MedicalResearch.com Interview with:
Ed Liu, M.D
President and CEO
The Jackson Laboratory (JAX)
MedicalResearch.com: What is the background for this study? What are the main findings?
Response: A few years ago we and others identified a complex genomic instability profile commonly found in the genomes of breast, ovarian and endometrial carcinomas, which is characterized by hundreds of isolated head-to-tail duplications of DNA segments, called tandem duplications. We refer to this configuration as the tandem duplicator phenotype, or TDP.
In this study, we perform a meta-analysis of over 2,700 cancer genomes from over 30 different tumor types and provide a detailed description of six different types of TDP, distinguished by the presence of tandem duplications of different sizes. Collectively, these profiles are found in ~50% of breast, ovarian and endometrial carcinomas as well as 10-30% of adrenocortical, esophageal, stomach and lung adeno-carcinomas. We show that distinct genetic abnormalities associate with the distinct TDPs, clearly suggesting that distinct molecular mechanisms are driving TDP formation. In particular, we provide strong evidence of a casual relationship between joint abrogation of the BRCA1 and TP53 tumor suppressor genes and the emergence of a short-span (~11 Kb) TDP profile. We also observe a significant association between hyper-activation of the CCNE1 pathway and TDP with medium-span (~230 Kb) tandem duplications, and between mutation of the CDK12 gene and medium- and large-span TDP (coexisting 230 Kb and 1.7 Kb tandem duplications).
Importantly, we find that different forms of TDP result in the perturbation of alternative sets of cancer genes, with short-span TDP profiles leading to the loss of tumor suppressor genes via double transections, and larger-span TDP profiles resulting in the duplication (i.e. copy number gain) of oncogenes and gene regulatory elements, such as super-enhancers and disease-associated SNPs.
MedicalResearch.com: What should readers take away from your report?
Response: The TDPs are common genomic instability profiles that originate following precise molecular deficiencies and have the potential to alter the activity of hundreds of genes in any given cancer genome. Given our improved understanding of the molecular drivers and of the recurrent genomic consequences of the tandem duplications emerging in the context of the TDP, assessing the TDP status of a tumor can inform about which drugs are more luckily to be effective in counteracting tumor growth.
MedicalResearch.com: What recommendations do you have for future research as a result of this work?
Response: Whereas we provide a strong validation of the role of BRCA1 and TP53 in inducing the short-span TDP profile, we still need to validate/establish the exact molecular underpinnings of the other TDP types. Also, follow-up research is focused on assessing the usefulness of TDP assessment as a predictive biomarker for therapy response in the clinical setting.
Understanding The Genesis And Oncogenic Consequences Of Tandem Duplicator Phenotypes In Human Cancers
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