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Research Highlight | Sep 6, 2017

Discovery of seven new ovarian cancer subtypes opens door for more targeted treatments

Dr. Shah

The discovery of seven new genetic subtypes of ovarian cancer may lead to targeted treatments for women diagnosed with this disease, including those with the most malignant form and those who do not respond well to current chemotherapy treatments.

The findings by a group of TFRI-funded scientists led by Dr. Sohrab Shah, senior scientist at the BC Cancer Agency, were published in Nature Genetics (May 2017, Dr. Yi Kan Wang first author). The new subtypes included two from high grade serous cancer (HGSC), the most malignant form, thought to originate in the fallopian tube with early evolutionary acquisition of TP53 mutation and LOH of chromosome 17. These account for up to 70 per cent of all ovarian cancer cases, and 80 per cent of women relapse despite initial treatment success. The other five new subtypes were discovered from three other tumour types: clear cell (CCOC), endometrioid (ENOC), and adult granulosa cell (GCT).

For the study, tumours from 133 patients with ovarian cancer were subjected to whole-genome sequencing to identify abnormalities in the DNA of ovarian cancer cells. The whole-genome point mutation and structural variation patterns were examined. The study suggests a sub-group of HGSC tumours may have increased capacity to repair events induced by genotoxic chemotherapy. This could explain why these cancers may not be responsive to PARP inhibitors and, in the independent cohorts presented here, show evidence of poor response to the chemotherapy drug cisplatin (typically used to treat ovarian cancer).

The results show a new stratification of the major histotypes of ovarian cancer using the tumour genome as a biomarker. The genome as a whole reflects aberrant DNA repair processes and thus can be used as means of identifying new therapeutic targets that transcends traditional gene-based biomarkers such as BRCA1 or BRCA2.    

Further, patterns of changes across the DNA inside cancer cells can help direct drug development efforts for the hardest-to-treat subtypes of ovarian cancer. These findings could be used to develop tests that can direct patients toward new investigational treatments that may help women with subtypes of the disease that are not responsive to standard treatments, as well as illuminate vulnerabilities to exploit in developing future intervention strategies.

Study: Genomic consequences of aberrant DNA repair mechanisms stratify ovarian cancer histotypes

Authors: Yi Kan Wang, Ali Bashashati, Michael S. Anglesio, Dawn R. Cochrane, Diljot S. Grewal, Gavin Ha, Andrew McPherson, Hugo M. Horlings, Janine Senz, Leah M. Prentice, Anthony N. Karnezis, Daniel Lai, Mohamed R. Aniba, Allen W. Zhang, Karey Shumansky, Celia Siu, Adrian Wan, Melissa K. McConechy, Hector Li-Chang, Alicia Tone, Diane Provencher, Manon de Ladurantaye, Hubert Fleury, Aikou Okamoto, Satoshi Yanagida, Nozomu Yanaihara, Misato Saito, Andrew J. Mungall, Richard Moore, Marco A. Marra, C. Blake Gilks, Anne-Marie Mes-Masson, Jessica N. McAlpine, Samuel Aparicio, David G. Huntsman & Sohrab P. Shah.

Funding: We wish to acknowledge generous long-term funding support from the BC Cancer Foundation, supporting the research program of S.P.S. and OvCaRe. The authors graciously thank the Gray Family Ovarian Clear Cell Carcinoma Research Resource, which provided funding critical to this project. Additional funding was provided by a Terry Fox Research Institute New Investigator grant to S.P.S. and a Canadian Cancer Society Research Institute Impact grant to D.G.H. and S.P.S.

TFRI LINKS, Summer 2017