AOCS programme

Background: Although several risk factors have been established for ovarian cancer, a better understanding of potentially modifiable risk factors is necessary in order to identify strategies for prevention. Aside from increasing age and a positive family history, the strongest known risk factors for epithelial ovarian cancer are nulliparity, no use of oral contraceptives, and having intact fallopian tubes. These factors are not readily modifiable. Ovarian cancer is very heterogeneous at both a histologic and genetic level, and there is increasing evidence that the different histologic subtypes of ovarian cancer may be etiologically different. Studies that treat ovarian cancers as a single entity, without accounting for this variability, may compromise their ability to identify factors associated with development of the disease. Similarly, common low-risk genetic variants may modify disease susceptibility and may alter the effects of ovarian cancer risk factors.

Objective: The aim of this program is to use histologic and novel molecular subtypes of ovarian tumors to study the association between epidemiologic risk factors, low-risk genes, and subtypes of ovarian cancer, thereby addressing the heterogeneity of the disease and of susceptibility to environmental exposures. To this end, we will establish a multi-centre population-based resource involving the collection of epidemiologic data and biospecimens, including fresh tumor tissue, from cases and matched controls.

Hypothesis: We hypothesize that different subtypes of ovarian cancer, at the histologic and genetic level, are etiologically distinct and will be associated with different epidemiologic risk factors, with an emphasis on potentially modifiable factors. Similarly, we propose that low-risk genes in key pathways may influence susceptibility to ovarian cancer and may modify the effects of known risk factors

Specific Aims:

•  To create a multi-centre resource covering over 1,000 population-based incident cases of primary epithelial ovarian cancer and a similar number of matched controls combining epidemiologic data and biospecimens (blood, urine, paraffin-embedded tumor blocks, and fresh tumor tissue)

•  To determine molecular subtypes of ovarian cancer by DNA microarray-based expression analysis of ovarian tumor samples and to link these subtypes to clinical and epidemiologic characteristics

•  To study associations between epidemiologic risk factors and ovarian cancer by histologic and tumor subtypes with an emphasis on potentially modifiable risk factors

•  To evaluate the association of variants in candidate low-risk genes (in double-stranded DNA repair pathways and androgen/progesterone pathways) and ovarian cancer, and to stratify these associations by tumor subtypes.

Study Design: This Program Project is based upon an Australian-wide collaborative population-based case-control study, the Australian Ovarian Cancer Study. Cases will be identified through an existing network of gynecologic oncologists covering more than 85% of the Australian population and interviewed by trained nurses as soon as possible after diagnosis. With their informed consent, participants will be interviewed, and blood, urine, and tumor (blocks and fresh tissue) will be collected. Controls will be identified through a population-based register and interviewed and asked to provide blood and urine samples, as for cases.