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Understanding pathogenicity of germline variation in cancer susceptibility genes from hallmarks of tumorigenesis


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Prof Clare Turnbull No more applications being accepted Funded PhD Project (Students Worldwide)

About the Project

For a full project proposal and details on how to apply using our online recruitment portal please see icr.ac.uk/phdsPlease note we only accept applications via the online application system apply.icr.ac.uk

BACKGROUND

Large-scale genomic sequencing in the normal population has revealed the extent of genetic variation to be much greater than initially anticipated. As such, rare variants are collectively common; interpretation of these rare variants in the context of disease susceptibility is highly challenging. 

Turnbull has set up the Cancer Variant interpretation Group UK (CanVIG-UK), which is a network that meets monthly, comprising >200 clinicians and molecular diagnostic laboratory scientists from each of the 23 NHS genetics services across UK and ROI (Garrett et al., 2020a). Through this we are generating a quantitative approach to generation and combination of evidence for interpretation of variants in cancer susceptibility genes (Garrett et al., 2020b). This is to improve national (and international) consistency in variant interpretation so as to best manage patients in regard of their correct germline cancer risk elevation.

Functional assays are emerging which seek to recapitulate clinical pathogenicity through quantifying impairment of a relevant cellular function in an ex vivo model (Gelman et al., 2019). Where a tumour has arisen in an individual carrying a rare variant, the tumorigenic processes can act as a functional reporter informing on the likely pathogenicity of the underlying germline variant (Jonsson et al., 2019). Through this project we seek to generate quantitate metrics corresponding to predictive value towards variant pathogenicity/benignity of stigmata of tumorigenesis relating to impairment of HRR, MMR and other relevant processes.

PROJECT AIMS

  • Quantitation of predictive value towards variant pathogenicity for tumour-gene combinations of ‘tumour assays’ including: loss-of-heterozygosity (Park et al., 2018);  signatures for deficiency in HRR, MMR, involving different patterns of SNVs, CNVs and gLOH. (Nik-Zainal et al., 2016, Alexandrov et al., 2013)
  • Integration of tumour-derived ‘assays of function’ with emerging ex-vivo MAVES (massive assays of variant effect) to refine predictive value

Candidates should hold, or, expect to gain either;

  • A first, or, upper-second class honours degree (or equivalent) in biological sciences including epidemiology/medical statistics
  • A masters degree in a relevant subject.

Please see our entry requirements, and how to apply

Successful candidates will undertake a four-year research training programme under the guidance of a team of our world-class researchers.


Funding Notes

Students receive an annual stipend, currently £21,000 per annum, as well as having tuition fees (both UK/EU and overseas) and project costs paid for the four-year duration. We are open to applications from any eligible candidates and are committed to attracting and developing the best minds in the world. We particularly welcome applicants from British Black and ethnic minority backgrounds, as they are under-represented at PhD level within the ICR and nationwide.

References

ALEXANDROV, L. B., NIK-ZAINAL, S., WEDGE, D. C., APARICIO, S. A., BEHJATI, S., BIANKIN, A. V., BIGNELL, G. R., BOLLI, N., BORG, A., BORRESEN-DALE, A. L., BOYAULT, S., BURKHARDT, B., BUTLER, A. P., CALDAS, C., DAVIES, H. R., DESMEDT, C., EILS, R., EYFJORD, J. E., FOEKENS, J. A., GREAVES, M., HOSODA, F., HUTTER, B., ILICIC, T., IMBEAUD, S., IMIELINSKI, M., JAGER, N., JONES, D. T., JONES, D., KNAPPSKOG, S., KOOL, M., LAKHANI, S. R., LOPEZ-OTIN, C., MARTIN, S., MUNSHI, N. C., NAKAMURA, H., NORTHCOTT, P. A., PAJIC, M., PAPAEMMANUIL, E., PARADISO, A., PEARSON, J. V., PUENTE, X. S., RAINE, K., RAMAKRISHNA, M., RICHARDSON, A. L., RICHTER, J., ROSENSTIEL, P., SCHLESNER, M., SCHUMACHER, T. N., SPAN, P. N., TEAGUE, J. W., TOTOKI, Y., TUTT, A. N., VALDES-MAS, R., VAN BUUREN, M. M., VAN 'T VEER, L., VINCENT-SALOMON, A., WADDELL, N., YATES, L. R., ZUCMAN-ROSSI, J., FUTREAL, P. A., MCDERMOTT, U., LICHTER, P., MEYERSON, M., GRIMMOND, S. M., SIEBERT, R., CAMPO, E., SHIBATA, T., PFISTER, S. M., CAMPBELL, P. J. & STRATTON, M. R. 2013. Signatures of mutational processes in human cancer. Nature, 500, 415-21.
GARRETT, A., CALLAWAY, A., DURKIE, M., CUBUK, C., ALIKIAN, M., BURGHEL, G. J., ROBINSON, R., IZATT, L., TALUKDAR, S., SIDE, L., CRANSTON, T., PALMER-SMITH, S., BARALLE, D., BERRY, I. R., DRUMMOND, J., WALLACE, A. J., NORBURY, G., ECCLES, D. M., ELLARD, S., LALLOO, F., EVANS, D. G., WOODWARD, E., TISCHKOWITZ, M., HANSON, H. & TURNBULL, C. 2020a. Cancer Variant Interpretation Group UK (CanVIG-UK): an exemplar national subspecialty multidisciplinary network. J Med Genet.
GARRETT, A., DURKIE, M., CALLAWAY, A., BURGHEL, G. J., ROBINSON, R., DRUMMOND, J., TORR, B., CUBUK, C., BERRY, I. R., WALLACE, A. J., ELLARD, S., ECCLES, D. M., TISCHKOWITZ, M., HANSON, H. & TURNBULL, C. 2020b. Combining evidence for and against pathogenicity for variants in cancer susceptibility genes: CanVIG-UK consensus recommendations. J Med Genet.
GELMAN, H., DINES, J. N., BERG, J., BERGER, A. H., BRNICH, S., HISAMA, F. M., JAMES, R. G., RUBIN, A. F., SHENDURE, J., SHIRTS, B., FOWLER, D. M. & STARITA, L. M. 2019. Recommendations for the collection and use of multiplexed functional data for clinical variant interpretation. Genome Med, 11, 85.
HUGHLEY, R., KARLIC, R., JOSHI, H., TURNBULL, C., FOULKES, W. D. & POLAK, P. 2020. Etiologic Index - A Case-Only Measure of BRCA1/2-Associated Cancer Risk. N Engl J Med, 383, 286-288.
JONSSON, P., BANDLAMUDI, C., CHENG, M. L., SRINIVASAN, P., CHAVAN, S. S., FRIEDMAN, N. D., ROSEN, E. Y., RICHARDS, A. L., BOUVIER, N., SELCUKLU, S. D., BIELSKI, C. M., ABIDA, W., MANDELKER, D., BIRSOY, O., ZHANG, L., ZEHIR, A., DONOGHUE, M. T. A., BASELGA, J., OFFIT, K., SCHER, H. I., O'REILLY, E. M., STADLER, Z. K., SCHULTZ, N., SOCCI, N. D., VIALE, A., LADANYI, M., ROBSON, M. E., HYMAN, D. M., BERGER, M. F., SOLIT, D. B. & TAYLOR, B. S. 2019. Tumour lineage shapes BRCA-mediated phenotypes. Nature, 571, 576-579.
NIK-ZAINAL, S., DAVIES, H., STAAF, J., RAMAKRISHNA, M., GLODZIK, D., ZOU, X., MARTINCORENA, I., ALEXANDROV, L. B., MARTIN, S., WEDGE, D. C., VAN LOO, P., JU, Y. S., SMID, M., BRINKMAN, A. B., MORGANELLA, S., AURE, M. R., LINGJAERDE, O. C., LANGEROD, A., RINGNER, M., AHN, S. M., BOYAULT, S., BROCK, J. E., BROEKS, A., BUTLER, A., DESMEDT, C., DIRIX, L., DRONOV, S., FATIMA, A., FOEKENS, J. A., GERSTUNG, M., HOOIJER, G. K., JANG, S. J., JONES, D. R., KIM, H. Y., KING, T. A., KRISHNAMURTHY, S., LEE, H. J., LEE, J. Y., LI, Y., MCLAREN, S., MENZIES, A., MUSTONEN, V., O'MEARA, S., PAUPORTE, I., PIVOT, X., PURDIE, C. A., RAINE, K., RAMAKRISHNAN, K., RODRIGUEZ-GONZALEZ, F. G., ROMIEU, G., SIEUWERTS, A. M., SIMPSON, P. T., SHEPHERD, R., STEBBINGS, L., STEFANSSON, O. A., TEAGUE, J., TOMMASI, S., TREILLEUX, I., VAN DEN EYNDEN, G. G., VERMEULEN, P., VINCENT-SALOMON, A., YATES, L., CALDAS, C., VAN'T VEER, L., TUTT, A., KNAPPSKOG, S., TAN, B. K., JONKERS, J., BORG, A., UENO, N. T., SOTIRIOU, C., VIARI, A., FUTREAL, P. A., CAMPBELL, P. J., SPAN, P. N., VAN LAERE, S., LAKHANI, S. R., EYFJORD, J. E., THOMPSON, A. M., BIRNEY, E., STUNNENBERG, H. G., VAN DE VIJVER, M. J., MARTENS, J. W., BORRESEN-DALE, A. L., RICHARDSON, A. L., KONG, G., THOMAS, G. & STRATTON, M. R. 2016. Landscape of somatic mutations in 560 breast cancer whole-genome sequences. Nature, 534, 47-54.
PARK, S., SUPEK, F. & LEHNER, B. 2018. Systematic discovery of germline cancer predisposition genes through the identification of somatic second hits. Nat Commun, 9, 2601.


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