title: The power of DNA double-strand break (DSB) repair testing to predict breast cancer susceptibility.
abstract: Most presently known breast cancer susceptibility genes have been linked to DSB repair. To identify novel markers that may serve as indicators for breast cancer risk, we performed DSB repair analyses using a case-control design. Thus, we examined 35 women with defined familial history of breast and/or ovarian cancer (first case group), 175 patients with breast cancer (second case group), and 245 healthy women without previous cancer or family history of breast cancer (control group). We analyzed DSB repair in peripheral blood lymphocytes (PBLs) by a GFP-based test system using 3 pathway-specific substrates. We found increases of microhomology-mediated nonhomologous end joining (mmNHEJ) and nonconservative single-strand annealing (SSA) in women with familial risk vs. controls (P=0.0001-0.0022) and patients with breast cancer vs. controls (P=0.0004-0.0042). Young age (<50) at initial diagnosis of breast cancer, which could be indicative of genetic predisposition, was associated with elevated SSA using two different substrates, amounting to similar odds ratios (ORs=2.54-4.46, P=0.0059-0.0095) as for familial risk (ORs=2.61-4.05, P=0.0007-0.0045). These findings and supporting validation data underscore the great potential of detecting distinct DSB repair activities in PBLs as method to estimate breast cancer susceptibility beyond limitations of genotyping and to predict responsiveness to therapeutics targeting DSB repair-dysfunctional tumors.
authors.affiliation: Department of Obstetrics and Gynecology, Ulm University, Prittwitzstrasse 43, 89075 Ulm, Germany.
authors.forename: Marlen
authors.initials: M
authors.lastname: Keimling
authors.forename: Miriam
authors.initials: M
authors.lastname: Deniz
authors.forename: Dominic
authors.initials: D
authors.lastname: Varga
authors.forename: Andreea
authors.initials: A
authors.lastname: Stahl
authors.forename: Hubert
authors.initials: H
authors.lastname: Schrezenmeier
authors.forename: Rolf
authors.initials: R
authors.lastname: Kreienberg
authors.forename: Isabell
authors.initials: I
authors.lastname: Hoffmann
authors.forename: Jochem
authors.initials: J
authors.lastname: König
authors.forename: Lisa
authors.initials: L
authors.lastname: Wiesmüller
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics*; D004249:DNA Damage; D004260:DNA Repair; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008875:Middle Aged