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(A*STAR) Can non-coding variants explain missing heritability in familial cancer?


Project Description

Heterozygous germline variants in a number of tumour suppressor genes cause a spectrum of familial cancers, including early onset breast-ovarian cancer, and colorectal cancer. In the majority of ascertained affected families coding variants resulting in loss of protein function are identified. However, a significant number of families remain unexplained at a molecular level. The missing heritability could be due to variants in genes that have yet to be associated with familial cancer or, as we believe is more likely, non-coding or structural variants in known genes that to date have been resistant to detection by traditional mutation detection methods. Recently, we have demonstrated the importance of a 5’UTR variant resulting in promoter hypermethylation of BRCA1 as a cause of familial breast-ovarian cancer.

This project will use complimentary approaches of RNA sequencing, bioinformatics, methylation analysis, and whole genome sequencing to define the genetic variants that result in familial cancer expanding mutational spectra and determining mechanisms that will be important in understanding how non-coding variation can alter gene expression.

Entry Requirements:
Applications should be submitted online and candidates should make direct contact with the Manchester supervisor to discuss their application directly. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.

Funding Notes

This project is available to UK/EU candidates. Funding covers fees (UK/EU rate) and stipend for four years. Overseas candidates can apply providing they can pay the difference in fees and are from an eligible country. Candidates will be required to split their time between Manchester and Singapore, as outlined on View Website.

As an equal opportunities institution we welcome applicants from all sections of the community regardless of gender, ethnicity, disability, sexual orientation and transgender status. All appointments are made on merit.

References

Evans DG, van Veen EM, Byers HJ, Wallace AJ, Ellingford JM, Beaman G, Santoyo-Lopez J, Aitman TJ, Eccles DM, Lalloo FI, Smith MJ, Newman WG. An inherited 5’UTR variant causing methylation associated silencing of BRCA1 as a cause of breast and ovarian cancer Am J Hum Genet 2018; 103(2):213-220.

Herman JG, Baylin SB. Gene silencing in cancer in association with promoter hypermethylation. NEJM 2003; 349, 2042-54.

Hitchins MP, Wong JJ, Suthers G, Suter CM, Martin DI, Hawkins NJ, Ward RL. Inheritance of a cancer-associated MLH1 germ-line epimutation. NEJM 2007;356:697-705

Hitchins MP. Constitutional epimutation as a mechanism for cancer causality and heritability? Nat Rev Cancer 2015;15:625-34.

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