Epithelial ovarian cancer histotypes are thought to have numerous distinct inherited risk factors, somatic
features, and clinical outcomes. Ovarian clear cell carcinoma (OCCC) is one of its rarer histotypes,
representing approximately seven percent of diagnoses. For women presenting at advanced stage, it is highly
lethal; the tumor tends to resist standard platinum-based chemotherapeutics. The more common histotypes,
high-grade serous and endometrioid epithelial ovarian cancer, have been extensively studied including
genomic characterization by large-scale efforts such as The Cancer Genome Atlas. Small-scale tumor profiling
studies in OCCC suggest that it is distinct from these histotypes and that molecular subtypes of OCCC are
likely to exist. Therefore, as the majority of findings from The Cancer Genome Atlas project are not expected to
be applicable to OCCC, improving our understanding of the biology of OCCC with the goal of identifying
genomic features which may lead to targeted OCCC therapeutics is of highest priority. We propose an
exploratory study of OCCC patients from six studies, including targeting DNA sequencing, methylation
profiling, and combined transcriptomic and proteomic expression analyses. We will identify which features
most strongly associate with the baseline clinical features of OCCC patients, such as age at diagnosis, tumor
grade, and stage, and with clinical outcomes, such as overall survival time and time to disease recurrence. To
accomplish our aims, we will establish a collaborative epidemiologic network including investigators of studies
representing the largest cohorts of OCCC cases with associated fresh frozen tumor specimens and clinical
annotation. Based on the results obtained, we will conduct targeted follow-up in an independent collection of
nearly 1,000 OCCC patients. As the majority of studied patients were enrolled into case-control studies which
included germline genotyping and epidemiologic risk factor questionnaires, the wealth of knowledge to be
gained is extensive. This will enable substantial progress towards the development of targeting therapeutics
against this rare, frequently chemo-resistant cancer and will readily foster additional etiologic, epidemiologic,
and clinical OCCC research.
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