Poster Presentation 43rd Lorne Genome Conference 2022

Massively parallel sequencing in high-risk hereditary prostate cancer families reveals rare DNA repair gene variants (#105)

Georgea R Foley 1 , James R Marthick 1 , Sionne Lucas 1 , Kelsie Raspin 1 , Annette Banks 1 , Janet L Stanford 2 , Elaine A Ostrander 3 , Liesel M FitzGerald 1 , Joanne L Dickinson 1
  1. Menzies Institute for Medical Research, Hobart, TAS, Australia
  2. Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
  3. Cancer Genetics and Comparative Genomics Branch, National Human Genome Research Institute, Bethesda, Maryland, USA

Prostate cancer (PrCa) is the second most diagnosed cancer worldwide and has a significant inherited component. Rare mutations play an important role in causing hereditary disease, and it is known that significant proportions of PrCa patients carry variants in DNA damage repair (DDR) genes. Here, massively parallel sequencing was applied to two independent high-risk familial PrCa datasets, with the aim of identifying rare DDR gene variants that contribute to disease risk.

Massively parallel sequencing data from Australian and North American familial PrCa datasets were examined for rare, likely deleterious variants in a panel of 35 genes involved in DDR. A range of criteria were used to prioritise variants for further investigation, including frequency (MAF <1%), mutation type (missense, nonsense, or splice), segregation with disease, and predicted deleteriousness (CADD >15). Statistical analysis of genotyping data available for 1,972 individuals (including familial cases, unaffected relatives, sporadic cases, and screened controls) from the Australian and North American datasets revealed statistically significant associations between PrCa risk and rare variants in ERCC3 (rs145201970, p=2.57x10-4) and BRIP1 (rs4988345, p=0.025). Additionally, a variant in PARP2 (rs200603922, p=0.028) was significantly associated with risk in the Australian dataset alone, while a variant in MUTYH (rs36053993, p=0.031) was significantly associated with risk in the North American dataset.

Discovery of rare, high-risk germline variants in DDR genes has proven challenging due to their very low frequency, impacting power to detect significant associations. There is, however, considerable impetus to characterise these variants, particularly in light of significant advances in the development of therapeutics targeting these pathways. Here, we have identified multiple rare DDR gene variants associated with familial PrCa risk. Subsequent investigation into the functional and/or biological effect of these variants may have wide-reaching implications on the burden of PrCa, especially in their roles as potential gene-based therapeutic targets.