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Hereditary element to 'sporadic' ovarian cancer
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A study led by a research group in the University of Washington has found that inherited (germline) mutations in genes known to be involved in ovarian cancer are present in 20% of women with no known family history or predisposition to ovarian cancer. The study, published yesterday in Nature Communications, also revealed the presence of germline mutations in genes not previously associated with ovarian cancer. The results of this study suggest that screening of women for ovarian cancer needs to take into account the fact that genetic susceptibility to ovarian cancer may not be obvious from a look at family history. While more than 20000 women are estimated to be afflicted with ovarian cancer, often it is not diagnosed until the cancer has spread due to a lack of definitive symptoms. As a result, there is a poor five –year survival rate for this cancer. The germline mutations identified in this study may not in themselves necessarily lead to cancer, however when linked to acquired (somatic) genetic changes that may occur during a woman’s life, these germline mutations would be sufficient to tip the balance. The authors consider the 20% figure to be conservative as on-going research is expected to reveal further mutations.

The study used large-scale exome-wide analysis to examine both tumour DNA and the woman’s own DNA from 429 ovarian carcinoma cases and 557 controls. These ovarian cancer cases were considered to have arisen sporadically, in the absence of any known familial susceptibility. By comparing the sequences, the researchers were able to identify the somatic mutations that had been acquired in the tumour. In addition, they could compare the ovarian cancer patients’ own DNA samples to those of control subjects to determine if there were germline variants in the cancer patients related to susceptibility to ovarian cancer. This genetic detective work revealed that in 20% of these apparently sporadic ovarian cancer cases, there were germline truncation variants and large deletions in genes belonging to the Fanconi pathway. This pathway is associated with cell division and repair of damaged or mutated DNA and includes the genes BRCA1 (breast cancer type 1 susceptibility protein) and BRCA2 (breast cancer type 2 susceptibility protein), which are widely known to be associated with predisposition to both ovarian and breast cancer. The study found that the ovarian cancer patients carried germline mutations in these genes which would lead to shortened (truncated) protein product, as well as mutations in another gene in this pathway, PALB2 (Partner and localizer of BRCA2). As well as these mutations which were already familiar in the field of ovarian cancer susceptibility, mutations were found in several other genes not previously known in this context, including NF1 (Neurofibromin), MAP3K4 (Mitogen-activated protein kinase kinase kinase 4), CDKN2B (Cyclin-dependent kinase 4 inhibitor B) and MLL3 (Histone-lysine N-methyltransferase 2C).

In all, the findings of this important paper should encourage better integration of knowledge of both inherited and acquired mutations in causing ovarian cancer and contribute to changes in screening practices for this devastating disease. The lead author of the paper, Dr. Li Ding, said: “We’re now able to obtain a fuller picture of the way cancer develops in a particular patient. More studies are needed, but our findings could have important implications for developing better screening strategies for ovarian cancer and improving early detection.”

Sources

Kanchi KL, Johnson KJ, Lu C, Raphael BJ, Wilson RK, Ding L et al. Integrated analysis of germline and somatic variants in ovarian cancer. Nature Communications. Jan. 22, 2014. (Available at
http://www.nature.com/ncomms/2014/140122...affil-auth

Press release: https://news.wustl.edu/news/Pages/26399.aspx
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