No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.
No evidence that protein truncating variants in BRIP1 are associated with breast cancer risk: implications for gene panel testing.
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DOI：
10.1136/jmedgenet-2015-103529
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发表时间：
2016-05
影响因子：
4
通讯作者：
Chenevix-Trench G
中科院分区：
文献类型：
--
作者：
Easton DF;Lesueur F;Decker B;Michailidou K;Li J;Allen J;Luccarini C;Pooley KA;Shah M;Bolla MK;Wang Q;Dennis J;Ahmad J;Thompson ER;Damiola F;Pertesi M;Voegele C;Mebirouk N;Robinot N;Durand G;Forey N;Luben RN;Ahmed S;Aittomäki K;Anton-Culver H;Arndt V;Australian Ovarian Cancer Study Group;Baynes C;Beckman MW;Benitez J;Van Den Berg D;Blot WJ;Bogdanova NV;Bojesen SE;Brenner H;Chang-Claude J;Chia KS;Choi JY;Conroy DM;Cox A;Cross SS;Czene K;Darabi H;Devilee P;Eriksson M;Fasching PA;Figueroa J;Flyger H;Fostira F;García-Closas M;Giles GG;Glendon G;González-Neira A;Guénel P;Haiman CA;Hall P;Hart SN;Hartman M;Hooning MJ;Hsiung CN;Ito H;Jakubowska A;James PA;John EM;Johnson N;Jones M;Kabisch M;Kang D;kConFab Investigators;Kosma VM;Kristensen V;Lambrechts D;Li N;Lifepool Investigators;Lindblom A;Long J;Lophatananon A;Lubinski J;Mannermaa A;Manoukian S;Margolin S;Matsuo K;Meindl A;Mitchell G;Muir K;NBCS Investigators;Nevelsteen I;van den Ouweland A;Peterlongo P;Phuah SY;Pylkäs K;Rowley SM;Sangrajrang S;Schmutzler RK;Shen CY;Shu XO;Southey MC;Surowy H;Swerdlow A;Teo SH;Tollenaar RA;Tomlinson I;Torres D;Truong T;Vachon C;Verhoef S;Wong-Brown M;Zheng W;Zheng Y;Nevanlinna H;Scott RJ;Andrulis IL;Wu AH;Hopper JL;Couch FJ;Winqvist R;Burwinkel B;Sawyer EJ;Schmidt MK;Rudolph A;Dörk T;Brauch H;Hamann U;Neuhausen SL;Milne RL;Fletcher O;Pharoah PD;Campbell IG;Dunning AM;Le Calvez-Kelm F;Goldgar DE;Tavtigian SV;Chenevix-Trench G
BRCA 1相互作用蛋白C末端解旋酶1（BRIP 1）是范可尼贫血互补（Fanconi Anaemia Complementation，FANC）组DNA修复蛋白家族中的一个。BRIP1中的双等位基因突变是FANC J组的原因，先前的研究也表明BRIP1中罕见的蛋白质截短变体与乳腺癌风险增加相关。这些研究已经导致BRIP1被纳入用于乳腺癌风险预测的靶向测序面板。我们评估了BRIP1的截短变异p.Arg798Ter（rs137852986）和10个错义变异，在48144例病例和43607例对照中，这些病例和对照来自乳腺癌协会联盟（BCAC）的41项研究。此外，我们对来自英国的13213例病例和5242例对照、来自三项基于人群的研究（作为乳腺癌家族登记的一部分）的1313例病例和1123例对照以及来自澳大利亚的1853例家族病例和2001例对照的BRIP1编码区进行了测序。在BCAC的23例病例和18例对照中观察到罕见的rs137852986截短等位基因（OR 1.09，95%CI 0.58至2.03，p=0.79）。在测序研究中，在34例病例（0.21%）和19例对照（0.23%）中发现了截短变体（合并OR 0.90，95% CI 0.48至1.70，p=0.75）。这些结果表明，BRIP1的截短变异，特别是p.Arg798Ter，与乳腺癌风险的大幅增加无关。这些观察结果对乳腺癌筛查小组的结果报告具有重要意义。
BRCA1 interacting protein C-terminal helicase 1 (BRIP1) is one of the Fanconi Anaemia Complementation (FANC) group family of DNA repair proteins. Biallelic mutations in BRIP1 are responsible for FANC group J, and previous studies have also suggested that rare protein truncating variants in BRIP1 are associated with an increased risk of breast cancer. These studies have led to inclusion of BRIP1 on targeted sequencing panels for breast cancer risk prediction. We evaluated a truncating variant, p.Arg798Ter (rs137852986), and 10 missense variants of BRIP1, in 48 144 cases and 43 607 controls of European origin, drawn from 41 studies participating in the Breast Cancer Association Consortium (BCAC). Additionally, we sequenced the coding regions of BRIP1 in 13 213 cases and 5242 controls from the UK, 1313 cases and 1123 controls from three population-based studies as part of the Breast Cancer Family Registry, and 1853 familial cases and 2001 controls from Australia. The rare truncating allele of rs137852986 was observed in 23 cases and 18 controls in Europeans in BCAC (OR 1.09, 95% CI 0.58 to 2.03, p=0.79). Truncating variants were found in the sequencing studies in 34 cases (0.21%) and 19 controls (0.23%) (combined OR 0.90, 95% CI 0.48 to 1.70, p=0.75). These results suggest that truncating variants in BRIP1, and in particular p.Arg798Ter, are not associated with a substantial increase in breast cancer risk. Such observations have important implications for the reporting of results from breast cancer screening panels.