Vinayak Bhandari, Medical Biophysics
Supervisor: Professor Rob Bristow MD PhD FRCPC FMedSci Director, Manchester Cancer Research Centre
Co-‐Director, CRUK Manchester Centre
Chief Academic Officer & Honorary Consultant, The Christie NHS Foundation Trust University Professor of Cancer Studies, The University of Manchester
PhD Thesis Title and Short Description:
The molecular landmarks of tumour evolution and hypoxia across cancers. Vinayak used computational methods to study cancers that have low levels of oxygen, defined the genetics of these tumours and developed biological signatures that can predict which patients have aggressive cancer.
Research and Awards:
Large genomic studies of cancer have mostly focused on characterizing the mutational profiles of tumours and discovering their driver mutations. How these tumours evolved prior to diagnosis within their unique and evolving microenvironments remains understudied. For example, sub-‐regions of hypoxia (low oxygen) exist in approximately half of all solid tumours but can be difficult and labour intensive to quantify. Despite being an adverse (and targetable) prognostic feature in multiple cancer types, the influence of hypoxia on tumour evolution and hypoxia-‐associated genomic alterations have not been described in large cohorts of primary tumours.
To address these gaps, Vinayak reconstructed the evolutionary histories of 293 localized prostate cancers and showed that specific genes, including MTOR, NKX3-‐1 and RB1, are biased to be mutated early or late during prostate cancer evolution (Cell, 2018). Vinayak next measured hypoxia using multiple mRNA-‐based signatures in 548 patients with localized prostate cancer. Hypoxia is associated with specific alterations in prostate cancer driver genes. Hypoxia-‐associated copy-‐number alterations are biased to occur early during tumour evolution, consistent with hypoxia being an early selective event. Vinayak then integrated hypoxia data with genomic, pathological and evolutionary information to stratify clinically-‐similar patients into distinct prognostic groups (Nature Genetics, 2019). Finally, Vinayak expanded this framework to assess the molecular and evolutionary landmarks of hypoxia across cancers: he quantified hypoxia across a diverse set of 10,808 tumours spanning 27 cancer types. Numerous alterations are enriched or depleted in hypoxic tumours and hypoxia applies a selective pressure early in the life-‐history of tumours across cancers. Vinayak further found the first potential example of the joint influence of a genomic alteration and hypoxia in guiding evolutionary trajectories across cancers (Nature Communications, 2020).
Overall, hypoxic tumours have distinct mutational landscapes and the aggressiveness of cancers is driven by the interplay of the tumour microenvironment, evolution and its mutational profile.
During his PhD, Vinayak was supported by numerous awards and scholarships including a Sage Bionetworks Young Investigator Award, Masters and Doctoral Frederick Banting and Charles Best Canada Graduate Scholarships, an Ontario Graduate Scholarship in addition to awards from the Canadian Cancer Society and the Terry Fox Research Institute. Vinayak also spent a summer at the University of Oxford’s Big Data Institute, merging UK and Canadian efforts to study prostate cancer, and this was supported by a CIHR Michael Smith Foreign Study Supplement.
Vinayak is now a Consultant and Senior Data Scientist with The Boston Consulting Group's advanced analytics and data science consulting practice, BCG Gamma.