. Additionally, further analysis was done to understand which genes were regulated to express more strongly or less strongly in the tumours. Further analysis was also done to investigate which sections of their genomes were lost or duplicated in the tumours.
Currently, all these different results are being used together to try and build a model of what happened in the tumour of each patient’s genome. In the additional work package, a subset of genes known to be involved with susceptibility to breast cancer was studied in 48 patients. The expected BRCA mutations were found, together with some other more novel mutations. This work is now being expanded to an additional 120 patients to help identify new mutations involved with cancer susceptibility.