Endometrial cancer is the most common invasive gynaecological cancer in Australian women, ranking sixth for incidence. Several histological subtypes are recognised and survival is poor for some of these Furthermore, very little is known regarding the role of germline genetic factors in endometrial cancer risk, except that an increased risk among relatives suggests a strong inherited component exists. A thorough examination of the genetic basis to disease within families has not been carried out, and the contribution from other lower-risk genes is unclear from studies to date. Our QIMR-based study group (including led by Prof Spurdle and Webb) set up a large integrated, multidisciplinary study of endometrial cancer, the Australian National Endometrial Cancer Study. This national population-based study of endometrial cancer recruited almost 1,500 incident cases of endometrial cancer, more than 1,500 cancer-free controls, and selected relatives of cases that report a family history of cancerThis broad project was initiated to clarify existing and identify new modifiable risk factors for endometrial cancer, especially for the more aggressive subtypes, and to comprehensively investigate the role of genetic factors in endometrial cancer risk and prognosis. . We have examinedthe genetic basis to disease within multiple-case families by analysis ofg detailed reported family histories for all cases. We have also screened cases with a strong family history of endometrial and other cancers for pathogenic variants in the different known high-risk cancer predisposition genes to delineate strategies to prioritise identification of pathogenic variant carriers at diagnosis. As a collaboration with Dr Nicola Waddell, we are currently analysing genome-wide sequence data for selected cases with a strong family history of cancer.
In addition, the Molecular Cancer Epidemiology Lab is leading international genome-wide association studies of endometrial cancer to identify common genetic variation, and the underlying biological pathways, important to risk of endometrial cancer. The Endometrial Cancer Association Consortium initiated by Prof Spurdle and now co-ordinated by Dr O’Mara, is an ongoing collaboration of > 10 different research groups largely from Europe and the USA,including close collaborations with investigators at Cambridge and Oxford Universities in the UK, At the endometrial cancer risk loci we have identified, we are using functional genomic techniques touncover the likely causal variants and their corresponding target genes. Our preliminary analyses have revealedseveral candidate genes which provide opportunities for drug repositioning and these will be followed up in drug sensitivity studies.
(Dr Tracy O’Mara, Dr Dylan Glubb, Dr Sharon Johnatty )