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Institute
EU-Project number / Contract (GA) number
- 223175 (3)
Engel, Christoph ; Rhiem, Kerstin ; Hahnen, Eric ; Loibl, Sibylle ; Weber, Karsten E. ; Seiler, Sabine ; Zachariae, Silke ; Hauke, Jan ; Wappenschmidt, Barbara ; Waha, Anke ; Blümcke, Britta ; Kiechle, Marion ; Meindl, Alfons ; Niederacher, Dieter ; Bartram, Claus R. ; Speiser, Dorothee ; Schlegelberger, Brigitte ; Arnold, Norbert ; Wieacker, Peter ; Leinert, Elena ; Gehrig, Andrea ; Briest, Susanne ; Kast, Karin ; Riess, Olaf ; Emons, Günter ; Weber, Bernhard H. F. ; Engel, Jutta ; Schmutzler, Rita K.
Background
There is no international consensus up to which age women with a diagnosis of triple-negative breast cancer (TNBC) and no family history of breast or ovarian cancer should be offered genetic testing for germline BRCA1 and BRCA2 (gBRCA) mutations. Here, we explored the association of age at TNBC diagnosis with the prevalence of pathogenic gBRCA mutations in this patient group.
Methods
The study comprised 802 women (median age 40 years, range 19-76) with oestrogen receptor, progesterone receptor, and human epidermal growth factor receptor type 2 negative breast cancers, who had no relatives with breast or ovarian cancer. All women were tested for pathogenic gBRCA mutations. Logistic regression analysis was used to explore the association between age at TNBC diagnosis and the presence of a pathogenic gBRCA mutation.
Results
A total of 127 women with TNBC(15.8%) were gBRCA mutation carriers (BRCA1: n = 118, 14.7%; BRCA2: n = 9, 1. 1%). The mutation prevalence was 32.9% in the age group 20-29 years compared to 6.9% in the age group 60-69 years. Logistic regression analysis revealed a significant increase of mutation frequency with decreasing age at diagnosis (odds ratio 1.87 per 10 year decrease, 95% CI 1.50-2.32, p < 0.001). gBRCA mutation risk was predicted to be > 10% for women diagnosed below approximately 50 years.
Conclusions
Based on the general understanding that a heterozygous mutation probability of 10% or greater justifies gBRCA mutation screening, women with TNBC diagnosed before the age of 50 years and no familial history of breast and ovarian cancer should be tested for gBRCA mutations. In Germany, this would concern approximately 880 women with newly diagnosed TNBC per year, of whom approximately 150 are expected to be identified as carriers of a pathogenic gBRCA mutation.
Weber-Lassalle, Nana ; Hauke, Jan ; Ramser, Juliane ; Richters, Lisa ; Groß, Eva ; Blümcke, Britta ; Gehrig, Andrea ; Kahlert, Anne-Karin ; Müller, Clemens R. ; Hackmann, Karl ; Honisch, Ellen ; Weber-Lassalle, Konstantin ; Niederacher, Dieter ; Borde, Julika ; Thiele, Holger ; Ernst, Corinna ; Altmüller, Janine ; Neidhardt, Guido ; Nürnberg, Peter ; Klaschik, Kristina ; Schroeder, Christopher ; Platzer, Konrad ; Volk, Alexander E. ; Wang-Gohrke, Shan ; Just, Walter ; Auber, Bernd ; Kubisch, Christian ; Schmidt, Gunnar ; Horvath, Judit ; Wappenschmidt, Barbara ; Engel, Christoph ; Arnold, Norbert ; Dworniczak, Bernd ; Rhiem, Kerstin ; Meindl, Alfons ; Schmutzler, Rita K. ; Hahnen, Eric
Background
Germline mutations in the BRIP1 gene have been described as conferring a moderate risk for ovarian cancer (OC), while the role of BRIP1 in breast cancer (BC) pathogenesis remains controversial.
Methods
To assess the role of deleterious BRIP1 germline mutations in BC/OC predisposition, 6341 well-characterized index patients with BC, 706 index patients with OC, and 2189 geographically matched female controls were screened for loss-of-function (LoF) mutations and potentially damaging missense variants. All index patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germline testing and tested negative for pathogenic BRCA1/2 variants.
Results
BRIP1 LoF mutations confer a high OC risk in familial index patients (odds ratio (OR) = 20.97, 95% confidence interval (CI) = 12.02–36.57, P < 0.0001) and in the subgroup of index patients with late-onset OC (OR = 29.91, 95% CI = 14.99–59.66, P < 0.0001). No significant association of BRIP1 LoF mutations with familial BC was observed (OR = 1.81 95% CI = 1.00–3.30, P = 0.0623). In the subgroup of familial BC index patients without a family history of OC there was also no apparent association (OR = 1.42, 95% CI = 0.70–2.90, P = 0.3030). In 1027 familial BC index patients with a family history of OC, the BRIP1 mutation prevalence was significantly higher than that observed in controls (OR = 3.59, 95% CI = 1.43–9.01; P = 0.0168). Based on the negative association between BRIP1 LoF mutations and familial BC in the absence of an OC family history, we conclude that the elevated mutation prevalence in the latter cohort was driven by the occurrence of OC in these families. Compared with controls, predicted damaging rare missense variants were significantly more prevalent in OC (P = 0.0014) but not in BC (P = 0.0693) patients.
Conclusions
To avoid ambiguous results, studies aimed at assessing the impact of candidate predisposition gene mutations on BC risk might differentiate between BC index patients with an OC family history and those without. In familial cases, we suggest that BRIP1 is a high-risk gene for late-onset OC but not a BC predisposition gene, though minor effects cannot be excluded.
Hauke, Jan ; Horvath, Judit ; Groß, Eva ; Gehrig, Andrea ; Honisch, Ellen ; Hackmann, Karl ; Schmidt, Gunnar ; Arnold, Norbert ; Faust, Ulrike ; Sutter, Christian ; Hentschel, Julia ; Wang-Gohrke, Shan ; Smogavec, Mateja ; Weber, Bernhard H. F. ; Weber-Lassalle, Nana ; Weber-Lassalle, Konstantin ; Borde, Julika ; Ernst, Corinna ; Altmüller, Janine ; Volk, Alexander E. ; Thiele, Holger ; Hübbel, Verena ; Nürnberg, Peter ; Keupp, Katharina ; Versmold, Beatrix ; Pohl, Esther ; Kubisch, Christian ; Grill, Sabine ; Paul, Victoria ; Herold, Natalie ; Lichey, Nadine ; Rhiem, Kerstin ; Ditsch, Nina ; Ruckert, Christian ; Wappenschmidt, Barbara ; Auber, Bernd ; Rump, Andreas ; Niederacher, Dieter ; Haaf, Thomas ; Ramser, Juliane ; Dworniczak, Bernd ; Engel, Christoph ; Meindl, Alfons ; Schmutzler, Rita K. ; Hahnen, Eric
The prevalence of germ line mutations in non-BRCA1/2 genes associated with hereditary breast cancer (BC) is low, and the role of some of these genes in BC predisposition and pathogenesis is conflicting. In this study, 5589 consecutive BC index patients negative for pathogenic BRCA1/2 mutations and 2189 female controls were screened for germ line mutations in eight cancer predisposition genes (ATM, CDH1, CHEK2, NBN, PALB2, RAD51C, RAD51D, and TP53). All patients met the inclusion criteria of the German Consortium for Hereditary Breast and Ovarian Cancer for germ line testing. The highest mutation prevalence was observed in the CHEK2 gene (2.5%), followed by ATM (1.5%) and PALB2 (1.2%). The mutation prevalence in each of the remaining genes was 0.3% or lower. Using Exome Aggregation Consortium control data, we confirm significant associations of heterozygous germ line mutations with BC for ATM (OR: 3.63, 95%CI: 2.67–4.94), CDH1 (OR: 17.04, 95%CI: 3.54–82), CHEK2 (OR: 2.93, 95%CI: 2.29–3.75), PALB2 (OR: 9.53, 95%CI: 6.25–14.51), and TP53 (OR: 7.30, 95%CI: 1.22–43.68). NBN germ line mutations were not significantly associated with BC risk (OR:1.39, 95%CI: 0.73–2.64). Due to their low mutation prevalence, the RAD51C and RAD51D genes require further investigation. Compared with control datasets, predicted damaging rare missense variants were significantly more prevalent in CHEK2 and TP53 in BC index patients. Compared with the overall sample, only TP53 mutation carriers show a significantly younger age at first BC diagnosis. We demonstrate a significant association of deleterious variants in the CHEK2, PALB2, and TP53 genes with bilateral BC. Both, ATM and CHEK2, were negatively associated with triple-negative breast cancer (TNBC) and estrogen receptor (ER)-negative tumor phenotypes. A particularly high CHEK2 mutation prevalence (5.2%) was observed in patients with human epidermal growth factor receptor 2 (HER2)-positive tumors.