Individuals with congenital heart disease (CHD) face a higher rate of ongoing health concerns than the general population, including higher cancer incidence. Potential contributors to the increased cancer include factors often shared among CHD patients, such as genetic variants and radiation exposure. Therefore, it is important to determine whether there are genetic susceptibilities to cancer that can be identified and mitigated among CHD patients. In preliminary analysis, there was a significant burden of damaging variants in cancer risk genes in a CHD cohort. Whether this genetic burden is consistent in additional CHD cohorts, and how mutations in cancer risk genes affect cell biology during cardiac development, is addressed in the following aims:Aim 1. Assess whether the burden of risk variants is (A) reproduced in an independent cohort of 2090 CHD participants compared with 12380 non-CHD participants, and (B) is age-dependent in cross-sectional analysis of 4836 CHD patients. Hypothesis 1: CHD will be consistently associated with a burden of risk variants. Hypothesis 2: The prevalence of risk variants will decrease with age in the CHD cohort starting in the fifth decade due to cancer-related mortality. Aim 2. Mutate human iPSCs and study the effects of damaging variants in 4 CHD+CA genes on cell proliferation, morphology, and transcription at baseline and during differentiation. Hypothesis 3: Damaging variants in CHD+CA genes will alter shared developmental pathways. These aims are important first steps towards the immediate goal of defining CHD genes that convey risk for cancer. If genetic risk contributes to the increased cancer incidence among individuals with CHD, it will be important to develop new clinical approaches to the prevention, diagnosis and treatment of cancer in the CHD population. These data would propel future studies to clarify the relative contribution of genetic and other risk factors such as radiation exposure. Aim 2 will begin to provide mechanistic insights that may uncover pathways that advance basic insights into CHD and cancer. In the long term, using computational approaches to integrate genetic risk common to cardiac development and oncogenesis can broaden our understanding of factors that contribute to CHD, and potentially uncover new preventative or therapeutic approaches.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 12/31/2021|