Division of Newborn Medicine, Department of Medicine, Boston Children's Hospital, Boston, Massachusetts.
Department of Pediatrics, Harvard Medical School, Boston, Massachusetts.
JAMA Cardiol. 2021 Apr 1;6(4):457-462. doi: 10.1001/jamacardio.2020.4947.
IMPORTANCE: 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. OBJECTIVE: 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. DESIGN, SETTING, AND PARTICIPANTS: 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. EXPOSURES: Presence of rare (allele frequency, <1 × 10-5) loss-of-function (LoF) variants in cancer risk genes. MAIN OUTCOMES AND MEASURES: 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. RESULTS: 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). CONCLUSIONS AND RELEVANCE: 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.
重要性：患有先天性心脏病（CHD）的患者 - 最常见的出生缺陷 - 癌症风险增加。确定导致癌症风险的变量对于识别需要长期监测和早期干预的 CHD 患者至关重要。 目的：比较 CHD 患者和对照参与者中癌症风险基因的破坏性变异频率，并确定 CHD 患者中具有癌症风险变异的相关临床变量。 设计、地点和参与者：这项多中心病例对照研究包括先前根据结构性心脏异常招募至儿科心脏基因组学联盟的 CHD 患者，这些患者在入组时没有遗传诊断。从 2 个父母研究中获得了使用受影响的成年参与者的已发表测序数据的许可。从 2010 年 12 月至 2019 年 4 月收集了这项研究的数据。 暴露：存在罕见的（等位基因频率，<1×10-5）失活（LoF）变异体在癌症风险基因中。 主要结果和措施：通过二项式检验统计评估 CHD 患者和对照参与者中癌症风险基因（在癌症基因共识数据库的体细胞突变目录中定义）中的 LoF 变异频率。 结果：共纳入 4443 名 CHD 患者（平均[范围]年龄，13.0[0-84]岁；3771 名中有 2225 名报告性别[59.0%]男性）和 9808 名对照参与者（平均[范围]年龄，52.1[1-92]岁；9808 名中有 4967 名[50.6%]男性）。与对照参与者相比，CHD 患者中调节癌症风险基因的 LoF 变异频率显着更高（4443 名患者中有 143 名[3.2%] vs 9808 名患者中有 166 名[1.7%]；优势比[OR]，1.93[95%CI，1.54-2.42]；P=1.38×10-12），并且在先前与癌症风险相关的 CHD 基因中（4443 名患者中有 58 名[1.3%] vs 9808 名患者中有 18 名[0.18%]；OR，7.2[95%CI，4.2-12.2]；P<2.2×10-16）。在发育中的心脏中高表达的 14 个受限制的癌症风险基因中，LoF 变异也被命名性增加。这些基因中的 7 个（ARHGEF12、CTNNB1、LPP、MLLT4、PTEN、TCF12 和 TFRC）在多个原因不明的 CHD 患者中存在 LoF 变异。在具有心脏外异常（1482 名患者中有 248 名[16.7%]；对照组：9808 名患者中有 1099 名[11.2%]；OR，1.59[95%CI，1.37-1.85]；P=1.3×10-10）和/或神经发育迟缓（1393 名患者中有 209 名[15.0%]；对照组：9808 名患者中有 1099 名[11.2%]；OR，1.40[95%CI，1.19-1.64]；P=9.6×10-6）的 CHD 患者中，LoF 变异的发生率最高。 结论和相关性：CHD 的基因型可能导致癌症风险增加。在本队列中，破坏性变异在主要编码调节蛋白的 216 个基因中很明显。与它们的基本发育功能一致，CHD 患者和这些基因中的破坏性变异通常具有心脏外表现。这些数据还可能暗示在原因不明的 CHD 患者中反复变异的癌症风险基因作为 CHD 基因。
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