Chemotherapy Choice Can Be Aided By Assessing TDP Profile

MedicalResearch.com Interview with:

Ed Liu, M.D President and CEO The Jackson Laboratory (JAX)

Dr. Ed Liu

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.  Continue reading

Blood Pressure Med Linked to Increased Risk of Pancreatic Cancer in Postmenopausal Women

MedicalResearch.com Interview with:

Zhensheng Wang, M.P.H., Ph.D. Postdoctoral Associate Duncan Cancer Center-Bondy Baylor College of Medicine Houston, TX, US

Dr. Wang

Zhensheng Wang, M.P.H., Ph.D.
Postdoctoral Associate
Duncan Cancer Center-Bondy
Baylor College of Medicine
Houston, TX

MedicalResearch.com: What is the background for this study?

Response: Our prior research consistently found a significant inverse association between circulating levels of soluble receptor for advanced glycation end products (sRAGE), an anti-inflammatory factor, and risk of pancreatic cancer. It has also been found that sRAGE levels or RAGE signaling are modulated by anti-hypertensive (anti-HT) medications, including angiotensin-converting-enzyme inhibitors (ACEi), β-blockers, and calcium channel blockers (CCBs). These medications have been shown in prior pre-clinical or experimental research to either increase sRAGE concentrations, decrease formation of advanced glycation end-products (AGEs), or dampen pro-inflammatory receptor for AGE (RAGE) signaling pathway. We therefore hypothesized that there would be an inverse association between use of anti-HT medications and risk of developing pancreatic cancer.

Pancreatic cancer is a major public health concern in the United States, as it is the 4th leading cause of cancer-related mortality with an estimated of 43,090 deaths in 2017. Pancreatic cancer typically occurs in elderly individuals who also have chronic comorbid medical conditions, such as hypertension. Anti-HT medication use in individuals ≥ 18 years old has increased from 63.5% in 2001-2002 to 77.3% in 2009-2010, according to the National Health and Nutrition Examination Survey in the U.S. Therefore, it is of great public health significance to address the potential association between anti-HT medication use and risk of pancreatic cancer in the general population.

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Rhabdomyosarcoma Can Develop From Hijacked Blood Vessel Cells

MedicalResearch.com Interview with:

Mark E. Hatley, M.D., Ph.D. Assistant Member Molecular Oncology Division, Department of Oncology St. Jude Children's Research Hospital Memphis, TN 38105

Dr. Hatley

Mark E. Hatley, M.D., Ph.D.
Assistant Member
Molecular Oncology Division, Department of Oncology
St. Jude Children’s Research Hospital
Memphis, TN 38105

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma occurring in children. Tumors appear histologically and genetically as undifferentiated skeletal muscle and are thus thought to solely originate from early skeletal muscle cells. However, tumors occur throughout the body, including sites devoid of skeletal muscle. In addition, tumor location is a key feature of staging and 40% of patients develop RMS in the head and neck. Interestingly, head and neck muscle development is distinct from the development of trunk and limb muscle. Previously we described a model of rhabdomyosarcoma which occurred specifically in the head and neck and originated from non-muscle cells. In this study we investigated how normal development programs are hijacked to drive rhabdomyosarcoma location.

We demonstrated that RMS can originate from immature blood vessel cells that lie in between muscle fibers specifically in the head and neck. During development, these cells are hijacked, and become reprogrammed into rhabdomyosarcoma rather than mature endothelial cells. These RMS cells express factors important in head and neck muscle development. Our findings highlight that cell of origin contributes to RMS location and may explain why a high proportion of RMS occurs in the head and neck.  Continue reading