Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer
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Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer. / Weber-Lassalle, Nana; Borde, Julika; Weber-Lassalle, Konstantin; Horváth, Judit; Niederacher, Dieter; Arnold, Norbert; Kaulfuß, Silke; Ernst, Corinna; Paul, Victoria G; Honisch, Ellen; Klaschik, Kristina; Volk, Alexander E; Kubisch, Christian; Rapp, Steffen; Lichey, Nadine; Altmüller, Janine; Lepkes, Louisa; Pohl-Rescigno, Esther; Thiele, Holger; Nürnberg, Peter; Larsen, Mirjam; Richters, Lisa; Rhiem, Kerstin; Wappenschmidt, Barbara; Engel, Christoph; Meindl, Alfons; Schmutzler, Rita K; Hahnen, Eric; Hauke, Jan.
In: BREAST CANCER RES, Vol. 21, No. 1, 29.04.2019, p. 55.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Germline loss-of-function variants in the BARD1 gene are associated with early-onset familial breast cancer but not ovarian cancer
AU - Weber-Lassalle, Nana
AU - Borde, Julika
AU - Weber-Lassalle, Konstantin
AU - Horváth, Judit
AU - Niederacher, Dieter
AU - Arnold, Norbert
AU - Kaulfuß, Silke
AU - Ernst, Corinna
AU - Paul, Victoria G
AU - Honisch, Ellen
AU - Klaschik, Kristina
AU - Volk, Alexander E
AU - Kubisch, Christian
AU - Rapp, Steffen
AU - Lichey, Nadine
AU - Altmüller, Janine
AU - Lepkes, Louisa
AU - Pohl-Rescigno, Esther
AU - Thiele, Holger
AU - Nürnberg, Peter
AU - Larsen, Mirjam
AU - Richters, Lisa
AU - Rhiem, Kerstin
AU - Wappenschmidt, Barbara
AU - Engel, Christoph
AU - Meindl, Alfons
AU - Schmutzler, Rita K
AU - Hahnen, Eric
AU - Hauke, Jan
PY - 2019/4/29
Y1 - 2019/4/29
N2 - BACKGROUND: The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).METHODS: A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs).RESULTS: We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC.CONCLUSIONS: Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.
AB - BACKGROUND: The role of the BARD1 gene in breast cancer (BC) and ovarian cancer (OC) predisposition remains elusive, as published case-control investigations have revealed controversial results. We aimed to assess the role of deleterious BARD1 germline variants in BC/OC predisposition in a sample of 4920 BRCA1/2-negative female BC/OC index patients of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).METHODS: A total of 4469 female index patients with BC, 451 index patients with OC, and 2767 geographically matched female control individuals were screened for loss-of-function (LoF) mutations and potentially damaging rare missense variants in BARD1. All patients met the inclusion criteria of the GC-HBOC for germline testing and reported at least one relative with BC or OC. Additional control datasets (Exome Aggregation Consortium, ExAC; Fabulous Ladies Over Seventy, FLOSSIES) were included for the calculation of odds ratios (ORs).RESULTS: We identified LoF variants in 23 of 4469 BC index patients (0.51%) and in 36 of 37,265 control individuals (0.10%), resulting in an OR of 5.35 (95% confidence interval [CI] = 3.17-9.04; P < 0.00001). BARD1-mutated BC index patients showed a significantly younger mean age at first diagnosis (AAD; 42.3 years, range 24-60 years) compared with the overall study sample (48.6 years, range 17-92 years; P = 0.00347). In the subgroup of BC index patients with an AAD < 40 years, an OR of 12.04 (95% CI = 5.78-25.08; P < 0.00001) was observed. An OR of 7.43 (95% CI = 4.26-12.98; P < 0.00001) was observed when stratified for an AAD < 50 years. LoF variants in BARD1 were not significantly associated with BC in the subgroup of index patients with an AAD ≥ 50 years (OR = 2.29; 95% CI = 0.82-6.45; P = 0.11217). Overall, rare and predicted damaging BARD1 missense variants were significantly more prevalent in BC index patients compared with control individuals (OR = 2.15; 95% CI = 1.26-3.67; P = 0.00723). Neither LoF variants nor predicted damaging rare missense variants in BARD1 were identified in 451 familial index patients with OC.CONCLUSIONS: Due to the significant association of germline LoF variants in BARD1 with early-onset BC, we suggest that intensified BC surveillance programs should be offered to women carrying pathogenic BARD1 gene variants.
KW - Journal Article
U2 - 10.1186/s13058-019-1137-9
DO - 10.1186/s13058-019-1137-9
M3 - SCORING: Journal article
C2 - 31036035
VL - 21
SP - 55
JO - BREAST CANCER RES
JF - BREAST CANCER RES
SN - 1465-5411
IS - 1
ER -