MedicalResearch.com Interview with:
Jacek Majewski PhD
Department of Human Genetics
McGill University and Genome Quebec Innovation Centre
MedicalResearch.com: What is the background for this study?
Response: Our lab, in collaboration with Dr. Nada Jabado, has been investigating the molecular genetics of pediatric glioblastoma – a deadly brain cancer. Several years ago, in the majority of our patients’ tumors we discovered mutations in genes that encode histone proteins. Those mutations disrupt the epigenome – that is the way the DNA is modified, silenced, or activated in the cancer cells. It appears that epigenome-modifying mutations are particularly important in pediatric cancers, and our hypothesis is that they act by diverting the normal developmental pathways into unrestrained proliferation. Many other studies have highlighted the significance of epigenome disruption in a number of cancers.
MedicalResearch.com: What are the main findings?
Response: In our most recent publication – “Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas”, we identified mutations in histone genes as well as in genes encoding histone-modifying enzymes in nearly 15% of patients with this common adult cancer.
MedicalResearch.com: What should readers take away from your report?
Response: The most general lesson from our research is that there is more than one way of looking at the data. Our main observation – mutations disrupting histone proteins – was not initially made by the group that produced the data: The Cancer Genome Atlas (TCGA). However, because raw data from published studies is generally placed in public repositories, allowing the scientific community to then re-analyze the information, we were able to use slightly different approaches to identify important mutations overlooked by the original study. This highlights the importance of data sharing and accessibility.
Of course, the main scientific issue is cancer-related. Because of our discovery, we were able to reach additional conclusions regarding the significance of epigenome disruption in head and neck cancers. Mutations in the histone genes have some functional similarities to mutations in the enzyme NSD1, which is responsible for adding methyl groups to the histone proteins. Using another subset of the data, DNA methylation, we were able to use statistical clustering approaches to show that the tumors from patients carrying histone and NSD1 mutations exhibited highly similar DNA methylation patterns.
Furthermore, we were able to use this methylation-based classification to delineate 5 subgroups of head and neck cancers: HPV-positive (caused by infection with human papilloma virus), epigenome-disrupted (carrying mutations in NSD1 or histone genes), as well as 3 other subgroups that do not have a clear molecular underpinning at this point. Head and neck cancers constitute a heterogeneous group of malignancies and currently used molecular classification techniques do not make full use of the available genomic information. We believe that our DNA methylation-based classification approach – pointing to epigenome disruption as one of the underlying drivers – is a valuable contribution to characterizing head and neck cancers.
Why do we want to classify cancers into subtypes? It is often found that different molecular subtypes have different survival prognoses and treatment options. This has been the case for molecular subtypes of breast cancers. The big hope of personalized or precision medicine in cancer is to provide the ability to target treatment towards underlying driver mutations and their downstream molecular mechanisms of action. Although today customized drug design is still in its infancy, we hope that in the future discoveries such as ours will allow drug development targeting specific mutations and provide new treatment options for many cancers.
MedicalResearch.com: What recommendations do you have for future research as a result of this study?
Response: Publicly available data contains troves of still unexplored information. Researchers should use public databases, in conjunction with their own experiments, to maximize gains in knowledge. We are only beginning to grasp the role of the epigenome in cancer development. This relatively new field will in the future provide great insights into how cancer proceeds, and perhaps how it should be controlled. Cancer is a terrible disease; modern genomewide studies have already greatly contributed to our understanding of molecular mechanisms in cancer, and hold promise into guiding future research into personalized, targeted therapies.
MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.
Simon Papillon-Cavanagh, Chao Lu, Tenzin Gayden, Leonie G Mikael, Denise Bechet, Christina Karamboulas, Laurie Ailles, Jason Karamchandani, Dylan M Marchione, Benjamin A Garcia, Ilan Weinreb, David Goldstein, Peter W Lewis, Octavia Maria Dancu, Sandeep Dhaliwal, William Stecho, Christopher J Howlett, Joe S Mymryk, John W Barrett, Anthony C Nichols, C David Allis, Jacek Majewski, Nada Jabado. Impaired H3K36 methylation defines a subset of head and neck squamous cell carcinomas. Nature Genetics, 2017; DOI: 10.1038/ng.3757
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