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Investigating Hereditary Cancer Predisposition – a combined genomics approach

Final Report Summary - IHCAP (Investigating Hereditary Cancer Predisposition – a combined genomics approach)

There were three key aims of the IHCAP project:

1) to investigate the inherited genetic architecture of unilateral breast cancer versus bilateral breast cancer.
As part of an international collaboration we performed exome sequencing in 245 matched pairs of DNA from women with unilateral breast cancer (UBC) and women with bilateral breast cancer(CBC). We identified nearly half a million genetic variants which we then prioritised and investigated the top genes further in 541 samples (268 UBC and 273 CBC). Through this approach we have identified three potential new candidates for breast cancer predisposition.

2) to investigate new genetic causes of hereditary breast-cancer.
We have undertaken exome sequencing of over 60 DNA samples from women with a strong family history of breast cancer that is unexplained. We have investigated one particular gene in great detail. This gene is called PALB2 and in 2014 we have published a seminal paper looking at breast cancer risk in 154 families who have mutations in this gene. Since then we have continued to recruit families (we now have over 800) and we have for the first time found an association between germline PALB2 mutations and ovarian cancer predisposition. We have also refined the breast cancer risks for the first time reported risk estimates for pancreatic cancer and male breast cancer. The manuscript is currently submitted for publication.

3) to investigate hereditary causes of benign and malignant tumours in families that are currently unexplained.
We have identified potential genetic causes for several families with unexplained clusters of benign and/or malignant tumours. For example we have identified the genetic cause of several rare skin tumour predisposition syndromes and coined the term of MALTA (MYH9 Associated eLasTin Aggregation) syndrome to emphasis to common underlying genetic cause for these conditions. This work has recently been published.