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  • TFRI's 8th ASM focuses on potential of precision medicine

    by TFRI Editor | Sep 06, 2017


    TFRI’s one-day 8th Annual Scientific Meeting on Saturday, Nov. 4, 2017 in Vancouver will feature talks related to the theme of the potential of precision medicine. There will be three plenaries  on the subjects of cancer biology, prognostic strategies and therapeutic strategies. A fourth plenary will feature concurrent rapid-fire talks by selected trainees who will be presenting abstracts at this year's CCRC meeting (Nov. 5-7th). 

    Among this year’s ASM key speakers are:  Dr. Connie Eaves, BC Cancer Agency; Dr. Ivan Topisirovic, McGill University and Dr. Brian Wilson, UHN, and more than 75 rapid-fire talks are expected. Registration for those invited and confirmed to attend the meeting closes on Thursday, Sept. 21, 2017.

    Visit our ASM site for more information and/or to register.  

    TFRI Links, Summer 2017
  • It’s not too late to join a Terry Fox Run research team!

    by TFRI Editor | Sep 06, 2017

    Dr. Singh team

    The annual Terry Fox Run is just around the corner and our purple-shirted research teams - along with their friends and families - will be out in full force again this year! To date, more than 16 teams have confirmed their participation in the upcoming run on Sunday, Sept. 17th. Many are returning teams from last year!

    Thank you so much for supporting cancer research and Terry’s cause. A special thanks to all our team captains for leading the charge. It’s not to late to join or form a team. Visit the TFF web site to find a team at your institution (select Sponsor a Participant/Search team name TFRI)  or join the TFRI-HQ site led by our captain Dr. Victor Ling.  We are hoping to top last year’s amazing success: TFRI was the top multi-province team last year raising more than $116,000. 

    TFRI Links, Summer 2017
  • Canadian, international researchers find new candidate drivers, subtype diversity in study of whole-genome landscape for children’s brain cancer

    by TFRI Admin | Sep 06, 2017


    Medulloblastoma is the most common childhood brain cancer, and current treatments often have debilitating effects on developing children – a situation that highlights the need for molecularly targeted treatments with reduced toxicity. The present study analyzed hundreds of sequenced medulloblastoma (MB) samples, identifying numerous new targets that could give children with this disease new, less harmful therapeutic options.

    The research was led by Dr. Michael Taylor (Toronto’s Hospital for Sick Children) and Dr. Peter Lichter (German Cancer Research Center, Heidelberg), and was recently published with first author Dr. Paul. A Northcott (Nature, July 2017).Targeted treatments for MB are limited despite a significant need for new therapies, a dilemma that spurred the team to undergo a deep dive into the full range of genetic lesions and molecular heterogeneity that contribute to the different MB subgroups.

    Previous research from Dr. Taylor’s group showed there are four main molecular subgroups –Wingless (WNT), Sonic hedgehog (SHH), Group 3 and Group 4 – that have distinct epigenetic and transcriptional signatures. In the present study, the team examined 491 sequenced, previously untreated medulloblastoma samples and the molecular heterogeneity among 1,256 epigenetically analyzed cases.

    The results were impressive: on an individual gene level, new candidate drivers were discovered in each of the different subgroups, and were assigned to most patients belonging to Group 3 and Group 4, greatly enhancing previous knowledge. For example, all 36 WNT MBs sequenced in this study were confidently explained by mutations in at least one or more driver genes, and the team assigned at least one driver gene to more than 95 per cent of patients with SHH MB. Further, new molecular subtypes were differentially enriched for specific driver events, including hotspot in-frame insertions that target KBTBD4 and ‘enhancer hijacking’ events that activate PRDM6.

    Applying integrative genomics to a large study of patient samples derived from medulloblastoma revealed a series of cancer genes and biologically relevant subtype diversity, some of which could be targeted with new, personalized therapeutics. The present study’s findings – combined with future research – will likely help to advance treatments and to improve prognosis for children and families affected by this devastating brain cancer.

    Study: The whole-genome landscape of medulloblastoma subtypes

    Authors: Paul A. Northcott Ivo Buchhalter, A. Sorana Morrissy, Volker Hovestadt, Joachim Weischenfeldt, Tobias Ehrenberger, Susanne Gröbner, Maia Segura-Wang, Thomas Zichner, Vasilisa A. Rudneva, Hans-Jörg Warnatz, Nikos Sidiropoulos, Aaron H. Phillips, Steven Schumacher, Kortine Kleinheinz, Sebastian M. Waszak, Serap Erkek, David T. W. Jones, Barbara C. Worst, Marcel Kool, Marc Zapatka, Natalie Jäger, Lukas Chavez, Barbara Hutter, Matthias Bieg, Nagarajan Paramasivam, Michael Heinold, Zuguang Gu, Naveed Ishaque, Christina Jäger-Schmidt, Charles D. Imbusch, Alke Jugold, Daniel Hübschmann, Thomas Risch, Vyacheslav Amstislavskiy, Francisco German Rodriguez Gonzalez, Ursula D. Weber, Stephan Wolf, Giles W. Robinson, Xin Zhou, Gang Wu, David Finkelstein, Yanling Liu, Florence M. G. Cavalli, Betty Luu, Vijay Ramaswamy, Xiaochong Wu, Jan Koster, Marina Ryzhova, Yoon-Jae Cho, Scott L. Pomeroy, Christel Herold-Mende, Martin Schuhmann, Martin Ebinger, Linda M. Liau, Jaume Mora, Roger E. McLendon, Nada Jabado, Toshihiro Kumabe, Eric Chuah, Yussanne Ma, Richard A. Moore, Andrew J. Mungall, Karen L. Mungall, Nina Thiessen, Kane Tse, Tina Wong, Steven J. M. Jones, Olaf Witt, Till Milde, Andreas Von Deimling, David Capper, Andrey Korshunov, Marie-Laure Yaspo, Richard Kriwacki, Amar Gajjar, Jinghui Zhang, Rameen Beroukhim, Ernest Fraenke, Jan O. Korbel, Benedikt Brors, Matthias Schlesner, Roland Eils, Marco A. Marra, Stefan M. Pfister, Michael D. Taylor & Peter Lichter.

    Funding: The MAGIC project is partially financially supported by the Terry Fox Research Institute. M.D.T. is supported by the Garron Family Chair in Childhood Cancer Research, and grants from the Cure Search Foundation, the National Institutes of Health (R01CA148699 and R01CA159859), the Pediatric Brain Tumor Foundation, the Terry Fox Research Institute, and b.r.a.i.n.child. This work was also supported by a Program Project Grant from the Terry Fox Research Institute. 

    TFRI LINKS, Summer 2017
  • Vancouver team identifies new class of molecules with potential in treating metastatic prostate cancer

    by TFRI Admin | Sep 06, 2017

    TFRI Link photo

    A recent study by a prolific TFRI-funded team has demonstrated that disrupting ERG transcriptional activity is sufficient to suppress the major characteristics of ERG-transformed prostate cancers. The finding could help develop new therapeutic tools for men battling ERG-expressing metastatic castration-resistant prostate cancer.

    There are currently few agents targeting cancer metastasis, and the need to create new therapeutics for these patients is great. Led by Drs. Michael Cox, Artem Cherkasov, and Paul Rennie (Vancouver Prostate Centre), the present study (Oncotarget, April 2017) describes the first-in-class small molecule targeting the DNA binding domain of the ETS-family transcription factor, ERG.

    Approximately half of all prostate cancers have a recurrent genomic re-arrangement called the TMPRSS2-ERG gene fusion. Numerous studies have associated ERG expression with more aggressive disease characteristics and indicate that ERG drives a genomic reprogramming that promotes cell migration and invasion. The small molecule ERG antagonist, VPC-18005, directly binds to the DNA binding domain of the ERG protein. This inhibits ERG transcriptional activity and suppresses cell motility associated with metastatic spread of the disease.

    In addition, the team’s lead compound provided a novel tool for cancer researchers to dissect the specific cellular pathways that are dysregulated by ERG during disease initiation and progression. Understanding these pathways will likely guide development of the next generation of therapeutic strategies for treating advanced prostate cancer.

    The present study heavily utilized computer-aided drug discovery pipeline that is applicable to the development of therapeutic agents to antagonize cancer targets previously considered ‘undruggable’. While the group reported that VPC-18005 is stable and orally bio-available, with minimal toxicity in mouse models, there is a need to further refine the compound’s structure.

    The team is currently using in-silico predictive algorithms to guide the design and testing of medicinal chemistry derivatives. Such small molecule tools will be critical to developing selective agents for ERG and its related ETS family members and may lead to development of agents to target additional ETS family members known to be oncogenic drivers in other malignancies.

    The agents described are the first step in developing therapeutics specifically for those prostate cancer patients whose disease carries the TMPRSS2-ERG re-arrangement. These treatments may function as single agents, but can also be explored in combination with existing and emerging therapies for advanced prostate cancer. Future anti-ERG drugs can be specifically prescribed to the 50 per cent of prostate cancer patients who are ERG-positive, and pave the way for precision medicine.

    Prostate cancer is the third leading cause of cancer-related death in Canadian men, and one of the most common cancers for this demographic.

    Study: Discovery and characterization of small molecules targeting the DNA-binding ETS domain of ERG in prostate cancer

    Authors: Miriam S. Butler, Mani Roshan-Moniri1, Michael Hsing1, Desmond Lau, Ari Kim, Paul Yen, Marta Mroczek, Mannan Nouri1, Scott Lien, Peter Axerio-Cilies, Kush Dalal, Clement Yau, Fariba Ghaidi1, Yubin Guo, Takeshi Yamazaki, Sam Lawn, Martin E. Gleave, Cheryl Y. Gregory-Evans, Lawrence P. McIntosh, Michael E. Cox, Paul S. Rennie, and Artem Cherkasov.

    Funding: The project was supported in part by funds provided by Terry Fox New Frontiers Program Project Grant (#TFF116129 to M.E.C).

    TFRI LINKS, Summer 2017
  • Vaccine shows promise in models, eradicates intra-abdominal tumours in over 90 per cent of mice

    by TFRI Admin | Sep 06, 2017

    Auer-full shot

    Despite advances in chemotherapy and surgery, patients diagnosed with peritoneal carcinomatosis, a disseminated intra-abdominal tumour, usually succumb to their disease. But there’s good news: cancer researchers in Ontario have found that an oncolytic virus may lead to a promising new therapy option for these patients.

    Led by Drs. Rebecca Auer and John Bell (Ottawa Hospital Research Institute), the team used cancer cells infected ex-vivo with an oncolytic virus (Maraba expressing IL-12) delivered as a personalized cancer vaccine (MG1-IL12 infected cell vaccine). The virus infected the cancer cells and secreted the immune stimulating cytokine IL-12 (a potent stimulator of NK and T cell–mediated tumour cell killing) locally, resulting in migration of highly activated natural killer (NK) cells towards the vaccine and significant tumour regression in mice.

    The findings, published in Cancer Immunology Research (March 2017), suggested the vaccine was most effective when delivered in close proximity to the tumour, which is why a model of peritoneal carcinomatosis (one of the most common and challenging sites of metastases for abdominal malignancies) was selected for the study. Patients with this disease typically have a very poor prognosis, with a median survival rate of just six to 12 months.

    The results of the present study were impressive: in a model of disseminated colon cancer peritoneal carcinomatosis, the infected cell vaccine could eradicate bulky disease and lead to complete cures in more than 90 per cent of mice. However, when the vaccine did not express IL-12 – or when a non-replicating virus vaccine was used – efficacy was significantly weakened. This highlighted the importance of both aspects being present in the infected cell vaccine, as well as the value of T-cells and NK cells.

    This study also highlighted the importance of viral replication in therapeutic efficacy, and the team is currently investigating what aspects of viral infection of cancer cells makes them immunogenic to exploit this further. Looking forward, the group will explore how immune escape happens in those murine models where the vaccine demonstrates efficacy but does not lead to cures in the majority of animals. The present paper resulted in a grant from the Ontario Institute of Cancer Research to undertake enabling studies on manufacturing this virus from human cancer cells with the view of translating these findings into patients with peritoneal carcinomatosis in the near future.

    Study: NK-cell recruitment is necessary for eradication of peritoneal carcinomatosis with an IL12-expressing maraba virus cellular vaccine

    Authors: Almohanad A. Alkayyal, Lee-Hwa Tai, Michael A. Kennedy, Christiano Tanese de Souza, Jiqing Zhang, Charles Lefebvre, Shalini Sahi, Abhirami A. Ananth, Ahmad Bakur Mahmoud, Andrew P. Makrigiannis, Greg O. Cron, Blair Macdonald, E. Celia Marginean, David F. Stojdl, John C. Bell, and Rebecca C. Auer.

    Funding: This work was supported in part by a grant from the Terry Fox Research Institute.

     TFRI LINKS, Summer 2017

  • Study finds diffuse optical spectroscopic (DOS) texture features can predict breast cancer response prior to neoadjuvant chemotherapy

    by TFRI Admin | Sep 06, 2017


    Thanks to advances in imaging, oncologists may one day be able to determine if a patient responds to chemotherapy before receiving treatment. A recent study by a TFRI-funded team has shown that diffuse optical spectroscopic (DOS) texture features can predict breast cancer response to neoadjuvant chemotherapy (NAC) in locally advanced breast cancer patients before therapy even begins.

    Led by Dr. Greg Czarnota (Sunnybrook Health Sciences Centre, Ontario), and published in The British Journal of Cancer (April 2017, Dr. William Tran first author), the finding has the potential to guide treatment, improve breast cancer therapeutics, and may even improve overall disease-free survival. Breast cancer is the second leading cause of cancer-related death in women, and nearly 20 per cent of diagnoses are of locally advanced breast cancer – with only half of patients surviving beyond five years.

    Previous research by Dr. Czarnota’s team demonstrated that DOS imaging was capable of monitoring response to neoadjuvant chemotherapy in patients with locally advanced breast cancer. In the present study, researchers set out to evaluate texture features of pre-treatment DOS maps as a way of predicting patient response to NAC.

    Thirty-seven locally advanced breast cancer patients with a median age of 50 were identified, imaged before treatment and categorized as either a responder or a non-responder based on ultimate pathological data.  Breast tissue parametric maps were constructed and texture analyses were performed based on grey-level co-occurrence matrices for feature extraction.

    The results were impressive: for the first time, it was demonstrated that textural heterogeneities in DOS measures of haemoglobin and oxygen content in breast tumours predict NAC response with high accuracy. DOS-based textural parametrics show significant potential as a way of measuring baseline tumour heterogeneity, as well as for markers to measure patient response to chemotherapy treatment. These markers could help personalize medicine for women with breast cancer, and may prevent those who will not respond to therapy from undergoing cytotoxic chemotherapy, guiding these patients instead to alternative treatments.

    Study: Predicting breast cancer response to neoadjuvant chemotherapy using pre-treatment diffuse optical spectroscopic texture analysis

    Authors: William T. Tran, Mehrdad J. Gangeh, Lakshmanan Sannachi, Lee Chin, Elyse Watkins, Silvio G Bruni, Rashin Fallah Rastegar, Belinda Curpen, Maureen Trudeau, Sonal Gandhi, Martin Yaffe, Elzbieta Slodkowska, Charmaine Childs, Ali Sadeghi-Naini and Gregory J. Czarnota.

    Funding:  This project was funded by the Terry Fox Research Institute, Canada.

    TFRI LINKS, Summer 2017
  • Why does relapse occur in aggressive leukemia? Canadian researchers crack the case

    by TFRI Admin | Sep 06, 2017


    For decades scientists and physicians have wondered what causes some people with cancer to relapse after an apparently successful course of treatment. Now a team of Canadian cancer researchers has discovered the answer to this age-old question, showing that rare and therapy-resistant leukemia stem cells are already present at diagnosis – well before any treatment has begun - in patients who experience relapses of acute myeloid leukemia (AML).

    The team, led by TFRI-funded Dr. John Dick (a senior scientist at Princess Margaret Cancer Centre), recently had their findings published in Nature (June 2017). There are two distinct cancer stem cell populations that can lead to relapse in AML, the paper suggests, rare therapy-resistant cells present at diagnosis that have the ability to regrow the disease in patients. AML is the deadliest form of leukemia, with cure rates significantly lower than some other forms of the disease.

    The team used an innovative, two-part approach for the study. Paired patient samples of blood taken at the initial clinic visit before treatment as well as after treatment when the disease recurred were analyzed to see what similarities and differences existed between samples. Detailed genetic studies were undertaken, and whole genome sequencing was used to examine every part of the DNA at diagnosis and at relapse to see in which cells genetic changes were occurring.

    Most people diagnosed with AML have 10 mutations in their leukemia cells, while some normal stem cells have up to three different mutations. Researchers in the present study were able to determine which mutations were only seen at relapse, using the team’s pre-existing knowledge of leukemic and normal stem cells to discover two cells types that can cause relapse.

    This finding builds onto a paper the team published in Nature in December 2016, which discovered a 17-gene signature derived from leukemia stem cells to predict at diagnosis which AML patients will respond to standard treatment and which will not. These new biomarkers have the potential to lead to clinical trials for targeted types of chemotherapy, compared to the one size fits all treatment AML patients currently receive.  

    Study: Tracing the origins of relapse in acute myeloid leukemia to stem cells

    Authors: Liran I. Shlush, Amanda Mitchell1, Lawrence Heisler, Sagi Abelson, Stanley W. K. Ng, Aaron Trotman-Grant, Jessie J. F. Medeiros, Abilasha Rao-Bhatia, Ivana Jaciw-Zurakowsky, Rene Marke, Jessica L. McLeod, Monica Doedens, Gary Bader, Veronique Voisin, ChangJiang Xu, John D. McPherson, Thomas J. Hudson, Jean C. Y. Wang, Mark D. Minden & John E. Dick.

    Funding: This work was supported by grants from the Ontario Institute for Cancer Research with funds from the Province of Ontario, the Cancer Stem Cell Consortium with funding from the Government of Canada through Genome Canada and the Ontario Genomics Institute (OGI-047), and the Canadian Institutes of Health Research (CSC-105367), the Canadian Cancer Society, The Terry Fox Foundation, a Canada Research Chair to J.E.D. L.I.S. was funded by the Benjamin Pearl Fellowship from the McEwen Centre for Regenerative Medicine and an American Society of Hematology Scholar Award. This research was funded in part by the Ontario Ministry of Health and Long-Term Care, whose views are not expressed here.

    TFRI LINKS, Summer 2017 

  • TP53 polymorphisms and MDM2 SNP309 are not correlated with pre-menopausal cancer risk, study suggests

    by TFRI Admin | Sep 06, 2017


     While significant accolades are given to scientists who discover genetic mutations that are linked to cancer, it is equally important to determine factors that are not correlated – something that is the focus of a new Canadian study team investigating polymorphisms and risk of pre-menopausal breast cancer.

    Only around five per cent of women diagnosed with breast cancer are under the age of 40, and of this population around five to eight per cent carry a germline (hereditary) mutation to the tumour suppressor gene. However, little research has been done on why early-onset breast cancer occurs in women without any apparent hereditary link. Hence, the study authors  (Human Mutation, January 2017) set out to examine the composite effects of TP53 variants (TP53 PIN3 and SNP309 of MDM2) on early-onset cancer risk in women without mutations to TP53 or the hereditary breast cancer-associated genes, BRCA1 and BRCA2.

    Led by Dr. David Malkin (The Hospital for Sick Children, Toronto), they assessed the spectrum of polymorphisms in TP53 and its negative regulatory gene, MDM2 in 40 female patients with pre-menopausal breast cancer. No significant correlation was found, and while one polymorphism was frequently found in the cohort, it was not associated with the risk of developing cancer before the age of 35 years in an extended cohort of 1,420 breast cancer cases. The study (first author Dr. Nardin Samuel) also showed that functional studies of the rs1800372:A>G polymorphic allele reveal it does not affect p53 transactivation function.

    While these findings suggest early-onset breast cancer is believed to be related to strong genetic predisposition, this cannot be attributed to TP53 polymorphisms alone, or MDM2 SNP309:T>G in the population surveyed. Many patients in the study’s cohort had an extensive familial – and often personal –  history of cancer despite testing negative for pathogenic mutations in TP53, and it is possible underlying genetic susceptibilities may exist. For example, polymorphic variants that contribute to risk may exist in the well-known cancer susceptibility genes CDH1, PTEN, STK11, and NF1.

    Looking forward, researchers suggest genome-wide sequencing of germline mutations and variants in larger patient cohorts may be a good approach to identifying novel driver genes. Further, continuing the search for answers in the underlying heritability of early-onset breast cancer risk will be crucial to better understand why some women get cancer at such a young age.

    Study: Assessment of TP53 polymorphisms and MDM2 SNP309 in pre-menopausal breast cancer risk

    Authors: Nardin Samuel, Badr Id Said, Tanya Guha, Ana Novokmet, Weili Li, Laxmi Silwal-Pandit, Anne-Lise Børrsen-Dale, Anita Langerød, Thomas J. Hudson, and David Malkin.

    Funding: Contract grant sponsors: Canadian Institutes for Health Research (CIHR); The Terry Fox Research Institute/Foundation; SickKids Foundation; Ontario Institute for Cancer Research, Ontario Ministry of Research and Innovation (Senior Investigator Award); Vanier Canada Graduate Scholarship through CIHR.

    TFRI LINKS, Summer 2017
  • Subtype-specific alterations in BCL2 linked to poor post-treatment outcomes in non-Hodgkin lymphoma

    by TFRI Admin | Sep 06, 2017


    TFRI funding for researchers at the Centre for Lymphoid Cancer (BC Cancer Agency) has resulted in the discovery that subtype-specific alterations in a driver gene for non-Hodgkin lymphoma (BCL2) is strongly associated with poor patient outcomes after treatment.

    The work by Drs. David Scott, Randy Gascoyne, Joseph Connors, and Christian Steidl was published in Blood (May 2017). Diffuse large B-cell lymphoma (DLBLC) is the most common type of non-Hodgkin lymphoma, predominantly affecting people in their mid-60s. BCL2 and MYC are critical driver genes for the disease and play key roles in in normal B-cell differentiation and tumourigenesis.

    Genetic alterations in both genes were profiled in the present study via next-generation sequencing and high-resolution SNP array in 347 de novo DLBCL patients that had already been treated with R-CHOP, the standard chemotherapy treatment for this disease. The team discovered the clinical impact of genetic aberrations in DLBLC needs to be placed in the context of the cell-of-origin molecular subtype and, when this is done, subtype-specific alterations in BCL2 are revealed as being strongly associated with poor outcomes post treatment.

    Further, this work showed that the incidence of MYC/BCL2 genetic alterations and their clinical significance were mainly dependent on cell-of-origin (COO) subtypes. There are two main subtypes of DLBLC based on COO, activated B-cell-like (ABC) subtype and the germinal center B-cell-like (GCB) subtype, both of which have different biology and clinical behaviour. In ABC and GCB subtypes, gain of BCL2 and translocation of BCL2 respectively often led to poor outcomes. The results suggest that COO subtype-specific biomarkers based on these BCL2 genetic alterations can be effectively used to risk-stratify patients with DLBCL treated with immunochemotherapy.

    This paper highlights the value of examining clinical correlates in large homogeneously treated population registry-based cohorts. The finding that BCL2 dysregulation is a common feature of patients with inferior survival will prioritize examination of therapeutic approaches that target BCL2, and hopefully result in better patient outcomes in the future.

    Study: Genetic profiling of MYC and BCL2 in diffuse large B-cell lymphoma determines cell-of-origin–specific clinical impact

    Authors: Daisuke Ennishi, Anja Mottok, Susana Ben-Neriah, Hennady P. Shulha, Pedro Farinha, Fong Chun Chan, Barbara Meissner, Merrill Boyle, Christoffer Hother, Robert Kridel, Daniel Lai, Saeed Saberi, Ali Bashashati, Sohrab P. Shah, Ryan D. Morin, Marco A. Marra, Kerry J. Savage, Laurie H. Sehn, Christian Steidl, Joseph M. Connors, Randy D. Gascoyne, and David W. Scott.

    Funding: This study was supported by a Program Project Grant from the Terry Fox Research Institute (Grant No. 1023 to R.D.G.)

    TFRI LINKS, Summer 2017
  • Discovery of seven new ovarian cancer subtypes opens door for more targeted treatments

    by TFRI Admin | Sep 06, 2017

    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

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