A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS.
A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS.
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DOI：
10.1136/gutjnl-2013-306571
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发表时间：
2015-01
期刊：
影响因子：
24.5
通讯作者：
Tomlinson I
中科院分区：
文献类型：
--
作者：
Rosmarin D;Palles C;Pagnamenta A;Kaur K;Pita G;Martin M;Domingo E;Jones A;Howarth K;Freeman-Mills L;Johnstone E;Wang H;Love S;Scudder C;Julier P;Fernández-Rozadilla C;Ruiz-Ponte C;Carracedo A;Castellvi-Bel S;Castells A;Gonzalez-Neira A;Taylor J;Kerr R;Kerr D;Tomlinson I
卡培他滨是一种口服 5-氟尿嘧啶 (5-FU) 前药，常用于治疗结直肠癌和其他肿瘤。大约 35% 的患者会出现剂量限制性毒性。少数已证实的 5-FU 毒性遗传生物标志物分别是候选位点二氢嘧啶脱氢酶 (DPYD) 和胸苷酸合酶 (TYMS) 的罕见变异和多态性。我们研究了 QUASAR2 临床试验中 968 名英国患者的 25 个候选 5-FU 通路基因附近的 1456 个多态性和罕见编码变异。我们确定了第一个与卡培他滨毒性一致相关的常见 DPYD 多态性，rs12132152（毒性等位基因频率（TAF）=0.031，OR=3.83，p=4.31×10−6）和 rs12022243（TAF=0.196，OR=1.69，p=2.55×10−5）。 rs12132152 与手足综合征特别密切相关（OR=6.1，p=3.6×10−8）。 rs12132152 和 rs12022243 关联彼此独立，并且与之前报道的 DPYD 毒性变异体无关。新一代测序还在一名严重毒性患者中发现了罕见的 DPYD 变异 p.Ala551Thr。使用功能预测和已发表的数据，我们将 p.Ala551Thr 指定为毒性的原因。我们发现位于ENOSF1内含子内的多态性rs2612091也与卡培他滨毒性相关（TAF=0.532，OR=1.59，p=5.28×10−6）。 ENSOF1 与 TYMS 相邻，两个基因/蛋白质之间的调控相互作用尚不明确。出乎意料的是，rs2612091 完全解释了之前报道的卡培他滨毒性与所谓功能性 TYMS 变体 5'VNTR 2R/3R 和 3'UTR 6 bp ins-del 之间的关联。此外，rs2612091 基因型与 ENOSF1 mRNA 水平一致相关，但与 TYMS 表达无关。 DPYD 具有罕见和常见的卡培他滨毒性变异体。 TYMS区域的毒性多态性实际上可能通过ENOSF1起作用。
Capecitabine is an oral 5-fluorouracil (5-FU) pro-drug commonly used to treat colorectal carcinoma and other tumours. About 35% of patients experience dose-limiting toxicity. The few proven genetic biomarkers of 5-FU toxicity are rare variants and polymorphisms, respectively, at candidate loci dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthase (TYMS). We investigated 1456 polymorphisms and rare coding variants near 25 candidate 5-FU pathway genes in 968 UK patients from the QUASAR2 clinical trial. We identified the first common DPYD polymorphisms to be consistently associated with capecitabine toxicity, rs12132152 (toxicity allele frequency (TAF)=0.031, OR=3.83, p=4.31×10−6) and rs12022243 (TAF=0.196, OR=1.69, p=2.55×10−5). rs12132152 was particularly strongly associated with hand-foot syndrome (OR=6.1, p=3.6×10−8). The rs12132152 and rs12022243 associations were independent of each other and of previously reported DPYD toxicity variants. Next-generation sequencing additionally identified rare DPYD variant p.Ala551Thr in one patient with severe toxicity. Using functional predictions and published data, we assigned p.Ala551Thr as causal for toxicity. We found that polymorphism rs2612091, which lies within an intron of ENOSF1, was also associated with capecitabine toxicity (TAF=0.532, OR=1.59, p=5.28×10−6). ENSOF1 is adjacent to TYMS and there is a poorly characterised regulatory interaction between the two genes/proteins. Unexpectedly, rs2612091 fully explained the previously reported associations between capecitabine toxicity and the supposedly functional TYMS variants, 5′VNTR 2R/3R and 3′UTR 6 bp ins-del. rs2612091 genotypes were, moreover, consistently associated with ENOSF1 mRNA levels, but not with TYMS expression. DPYD harbours rare and common capecitabine toxicity variants. The toxicity polymorphism in the TYMS region may actually act through ENOSF1.
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影响因子：
30.8
作者：
Marchini, Jonathan;Howie, Bryan;Donnelly, Peter
通讯作者：
Donnelly, Peter
影响因子：
2.6
作者：
Thorn CF;Marsh S;Carrillo MW;McLeod HL;Klein TE;Altman RB
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Altman RB
影响因子：
4.5
作者：
Stranger BE;Montgomery SB;Dimas AS;Parts L;Stegle O;Ingle CE;Sekowska M;Smith GD;Evans D;Gutierrez-Arcelus M;Price A;Raj T;Nisbett J;Nica AC;Beazley C;Durbin R;Deloukas P;Dermitzakis ET
通讯作者：
Dermitzakis ET
影响因子：
30.8
作者：
Dunlop MG;Dobbins SE;Farrington SM;Jones AM;Palles C;Whiffin N;Tenesa A;Spain S;Broderick P;Ooi LY;Domingo E;Smillie C;Henrion M;Frampton M;Martin L;Grimes G;Gorman M;Semple C;Ma YP;Barclay E;Prendergast J;Cazier JB;Olver B;Penegar S;Lubbe S;Chander I;Carvajal-Carmona LG;Ballereau S;Lloyd A;Vijayakrishnan J;Zgaga L;Rudan I;Theodoratou E;Colorectal Tumour Gene Identification (CORGI) Consortium;Starr JM;Deary I;Kirac I;Kovacević D;Aaltonen LA;Renkonen-Sinisalo L;Mecklin JP;Matsuda K;Nakamura Y;Okada Y;Gallinger S;Duggan DJ;Conti D;Newcomb P;Hopper J;Jenkins MA;Schumacher F;Casey G;Easton D;Shah M;Pharoah P;Lindblom A;Liu T;Swedish Low-Risk Colorectal Cancer Study Group;Smith CG;West H;Cheadle JP;COIN Collaborative Group;Midgley R;Kerr DJ;Campbell H;Tomlinson IP;Houlston RS
通讯作者：
Houlston RS
影响因子：
45.3
作者：
Haller, Daniel G.;Rothenberg, Mace L.;Olivatto, Luis O.
通讯作者：
Olivatto, Luis O.