||5U01CA250476-03 Interpret this number
||De Vivo, Immaculata
||Brigham And Women'S Hospital
||Comprehensive Molecular Characterization of Endometrial Cancer, Etiologic Heterogeneity, and Racial Disparities
Endometrial cancer (EC) is the most common gynecologic cancer in the US. Incidence is increasing, especially
for aggressive, understudied tumors that confer poor prognosis and are more often seen in African Americans
(AAs). EC has one of the largest survival disparities of all cancers: AAs have >2-fold higher mortality vs. other
racial/ethnic groups. The disparity remains after accounting for stage, histology, comorbidities, and treatment.
The etiology of aggressive tumors and 2-fold survival disparity are large knowledge gaps in EC. The Cancer
Genome Atlas (TCGA) achieved milestones in clarifying endometrial tumor biology. Using exome sequence
data, TCGA defined 4 new tumor subtypes with prognostic significance and showed these data can refine
subtype classification beyond classic histology. But TCGA used mostly good prognosis endometrioid tumors
(>90%) and tumors in white women—with only 46 AAs—to define these subtypes. Our pilot analysis of AA vs.
non-AA tumors in these sparse data suggested AAs more often had mutational features suggestive of poor
outcomes. We hypothesize somatic differences in AA vs. non-AA tumors may help explain the large survival
disparity. Here, we will use the largest, most diverse population to date—including 1,011 AA and 2,043 non-AA
cases in the Epidemiology of Endometrial Cancer Consortium (E2C2)—to study genomic variation across the
full spectrum of endometrial tumors, distinct risk factor profiles across tumor types, and the role of underlying
tumor biology in driving the 2-fold survival disparity. We will: define the mutational landscape and novel
tumor subtypes using whole-exome sequence data in 3,054 endometrial tumors and compare these in
AA vs. non-AA cases. This will use exhaustive genomic profiling of point mutations, indels, and copy number
alterations. Next, we will identify differences in risk factor associations by tumor molecular subtypes in
3,054 cases and 3,054 matched controls. Despite many known EC risk factors, TCGA was not designed to
study these in concert with somatic changes. We will combine tumor profiling data in cases with information on
known germline genetic and epidemiologic risk factors in cases and controls to study distinct risk factor profiles
by tumor subtypes. Finally, we will 3) determine the extent to which tumor molecular subtypes explain the
2-fold survival disparity in AA and non-AA cases: Having characterized tumor genomes, we will use
mediation analysis to determine the extent to which tumor molecular profiles in AAs and non-AAs explain the
survival disparity. Leveraging E2C2 resources and collaborations, we will characterize the biology and risk
profiles of the component subtypes of EC, including aggressive tumors, and somatic differences that drive the
survival disparity. Long-term this can lead to refined risk prediction tools, improved targeting of disease
prevention and treatment, and strategies to reduce longstanding racial disparities in mortality. Our study will
also build a unique platform on which to perform future population-based -omics studies of EC.
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