Poster Presentation 39th Annual Lorne Genome Conference 2018

Mutational Landscape of Familial Breast Cancers (#222)

Katia Nones 1 , Julie Johnson 2 , Xavier De Luca 2 , Sriganesh Srihari 3 , Kaltin Ferguson 2 , Lynne Reid 2 , Amy M McCart Reed 2 , Stephen Kazakoff 1 , Ann-Marie Patch 1 , Felicity Newell 1 , Vanessa Lakis 1 , Oliver Holmes 1 , Qinying Xu 1 , Scott Wood 1 , Conrad Leonard 1 , The Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab) 4 , Australian Breast Cancer Tissue Bank (ABCTB) 5 , Brisbane Breast Bank (BBB) 2 , Mark Ragan 3 , Georgia Chenevix-Trench 1 , Kum Kum Khanna 1 , Sunil Lakhani 2 , John V Pearson 1 , Nic Waddell 1 , Peter Simpson 2
  1. QIMR Berghofer, Brisbane, QLD, Australia
  2. UQ Centre For Clinical Research, The University Of Queensland, Brisbane, Queensland, Australia
  3. Institute of Molecular Biosciences, The University Of Queensland, Brisbane, QLD, Australia
  4. The Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer , Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
  5. Australian Breast Cancer Tissue Bank , University of Sydney at the Westmead Institute for Medical Research, Sydney, NSW, Australia

Mutations in BRCA1 and BRCA2 genes are associated with approximately 45% of families with multiple cases of breast cancer and up to 90% of families with both breast and ovarian cancer. However, a proportion of women with hereditary breast cancer have no identified pathogenic variants in genes predisposing them to breast cancer. To better understand the aetiology of familial breast cancer we are conducting a whole genome analysis of tumours from familial cases with BRCA1 (n=26), BRCA2 (n=22) and non-BRCA1/2 (n=32) germline mutation carriers. Biospecimens and clinical data were obtained from kConFab, the Brisbane Breast Bank and the Australian Breast Cancer Tissue Bank. Whole genome sequencing (WGS) was performed for 80 matched tumour/normal pairs (60x and 30x coverage, respectively). Whole genome methylation arrays were analysed for 67 tumours and RNASeq for 37 tumours. Comparative analysis with data from 99 sporadic breast tumours from The Cancer Genome Atlas is underway to identify potential similarities or differences between familial and sporadic tumours. The complete spectrum of somatic and germline of mutations has been evaluated, including SNPs, indels, copy number changes and structural rearrangements, and mutational signatures. Our aim is to identify potential mutations or mechanisms underlying familial non-BRCA1/2 breast cancers. BRCA1, BRCA2 and non-BRCA1/2 tumours exhibited a different burden of mutations, different spectrum of mutational signatures and different telomere length. In 5 non-BRCA1/2 cases mutational signatures suggests that deficiency in the Homologous Recombination (HR) pathway might be driving the development of those tumours but not through BRCA1 or BRCA2 mutation. We will present our most recent findings in detecting the mechanisms underlying familial breast cancers that in the future could help the management of families where the underlying cause is unclear.