16P - Next-generation sequencing of epigenetically silenced genes in BRCAx cases and ancestry matched controls

Date 08 May 2014
Event IMPAKT 2014
Session Welcome reception and Poster Walk
Topics Breast Cancer
Personalised Medicine
Translational Research
Presenter Fatima Aloraifi
Citation Annals of Oncology (2014) 25 (suppl_1): i5-i7. 10.1093/annonc/mdu065
Authors F. Aloraifi1, J. McGreevy1, T. McDevitt2, A. Green2, A. Bracken1, J. Geraghty3
  • 1Smurfit Institute Of Genetics, Trinity College Dublin, 2 - Dublin/IE
  • 2Genetics, National Centre for Medical Genetics, 14 - Dublin/IE
  • 3St Vincents University Hospital, University College Dublin, 4 - Dublin/IE


Breast cancer is the leading cause of cancer deaths in females worldwide occurring in both hereditary and sporadic forms. However, only about 20 of familial breast cancer cases are attributed to mutations in BRCA1 and BRCA2, while a further 510 is attributed to mutations in other rare susceptibility genes such as TP53, ATM and CHEK2 (1). Despite extensive efforts to explain the missing heritability of this disease, the majority of familial clustering in breast cancer remains largely unexplained. Hypermethylation silences the promoters of tumor suppressor genes and is one of the best-known lesions of tumor formation (2). Here, we hypothesize that these epigenetically silenced genes may also harbor germline pathogenic mutations and thus predispose to breast cancer. In this present study, we applied targeted capture and high-throughput sequencing of 48 epigenetically silenced genes in breast cancer in 104 non-BRCA1/2 (BRCAx) cases and 101 ancestry-matched controls from Ireland. After extensive filtration, subjecting the variants to multiple in-silico tools and validation independently by Sanger sequencing, we identified a novel germline likely pathogenic missense mutation in the GHSR gene. GHSR encodes Growth Hormone Secretagogue Receptor, of which its down-regulation has been linked to breast cancer cell invasion (3). Consistently, we detected this GHSR mutation in a BRCAx case who exhibited a high-grade metastatic breast cancer and none of the controls. Since the majority of familial breast cancer is largely unaccounted for, we sought to discover other predisposing mutations. With the dramatic efficiency and drop in sequencing costs analyzing large numbers of samples has been made possible. However, determining the pathogenecity of variants remains challenging and further follow-up studies on an extended cohort will have to be performed before we can utilize these findings in a clinical context. (1) Lalloo et al. (2012). Familial breast cancer. Clin Genet, 82(2), 105114. (2) Esteller. (2008). Epigenetics in cancer. N Engl J Med, 358(11), 114859. (3) Botla et al. (2012). Diagnostic values of GHSR DNA methylation pattern in breast cancer. Breast Cancer Res Treat, 135(3), 705713.


All authors have declared no conflicts of interest.