Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.
Association of Damaging Variants in Genes With Increased Cancer Risk Among Patients With Congenital Heart Disease.
复制标题
DOI：
10.1001/jamacardio.2020.4947
复制
发表时间：
2021-04-01
期刊：
影响因子：
24
通讯作者：
Seidman CE
中科院分区：
文献类型：
--
作者：
Morton SU;Shimamura A;Newburger PE;Opotowsky AR;Quiat D;Pereira AC;Jin SC;Gurvitz M;Brueckner M;Chung WK;Shen Y;Bernstein D;Gelb BD;Giardini A;Goldmuntz E;Kim RW;Lifton RP;Porter GA Jr;Srivastava D;Tristani-Firouzi M;Newburger JW;Seidman JG;Seidman CE
先天性心脏病（CHD）患者的损害性基因变异是否会导致癌症风险增加？在这项病例对照研究中，与9808名对照参与者相比，4443名CHD患者中癌症风险基因的功能丧失变异增加了约1.3倍。这种负担在先前与CHD相关的癌症风险基因中最高（7.2倍）或调节基因表达（1.9倍）;患有CHD和心外异常和/或神经发育迟缓的患者在癌症风险基因中具有最高的破坏性变异率。冠心病患者的遗传分析可以确定心脏畸形的确切原因，也可以确定冠心病患者和癌症风险增加的确切原因。这项病例对照研究比较了先天性心脏病患者与对照参与者中破坏性癌症风险基因变异的频率，并确定了相关的临床变量。先天性心脏病（CHD）是最常见的出生缺陷，其患者患癌症的风险增加。识别有助于癌症风险的变量对于识别需要纵向监测和早期干预的CHD患者至关重要。比较CHD患者和对照受试者中癌症风险基因中破坏性变异的频率，并确定具有癌症风险变异的CHD患者的相关临床变量。这项多中心病例对照研究纳入了CHD受试者，这些受试者先前已被招募到儿科心脏基因组学联盟，招募时存在结构性心脏异常，但未进行基因诊断。从2项母研究中获得了使用未受影响的成年受试者的已发表测序数据的许可。本研究的数据收集时间为2010年12月至2019年4月。在癌症风险基因中存在罕见的（等位基因频率，<1 × 10−5）功能丧失（LoF）变异。在CHD患者和对照受试者中，通过二项式检验对癌症风险基因中LoF变体的频率（在癌症-癌症基因共识数据库中的体细胞突变目录中定义）进行了统计学评估。共纳入4443例CHD患者（平均[范围]年龄，13.0 [0-84]岁; 3771例中有2225例报告了性别[59.0%]为男性）和9808例对照受试者（平均[范围]年龄，52.1 [1-92]岁; 9808例中有4967例报告了性别[50.6%]为男性）。冠心病患者中调节性癌症风险基因的LoF变异频率显著高于对照组（4443例中143例[3.2%] vs 9808例中166例[1.7%];比值比[OR]，1.93 [95%CI，1.54-2.42]; P = 1.38 × 10−12），以及先前与癌症风险相关的CHD基因（58/4443 [1.3%] vs 18/9808 [0.18%]; OR，7.2 [95%CI，4.2-12.2]; P < 2.2 × 10−16）。LoF变体在14个限制性癌症风险基因中也名义上增加，这些基因在发育中的心脏中具有高表达。其中7个基因（ARHGEF 12、CTNNB 1、LPP、MLLT 4、PTEN、TCF 12和TFRC）在多名不明原因CHD患者中携带LoF变体。癌症风险基因中LoF变异发生率最高的是冠心病和心外畸形患者（248/1482人[16.7%]，对照组1099/9808人[11.2%]，OR为1.59 [95%CI为1.37-1.85]; P = 1.3 × 10−10）和/或神经发育迟缓（1393人中的209人[15.0%];对照组：9808人中的1099人[11.2%]; OR，1.40 [95%CI，1.19-1.64]; P = 9.6 × 10−6）。CHD的基因型可能导致癌症风险增加。在这个队列中，破坏性变异在主要编码调节蛋白的216个基因中很突出。与其基本的发育功能一致，患有CHD和这些基因的破坏性变体的患者通常具有心外表现。这些数据也可能涉及癌症风险基因，这些基因在不明原因的CHD患者中反复变化，作为CHD基因。
Do damaging gene variants account for increased cancer risk in patients with congenital heart disease (CHD)? In this case-control study, loss-of-function variants in cancer risk genes were increased approximately 1.3-fold in 4443 patients with CHD compared with 9808 control participants. This burden was highest in cancer risk genes previously associated with CHD (7.2-fold) or that regulate gene expression (1.9-fold); patients with CHD and extracardiac anomalies and/or neurodevelopmental delay had the highest rates of damaging variants in cancer risk genes. Genetic analyses of patients with CHD may identify precise causes of heart malformations and also patients with CHD and increased cancer risks. This case-control study compares the frequency of damaging cancer risk gene variants in patients with congenital heart disease vs control participants and identifies associated clinical variables. Patients with congenital heart disease (CHD), the most common birth defect, have increased risks for cancer. Identification of the variables that contribute to cancer risk is essential for recognizing patients with CHD who warrant longitudinal surveillance and early interventions. To compare the frequency of damaging variants in cancer risk genes among patients with CHD and control participants and identify associated clinical variables in patients with CHD who have cancer risk variants. This multicenter case-control study included participants with CHD who had previously been recruited to the Pediatric Cardiac Genomics Consortium based on presence of structural cardiac anomaly without genetic diagnosis at the time of enrollment. Permission to use published sequencing data from unaffected adult participants was obtained from 2 parent studies. Data were collected for this study from December 2010 to April 2019. Presence of rare (allele frequency, <1 × 10−5) loss-of-function (LoF) variants in cancer risk genes. Frequency of LoF variants in cancer risk genes (defined in the Catalogue of Somatic Mutations in Cancer–Cancer Gene Consensus database), were statistically assessed by binomial tests in patients with CHD and control participants. A total of 4443 individuals with CHD (mean [range] age, 13.0 [0-84] years; 2225 of 3771 with reported sex [59.0%] male) and 9808 control participants (mean [range] age, 52.1 [1-92] years; 4967 of 9808 [50.6%] male) were included. The frequency of LoF variants in regulatory cancer risk genes was significantly higher in patients with CHD than control participants (143 of 4443 [3.2%] vs 166 of 9808 [1.7%]; odds ratio [OR], 1.93 [95% CI, 1.54-2.42]; P = 1.38 × 10−12), and among CHD genes previously associated with cancer risk (58 of 4443 [1.3%] vs 18 of 9808 [0.18%]; OR, 7.2 [95% CI, 4.2-12.2]; P < 2.2 × 10−16). The LoF variants were also nominally increased in 14 constrained cancer risk genes with high expression in the developing heart. Seven of these genes (ARHGEF12, CTNNB1, LPP, MLLT4, PTEN, TCF12, and TFRC) harbored LoF variants in multiple patients with unexplained CHD. The highest rates for LoF variants in cancer risk genes occurred in patients with CHD and extracardiac anomalies (248 of 1482 individuals [16.7%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.59 [95% CI, 1.37-1.85]; P = 1.3 × 10−10) and/or neurodevelopmental delay (209 of 1393 individuals [15.0%]; control: 1099 of 9808 individuals [11.2%]; OR, 1.40 [95% CI, 1.19-1.64]; P = 9.6 × 10−6). Genotypes of CHD may account for increased cancer risks. In this cohort, damaging variants were prominent in the 216 genes that predominantly encode regulatory proteins. Consistent with their fundamental developmental functions, patients with CHD and damaging variants in these genes often had extracardiac manifestations. These data may also implicate cancer risk genes that are repeatedly varied in patients with unexplained CHD as CHD genes.
登录
查看更多内容
影响因子：
3.9
作者：
Qi, Hongjian;Dong, Chengliang;Chung, Wendy K.;Wang, Kai;Shen, Yufeng
通讯作者：
Shen, Yufeng
影响因子：
37.8
作者：
Ladouceur, Virginie Beausejour;Lawler, Patrick R.;Marelli, Ariane J.
通讯作者：
Marelli, Ariane J.
影响因子：
30.8
作者：
Jin SC;Homsy J;Zaidi S;Lu Q;Morton S;DePalma SR;Zeng X;Qi H;Chang W;Sierant MC;Hung WC;Haider S;Zhang J;Knight J;Bjornson RD;Castaldi C;Tikhonoa IR;Bilguvar K;Mane SM;Sanders SJ;Mital S;Russell MW;Gaynor JW;Deanfield J;Giardini A;Porter GA Jr;Srivastava D;Lo CW;Shen Y;Watkins WS;Yandell M;Yost HJ;Tristani-Firouzi M;Newburger JW;Roberts AE;Kim R;Zhao H;Kaltman JR;Goldmuntz E;Chung WK;Seidman JG;Gelb BD;Seidman CE;Lifton RP;Brueckner M
通讯作者：
Brueckner M
影响因子：
64.5
作者：
Huang KL;Mashl RJ;Wu Y;Ritter DI;Wang J;Oh C;Paczkowska M;Reynolds S;Wyczalkowski MA;Oak N;Scott AD;Krassowski M;Cherniack AD;Houlahan KE;Jayasinghe R;Wang LB;Zhou DC;Liu D;Cao S;Kim YW;Koire A;McMichael JF;Hucthagowder V;Kim TB;Hahn A;Wang C;McLellan MD;Al-Mulla F;Johnson KJ;Cancer Genome Atlas Research Network;Lichtarge O;Boutros PC;Raphael B;Lazar AJ;Zhang W;Wendl MC;Govindan R;Jain S;Wheeler D;Kulkarni S;Dipersio JF;Reimand J;Meric-Bernstam F;Chen K;Shmulevich I;Plon SE;Chen F;Ding L
通讯作者：
Ding L
影响因子：
13.8
作者：
Mandalenakis, Zacharias;Karazisi, Christina;Dellborg, Mikael
通讯作者：
Dellborg, Mikael