Germline predisposition to gene-specific somatic mutagenesis

Primary supervisor: Veronica Kinsler, Francis Crick Institute/ UCL

Project

Genetic predisposition to cancer has most often been studied with respect to clinical/histological diagnosis. This thinking led to the discovery of high penetrance loci in families with recognizable cancer syndromes [1, 2], and to the construction of polygenic risk scores from multiple low penetrance loci [3]. Despite these important advances, a substantial proportion of heredity in many cancers remains unexplained [4-6]. On the basis of the clinical observation of rare disease families with recurrent congenital somatic mutations in more than one child, we hypothesised that germline predisposition to somatic mutation in specific genes may exist. Such loci could be missed by low penetrance risk scores which group cancers by clinical diagnosis, particularly if the locus operates in an allele-specific manner. We therefore chose to re-examine the issue of genetic predisposition to cancer from the perspective of which genetic drivers they contain. We have now identified germline more than one locus associated with somatic variation in specific oncogenes in rare paediatric oncogene-driven diseases (unpublished data). Extrapolating from these findings we have demonstrated the same germline variation at increased frequency in adult cancer population databases (unpublished data), confirming that the germline-somatic association represents a recurrent molecular mechanism.

The successful candidate will dissect the molecular mechanisms involved in the association between the germline locus and the somatic mutagenesis in the oncogene NRAS. The student will be trained and supported in a variety of molecular genetics and cell biology techniques such as human primary and cell line culture, next generation sequencing of various types including single cell work, HiC and structural variant analysis, high throughput CRISPR screening, massively parallel reporter assays, transcription factor assays, replication stress and DNA damage assays, as well as standard immunoblotting/immunocytochemistry/expression studies. Some bioinformatics analysis of results data will be expected with appropriate instruction however the group has excellent bioinformatics support, and the project will be primarily wet lab based.

Students are highly valued team members in the Kinsler lab. We have a hard working but very supportive group, with projects linked by the study of the genetics and biological mechanisms of oncogene driven diseases, increasingly focused on therapeutics.

References

1. Samadder NJ, Baffy N, Giridhar KV, Couch FJ, Riegert-Johnson D. Hereditary Cancer Syndromes-A Primer on Diagnosis and Management, Part 2: Gastrointestinal Cancer Syndromes. Mayo Clin Proc. 2019;94; 1099-1116.
2. Samadder NJ, Giridhar KV, Baffy N, Riegert-Johnson D, Couch FJ. Hereditary Cancer Syndromes-A Primer on Diagnosis and Management: Part 1: Breast-Ovarian Cancer Syndromes. Mayo Clin Proc. 2019;94; 1084-1098
3. Huntley C, Torr B, Sud A, Rowlands CF, Way R, Snape K, et al. Utility of polygenic risk scores in UK cancer screening: a modelling analysis. Lancet Oncol. 2023;24; 658-668.
4. Schubert SA, Morreau H, de Miranda N, van Wezel T. The missing heritability of familial colorectal cancer. Mutagenesis. 2020;35; 221-231.
5. Fatapour Y, Brody JP. Genetic Risk Scores and Missing Heritability in Ovarian Cancer. Genes (Basel). 2023;14.
6. Derpoorter C, Van Paemel R, Vandemeulebroecke K, Vanhooren J, De Wilde B, Laureys G, et al. Whole genome sequencing and inheritance-based variant filtering as a tool for unraveling missing heritability in pediatric cancer. Pediatr Hematol Oncol. 2023;40; 326-340.