POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients.
POLRMT as a Novel Susceptibility Gene for Cardiotoxicity in Epirubicin Treatment of Breast Cancer Patients.
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DOI：
10.3390/pharmaceutics13111942
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发表时间：
2021-11-16
期刊：
影响因子：
5.4
通讯作者：
Gonzalez-Neira A
中科院分区：
文献类型：
--
作者：
Velasco-Ruiz A;Nuñez-Torres R;Pita G;Wildiers H;Lambrechts D;Hatse S;Delombaerde D;Van Brussel T;Alonso MR;Alvarez N;Herraez B;Vulsteke C;Zamora P;Lopez-Fernandez T;Gonzalez-Neira A
蒽环类药物是乳腺癌（BC）中最常用的化疗药物之一。然而，它们的使用受到蒽环类药物诱导的心脏毒性（AIC）的阻碍。目前已知的临床和遗传风险因素不能完全解释观察到的个体间变异性，只能有限地预测哪些患者更有可能发生这种严重毒性。为了确定新的预测基因，我们在表柔比星治疗的BC患者中进行了两阶段全基因组关联研究。在发现阶段，我们对227名患者的队列中超过700，000个单核苷酸变异进行了基因分型。最有趣的发现是rs62134260，位于POLRMT上游4kb处（OR = 5.76，P = 2.23 × 10−5）。我们在123例患者的验证队列中复制了这种关联（P = 0.021）。该变体调节POLRMT的表达，POLRMT是编码线粒体DNA指导的RNA聚合酶的基因，负责线粒体基因表达。携带风险等位基因的个体在心脏组织中POLRMT的表达降低，这可能导致在应激条件下维持心肌细胞中健康线粒体群体的能力受损，就像用表阿霉素治疗一样。这一发现表明AIC的发展涉及一种新的分子机制，并可能提高我们预测高危患者的能力。
Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10−5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the risk allele had a decreased expression of POLRMT in heart tissue that may cause an impaired capacity to maintain a healthy mitochondrial population in cardiomyocytes under stressful conditions, as is treatment with epirubicin. This finding suggests a novel molecular mechanism involved in the development of AIC and may improve our ability to predict patients who are at risk.
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影响因子：
14.9
作者：
Howe KL;Achuthan P;Allen J;Allen J;Alvarez-Jarreta J;Amode MR;Armean IM;Azov AG;Bennett R;Bhai J;Billis K;Boddu S;Charkhchi M;Cummins C;Da Rin Fioretto L;Davidson C;Dodiya K;El Houdaigui B;Fatima R;Gall A;Garcia Giron C;Grego T;Guijarro-Clarke C;Haggerty L;Hemrom A;Hourlier T;Izuogu OG;Juettemann T;Kaikala V;Kay M;Lavidas I;Le T;Lemos D;Gonzalez Martinez J;Marugán JC;Maurel T;McMahon AC;Mohanan S;Moore B;Muffato M;Oheh DN;Paraschas D;Parker A;Parton A;Prosovetskaia I;Sakthivel MP;Salam AIA;Schmitt BM;Schuilenburg H;Sheppard D;Steed E;Szpak M;Szuba M;Taylor K;Thormann A;Threadgold G;Walts B;Winterbottom A;Chakiachvili M;Chaubal A;De Silva N;Flint B;Frankish A;Hunt SE;IIsley GR;Langridge N;Loveland JE;Martin FJ;Mudge JM;Morales J;Perry E;Ruffier M;Tate J;Thybert D;Trevanion SJ;Cunningham F;Yates AD;Zerbino DR;Flicek P
通讯作者：
Flicek P
影响因子：
30.8
作者：
Das, Sayantan;Forer, Lukas;Schoenherr, Sebastian;Sidore, Carlo;Locke, Adam E.;Kwong, Alan;Vrieze, Scott I.;Chew, Emily Y.;Levy, Shawn;McGue, Matt;Schlessinger, David;Stambolian, Dwight;Loh, Po-Ru;Iacono, William G.;Swaroop, Anand;Scott, Laura J.;Cucca, Francesco;Kronenberg, Florian;Boehnke, Michael;Abecasis, Goncalo R.;Fuchsberger, Christian
通讯作者：
Fuchsberger, Christian
影响因子：
9.2
作者：
Chang CC;Chow CC;Tellier LC;Vattikuti S;Purcell SM;Lee JJ
通讯作者：
Lee JJ
影响因子：
4.6
作者：
Christidi, Effimia;Huang, Haojun;Brunham, Liam R.
通讯作者：
Brunham, Liam R.
影响因子：
2.1
作者：
Hertz, Daniel L.;Caram, Megan V.;Rae, James M.
通讯作者：
Rae, James M.