With more than 35 peer-reviewed scientific publications, findings from the POG program are influencing precision oncology approaches around the world.

POG publications

NPJ Precision Oncology, 2018
Authors
My Linh Thibodeau, Melika Bonakdar, Eric Zhao, Karen L. Mungall, Caralyn Reisle, Wei Zhang, Morgan H. Bye, Nina Thiessen, Dustin Bleile, Andrew J. Mungall, Yussanne P. Ma, Martin R. Jones, Daniel J. Renouf, Howard J. Lim, Stephen Yip, Tony Ng, Cheryl Ho, Janessa Laskin, Marco A. Marra, Kasmintan A. Schrader, and Steven J. M. Jones
Publication Abstract

Eccrine porocarcinomas (EPs) are rare malignant tumours of the intraepidermic sweat gland duct and most often arise from benign eccrine poromas. Some recurrent somatic genomic events have been identified in these malignancies, but very little is known about the complexity of their molecular pathophysiology. We describe the whole genome and whole transcriptome genomic profiling of a metastatic EP in a 66-year-old male patient with a previous history of localized porocarcinoma of the scalp. Whole genome and whole transcriptome genomic profiling was performed on the metastatic EP. Whole genome sequencing was performed on blood-derived DNA in order to allow a comparison between germline and somatic events. We found somatic copy losses of several tumour suppressor genes including APC, PTEN and CDKN2A, CDKN2B and CDKN1A. We identified a somatic hemizygous CDKN2A pathogenic splice site variant. De novo transcriptome assembly revealed abnormal splicing of CDKN2A p14ARF and p16INK4a. Elevated expression of oncogenes EGFR and NOTCH1 was noted and no somatic mutations were found in these genes. Wnt pathway somatic alterations were also observed. In conclusion, our results suggest that the molecular pathophysiology of malignant EP features high complexity and subtle interactions of multiple key genes. Cell cycle dysregulation and CDKN2A loss of function was found to be a new potential driver in EP tumourigenesis. Moreover, the combination of somatic copy number variants and abnormal gene expression perhaps partly related to epigenetic mechanisms, all likely contribute to the development of this rare malignancy in our patient.

Clinical Cancer Research, 2017
Authors
Eric Y. Zhao, Yaoqing Shen, Erin Pleasance, Katayoon Kasaian, Sreeja Leelakumari, Martin Jones, Pinaki Bose, Carolyn Ch'ng, Caralyn Reisle, Peter Eirew, Richard Corbett, Karen L. Mungall, Nina Thiessen, Yussanne Ma, Jacqueline E. Schein, Andrew J. Mungall, Yongjun Zhao, Richard A. Moore, Wendie Den Brok, Sheridan Wilson, Diego Villa, Tamara Shenkier, Caroline Lohrisch, Stephen Chia, Stephen Yip, Karen Gelmon, Howard Lim, Daniel Renouf, Sophie Sun, Kasmintan A. Schrader, Sean Young, Ian Bosdet, Aly Karsan, Janessa Laskin, Marco A. Marra and Steven J.M. Jones
Publication Abstract

Purpose: Recent studies have identified mutation signatures of homologous recombination deficiency (HRD) in over 20% of breast cancers, as well as pancreatic, ovarian, and gastric cancers. There is an urgent need to understand the clinical implications of HRD signatures. Whereas BRCA1/2 mutations confer sensitivity to platinum-based chemotherapies, it is not yet clear whether mutation signatures can independently predict platinum response.Experimental Design: In this observational study, we sequenced tumor whole genomes (100× depth) and matched normals (60×) of 93 advanced-stage breast cancers (33 platinum-treated). We computed a published metric called HRDetect, independently trained to predict BRCA1/2 status, and assessed its capacity to predict outcomes on platinum-based chemotherapies. Clinical endpoints were overall survival (OS), total duration on platinum-based therapy (TDT), and radiographic evidence of clinical improvement (CI).Results: HRDetect predicted BRCA1/2 status with an area under the curve (AUC) of 0.94 and optimal threshold of 0.7. Elevated HRDetect was also significantly associated with CI on platinum-based therapy (AUC = 0.89; P = 0.006) with the same optimal threshold, even after adjusting for BRCA1/2 mutation status and treatment timing. HRDetect scores over 0.7 were associated with a 3-month extended median TDT (P = 0.0003) and 1.3-year extended median OS (P = 0.04).Conclusions: Our findings not only independently validate HRDetect, but also provide the first evidence of its association with platinum response in advanced breast cancer. We demonstrate that HRD mutation signatures may offer clinically relevant information independently of BRCA1/2 mutation status and hope this work will guide the development of clinical trials.

Annals of Oncology, 2017
Authors
M R Jones, H Lim, Y Shen, E Pleasance, C Ch'ng, C Reisle, S Leelakumari, C Zhao, S Yip, J Ho, E Zhong, T Ng, D Ionescu, D F Schaeffer, A J Mungall, K L Mungall, Y Zhao, R A Moore, Y Ma, S Chia, C Ho, D J Renouf, K Gelmon , S J M Jones, M A Marra, J Laskin
Publication Abstract

Background: NRG1 fusion-positive lung cancers have emerged as potentially actionable events in lung cancer, but clinical support is currently limited and no evidence of efficacy of this approach in cancers beyond lung has been shown.

Patients and methods: Here, we describe two patients with advanced cancers refractory to standard therapies. Patient 1 had lung adenocarcinoma and patient 2 cholangiocarcinoma. Whole-genome and transcriptome sequencing were carried out for these cases with select findings validated by fluorescence in situ hybridization.

Results: Both tumors were found to be positive for NRG1 gene fusions. In patient 1, an SDC4-NRG1 gene fusion was detected, similar gene fusions having been described in lung cancers previously. In patient 2, a novel ATP1B1-NRG1 gene fusion was detected. Cholangiocarcinoma is not a disease type in which NRG1 fusions had been described previously. Integrative genome analysis was used to assess the potential functional significance of the detected genomic events including the gene fusions, prioritizing therapeutic strategies targeting the HER-family of growth factor receptors. Both patients were treated with the pan HER-family kinase inhibitor afatinib and both displayed significant and durable response to treatment. Upon progression sites of disease were sequenced. The lack of obvious genomic events to describe the disease progression indicated that broad transcriptomic or epigenetic mechanisms could be attributed to the lack of prolonged response to afatinib.

Conclusion: These observations lend further support to the use of pan HER-tyrosine kinase inhibitors for the treatment of NRG1 fusion-positive in both cancers of lung and hepatocellular origin and indicate more broadly that cancers found to be NRG1 fusion-positive may benefit from such a clinical approach regardless of their site of origin.

Clinical trial information: Personalized Oncogenomics (POG) Program of British Columbia: Utilization of Genomic Analysis to Better Understand Tumour Heterogeneity and Evolution (NCT02155621).

Keywords: NRG1 gene fusion; afatinib; integrative genomic analysis; intrahepatic cholangiocarcinoma; lung adenocarcinoma; personalized medicine.

Cold Spring Harbor Molecular Case Studies, 2018
Authors
Hui-Li Wong, Kevin C Yang, Yaoqing Shen, Eric Y Zhao, Jonathan M Loree, Hagen F Kennecke, Steve E Kalloger, Joanna M Karasinska, Howard J Lim, Andrew J Mungall, Xiaolan Feng, Janine M Davies, Kasmintan Schrader, Chen Zhou, Aly Karsan, Steven J M Jones, Janessa Laskin, Marco A Marra, David F Schaeffer, Sharon M Gorski, Daniel J Renouf
Publication Abstract

Pancreatic neuroendocrine tumors (PNETs) are a genomically and clinically heterogeneous group of pancreatic neoplasms often diagnosed with distant metastases. Recurrent somatic mutations, chromosomal aberrations, and gene expression signatures in PNETs have been described, but the clinical significance of these molecular changes is still poorly understood, and the clinical outcomes of PNET patients remain highly variable. To help identify the molecular factors that contribute to PNET progression and metastasis, and as part of an ongoing clinical trial at the BC Cancer Agency (clinicaltrials.gov ID: NCT02155621), the genomic and transcriptomic profiles of liver metastases from five patients (four PNETs and one neuroendocrine carcinoma) were analyzed. In four of the five cases, we identified biallelic loss of MEN1 and DAXX as well as recurrent regions with loss of heterozygosity. Several novel findings were observed, including focal amplification of MYCN concomitant with loss of APC and TP53 in one sample with wild-type MEN1 and DAXX Transcriptome analyses revealed up-regulation of MYCN target genes in this sample, confirming a MYCN-driven gene expression signature. We also identified a germline NTHL1 fusion event in one sample that resulted in a striking C>T mutation signature profile not previously reported in PNETs. These varying molecular alterations suggest different cellular pathways may contribute to PNET progression, consistent with the heterogeneous clinical nature of this disease. Furthermore, genomic profiles appeared to correlate well with treatment response, lending support to the role of prospective genotyping efforts to guide therapy in PNETs.

Cold Spring Harbor Molecular Case Studies, 2017
Authors
Jasleen K Grewal, Peter Eirew, Martin Jones, Kenrry Chiu, Basile Tessier-Cloutier, Anthony N Karnezis, Aly Karsan, Andy Mungall, Chen Zhou, Stephen Yip, Anna V Tinker, Janessa Laskin, Marco Marra, Steven J M Jones
Publication Abstract

Whole-genome and transcriptome sequencing were performed to identify potential therapeutic strategies in the absence of viable treatment options for a patient initially diagnosed with vulvar adenocarcinoma. Genomic events were prioritized by comparison against variant distributions in the TCGA pan-cancer data set and complemented with detailed transcriptome sequencing and copy-number analysis. These findings were considered against published scientific literature in order to evaluate the functional effects of potentially relevant genomic events. Analysis of the transcriptome against a background of 27 TCGA cancer types led to reclassification of the tumor as a primary HER2+ mammary-like adenocarcinoma of the vulva. This revised diagnosis was subsequently confirmed by follow-up immunohistochemistry for a mammary-like adenocarcinoma. The patient was treated with chemotherapy and targeted therapies for HER2+ breast cancer. The detailed pathology and genomic findings of this case are presented herein.

Current Oncology, 2017
Authors
N. Chooback, MD, Y. Shen, PhD, M. Jones, PhD, K. Kasaian, PhD, M. Martin, MD, T. Ng, MD PhD, T. Thomson, MD, M. Marra, PhD, J. Laskin, MD, and C. Ho, MD
Publication Abstract

The most common benign salivary tumour is a pleomorphic adenoma. Transformation to malignancy, carcinoma ex pleomorphic adenoma (cxpa), occurs in 6% of cases. Management focuses on surgical resection and radiotherapy; however, rare cases require systemic management. We present the case of a 60-year-old woman with a cxpa of the left parotid gland who required systemic therapy for locally recurrent disease. Treatment options were guided by the literature concerning malignant salivary gland tumour and by whole-genome and transcriptome sequencing of the tumour. The patient received multiple systemic agents during the course of her disease, with cyclophosphamide–doxorubicin–cisplatin providing the best control (partial response). Genomeand transcriptome-directed therapy, including sorafenib and vismodegib, were utilized with limited clinical benefit. Malignant transformation in cxpa is a complex process, and therapy directed at a single tumour pathway might not be sufficient to control disease.

Human Resources for Health, 2017
Authors
Peter Chow-White, Dung Ha , Janessa Laskin
Publication Abstract

Background

It has been over a decade since the completion of the Human Genome Project (HGP), genomic sequencing technologies have yet to become parts of standard of care in Canada. This study investigates medical oncologists’ (MOs) genomic literacy and their experiences based on their participation in a cancer genomics trial in British Columbia, Canada.

Methods

The authors conducted a survey of MOs from British Columbia, Canada (n = 31, 52.5% response rate), who are actively involved in a clinical genomics trial called Personalized Onco-Genomics (POG). The authors also measured MOs’ level of genomic knowledge and attitudes about clinical genomics in cancer medicine.

Results

The findings show a low to moderate level of genomic literacy among MOs. MOs located outside the Vancouver area (the major urban center) reported less knowledge about new genetics technologies compared to those located in the major metropolitan area (26.7 vs 73.3%, P < 0.07, Fisher exact test). Forty-two percent of all MOs thought medical training programs do not offer enough genomic training. The majority of the respondents thought genomics will have major impact on drug discovery (67.7%), and treatment selection (58%) in the next 5 years. They also thought the major challenges are cost (61.3%), patient genomic literacy (48.3%), and clinical utility of genomics (42%).

Conclusions

The data suggest a high need to increase genomic literacy among MOs and other doctors in medical school training programs and beyond, especially to physicians in regional areas who may need more educational interventions. Initiatives like POG play a critical role in the education of MOs and the integration of big data clinical genomics into cancer care.

Cold Spring Harbor Molecular Case Studies, 2017
Authors
My Linh Thibodeau, Caralyn Reisle, Eric Zhao, Lee Ann Martin, Yazeed Alwelaie, Karen L Mungall, Carolyn Ch'ng, Ruth Thomas, Tony Ng, Stephen Yip, Howard J Lim, Sophie Sun, Sean S Young, Aly Karsan, Yongjun Zhao, Andrew J Mungall, Richard A Moore, Daniel J Renouf, Karen Gelmon, Yussanne P Ma, Malcolm Hayes, Janessa Laskin, Marco A Marra, Kasmintan A Schrader, Steven J M Jones
Publication Abstract

We describe a woman with the known pathogenic germline variant CHEK2:c.1100delC and synchronous diagnoses of both pelvic genital type leiomyosarcoma (LMS) and metastatic invasive ductal breast carcinoma. CHEK2 (checkpoint kinase 2) is a tumor-suppressor gene encoding a serine/threonine-protein kinase (CHEK2) involved in double-strand DNA break repair and cell cycle arrest. The CHEK2:c.1100delC variant is a moderate penetrance allele resulting in an approximately twofold increase in breast cancer risk. Whole-genome and whole-transcriptome sequencing were performed on the leiomyosarcoma and matched blood-derived DNA. Despite the presence of several genomic hits within the double-strand DNA damage pathway (CHEK2 germline variant and multiple RAD51B somatic structural variants), tumor profiling did not show an obvious DNA repair deficiency signature. However, even though the LMS displayed clear malignant features, its genomic profiling revealed several characteristics classically associated with leiomyomas including a translocation, t(12;14), with one breakpoint disrupting RAD51B and the other breakpoint upstream of HMGA2 with very high expression of HMGA2 and PLAG1 This is the first report of LMS genomic profiling in a patient with the germline CHEK2:c.1100delC variant and an additional diagnosis of metastatic invasive ductal breast carcinoma. We also describe a possible mechanistic relationship between leiomyoma and LMS based on genomic and transcriptome data. Our findings suggest that RAD51B translocation and HMGA2 overexpression may play an important role in LMS oncogenesis.

Molecular Genetics and Genomic Medicine, 2017
Authors
Deirdre Weymann, Janessa Laskin, Robyn Roscoe, Kasmintan A Schrader, Stephen Chia, Stephen Yip, Winson Y Cheung, Karen A Gelmon, Aly Karsan, Daniel J Renouf, Marco Marra, Dean A Regier
Publication Abstract

Background: Limited data exist on the real-world costs of applying whole-genome analysis (WGA) in a clinical setting. We estimated the costs of applying WGA to guide treatments for patients with advanced cancers and characterized how costs evolve over time.

Methods: The setting is the British Columbia Cancer Agency Personalized OncoGenomics (POG) program in British Columbia, Canada. Cost data were obtained for patients who enrolled in the program from 2012 to 2015. We estimated mean WGA costs using bootstrapping. We applied time series analysis and produced 10-year forecasts to determine when costs are expected to reach critical thresholds.

Results: The mean cost of WGA over the study period was CDN$34,886 per patient (95% CI: $34,051, $35,721). Over time, WGA costs decreased, driven by a reduction in costs of sequencing. Yet, costs of other components of WGA increased. Forecasting showed WGA costs may not reach critical thresholds within the next 10 years.

Conclusion: WGA costs decreased over the studied time horizon, but expenditures needed to realize WGA remain significant. Future research exploring costs and benefits of WGA-guided cancer care are crucial to guide health policy.

Current Oncology, 2016
Authors
B S Sheffield, B Tessier-Cloutier, H Li-Chang, Y Shen, E Pleasance, K Kasaian, Y Li, S J M Jones, H J Lim, D J Renouf, D G Huntsman, S Yip, J Laskin, M Marra, D F Schaeffer
Publication Abstract

Background: Gastrointestinal carcinomas are genomically complex cancers that are lethal in the metastatic setting. Whole-genome and transcriptome sequencing allow for the simultaneous characterization of multiple oncogenic pathways.

Methods: We report 3 cases of metastatic gastrointestinal carcinoma in patients enrolled in the Personalized Onco-Genomics program at the BC Cancer Agency. Real-time genomic profiling was combined with clinical expertise to diagnose a carcinoma of unknown primary, to explore treatment response to bevacizumab in a colorectal cancer, and to characterize an appendiceal adenocarcinoma.

Results: In the first case, genomic profiling revealed an IDH1 somatic mutation, supporting the diagnosis of cholangiocarcinoma in a malignancy of unknown origin, and further guided therapy by identifying epidermal growth factor receptor amplification. In the second case, a BRAF V600E mutation and wild-type KRAS profile justified the use of targeted therapies to treat a colonic adenocarcinoma. The third case was an appendiceal adenocarcinoma defined by a p53 inactivation; Ras/raf/mek, Akt/mtor, Wnt, and notch pathway activation; and overexpression of ret, erbb2 (her2), erbb3, met, and cell cycle regulators.

Summary: We show that whole-genome and transcriptome sequencing can be achieved within clinically effective timelines, yielding clinically useful and actionable information.

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