Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.
Evaluation of the association of heterozygous germline variants in NTHL1 with breast cancer predisposition: an international multi-center study of 47,180 subjects.
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NTHL1 杂合种系变异与乳腺癌易感性关联的评估：一项针对 47,180 名受试者的国际多中心研究。
DOI：
10.1038/s41523-021-00255-3
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发表时间：
2021-05-12
影响因子：
5.9
通讯作者：
Campbell IG
中科院分区：
文献类型：
--
作者：
Li N;Zethoven M;McInerny S;Devereux L;Huang YK;Thio N;Cheasley D;Gutiérrez-Enríquez S;Moles-Fernández A;Diez O;Nguyen-Dumont T;Southey MC;Hopper JL;Simard J;Dumont M;Soucy P;Meindl A;Schmutzler R;Schmidt MK;Adank MA;Andrulis IL;Hahnen E;Engel C;Lesueur F;Girard E;Neuhausen SL;Ziv E;Allen J;Easton DF;Scott RJ;Gorringe KL;James PA;Campbell IG
碱基切除修复 (BER) 基因 NTHL1 中的双等位基因功能丧失 (LoF) 变异会导致包括乳腺癌在内的高风险遗传性多肿瘤综合征，但杂合变异对遗传性乳腺癌的影响尚不清楚。对 4985 名患有乳腺癌的女性（富含家族特征）和 4786 名无癌症女性的分析揭示了 NTHL1 LoF 变异的显着丰富。免疫组织化学证实杂合子携带者肿瘤中 NTHL1 表达降低，但不存在 NTHL1 双等位基因丢失特征突变特征 (SBS 30)。该分析扩展到来自 10 项国际研究的 27,421 例乳腺癌病例和 19,759 名对照，显示 138 例病例和 93 名对照具有杂合 LoF 变异（OR 1.06，95% CI：0.82–1.39），316 例病例和 179 名对照具有错义变异（OR 1.31，95% CI： 1.09–1.57）。通过许多计算机生物信息学预测工具选择的有害特征或位于核酸内切酶 III 功能域内的错义变体显示出与乳腺癌更强的关联。对携带者乳腺癌的体细胞测序表明，与 NTHL1 相关的风险似乎是通过单倍体不足起作用的，这与其他描述的低外显率乳腺癌基因一致。这项大型国际多中心研究的数据表明，NTHL1 杂合致病性种系编码变异可能与低至中度乳腺癌风险增加相关。
Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
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影响因子：
64.8
作者：
Burrell RA;McClelland SE;Endesfelder D;Groth P;Weller MC;Shaikh N;Domingo E;Kanu N;Dewhurst SM;Gronroos E;Chew SK;Rowan AJ;Schenk A;Sheffer M;Howell M;Kschischo M;Behrens A;Helleday T;Bartek J;Tomlinson IP;Swanton C
通讯作者：
Swanton C
影响因子：
12.3
作者：
Kuilman T;Velds A;Kemper K;Ranzani M;Bombardelli L;Hoogstraat M;Nevedomskaya E;Xu G;de Ruiter J;Lolkema MP;Ylstra B;Jonkers J;Rottenberg S;Wessels LF;Adams DJ;Peeper DS;Krijgsman O
通讯作者：
Krijgsman O
影响因子：
3.9
作者：
Kosoy, Roman;Nassir, Rami;Tian, Chao;White, Phoebe A.;Butler, Lesley M.;Silva, Gabriel;Kittles, Rick;Alarcon-Riquelme, Marta E.;Gregersen, Peter K.;Belmont, John W.;De La Vega, Francisco M.;Seldin, Michael F.
通讯作者：
Seldin, Michael F.
影响因子：
28.2
作者：
Birkbak NJ;Wang ZC;Kim JY;Eklund AC;Li Q;Tian R;Bowman-Colin C;Li Y;Greene-Colozzi A;Iglehart JD;Tung N;Ryan PD;Garber JE;Silver DP;Szallasi Z;Richardson AL
通讯作者：
Richardson AL
影响因子：
29.4
作者：
Elsayed FA;Grolleman JE;Ragunathan A;NTHL1 study group;Buchanan DD;van Wezel T;de Voer RM
通讯作者：
de Voer RM