Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Medicine, Weill Cornell Medical College, New York, New York.
JAMA Netw Open. 2021 Jul 1;4(7):e2114753. doi: 10.1001/jamanetworkopen.2021.14753.
Among patients with esophagogastric cancers, only individuals who present with known features of heritable cancer syndromes are referred for genetic testing. Broader testing might identify additional patients with germline alterations.
To examine the prevalence of likely pathogenic or pathogenic (LP/P) germline alterations among patients with esophagogastric cancer and to assess associations between germline variant prevalence and demographic and clinicopathologic features.
DESIGN, SETTING, AND PARTICIPANTS: This cross-sectional study was performed at a tertiary referral cancer center from January 1, 2014, to December 31, 2019, in 515 patients with esophagogastric cancer who consented to tumor and blood sequencing.
Presence or absence of LP/P variants in up to 88 genes associated with cancer predisposition syndromes as identified by targeted sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets).
Among 515 patients (median age, 59 years; range, 18-87 years; 368 [71.5%] male; 398 [77.3%] White), 243 (47.2%) had gastric cancer, 111 (21.6%) had gastroesophageal junction (GEJ) cancer, and 161 (31.3%) had esophageal cancer. A total of 48 patients with gastric cancer (19.8%), 16 (14.4%) with GEJ cancer, and 17 (10.6%) with esophageal cancer had LP/P germline variants. The number of LP/P variants in high- and moderate-penetrance genes was significantly higher in patients with gastric cancer (29 [11.9%]; 95% CI, 8.1%-16.7%) vs patients with esophageal cancer (8 [5.0%]; 95% CI, 2.2%-9.6%; P = .03), and the difference was greater for high-penetrance germline alterations in patients with gastric cancer (25 [10.3%]; 95% CI, 6.8%-14.8%) vs in patients with esophageal cancer (3 [1.9%]; 95% CI, 0.38%-5.3%; P = .001). The most frequent high- and moderate-penetrance LP/P alterations were in BRCA1/2 (14 [2.7%]), ATM (11 [2.1%]), CDH1 (6 [1.2%]), and MSH2 (4 [0.8%]). Those with early-onset disease (≤50 years of age at diagnosis) were more likely to harbor an LP/P germline variant (29 [21.0%]; 95% CI, 14.5%-28.8%) vs those with late-onset disease (patients >50 years of age at diagnosis) (52 [13.8%]; 95% CI, 10.5%-17.7%; P = .046). ATM LP/P variants occurred in 6 patients (4.3%; 95% CI, 1.6%-9.1%) with early-onset esophagogastric cancer vs 5 (1.3%; 95% CI, 0.4%-3.1%; P = .08) of those with late-onset esophagogastric cancer.
These results suggest that pathogenic germline variants are enriched in gastric and early-onset esophagogastric cancer and that germline testing should be considered in these populations. The role of ATM alterations in esophagogastric cancer risk warrants further investigation.
在患有食管胃癌症的患者中，只有那些具有遗传性癌症综合征已知特征的患者才会被转介进行基因检测。更广泛的检测可能会发现更多具有种系改变的患者。
研究食管胃癌症患者中可能具有致病性或致病性（LP/P）种系改变的患病率，并评估种系变异患病率与人口统计学和临床病理特征之间的关系。
设计、地点和参与者：这项横断面研究于 2014 年 1 月 1 日至 2019 年 12 月 31 日在一家三级转诊癌症中心进行，共有 515 名同意进行肿瘤和血液测序的食管胃癌症患者参与。
通过靶向测序（纪念斯隆凯特琳综合行动癌症靶基因突变分析）鉴定出 88 个与癌症易感性综合征相关的基因中存在或不存在 LP/P 变体。
在 515 名患者中（中位年龄 59 岁；范围 18-87 岁；368 [71.5%]为男性；398 [77.3%]为白人），243 名（47.2%）患有胃癌，111 名（21.6%）患有胃食管交界处（GEJ）癌症，161 名（31.3%）患有食管癌。48 名（19.8%）患有胃癌的患者、16 名（14.4%）患有 GEJ 癌症的患者和 17 名（10.6%）患有食管癌的患者存在 LP/P 种系变体。胃癌患者高、中度外显率基因中的 LP/P 变体数量明显高于食管癌患者（29 [11.9%]；95%CI，8.1%-16.7%；vs 8 [5.0%]；95%CI，2.2%-9.6%；P=0.03），并且胃癌患者高外显率种系改变的差异更大（25 [10.3%]；95%CI，6.8%-14.8%；vs 3 [1.9%]；95%CI，0.38%-5.3%；P=0.001）。最常见的高、中度外显率 LP/P 改变是 BRCA1/2（14 [2.7%]）、ATM（11 [2.1%]）、CDH1（6 [1.2%]）和 MSH2（4 [0.8%]）。发病年龄≤50 岁的患者更有可能携带 LP/P 种系变异（29 [21.0%]；95%CI，14.5%-28.8%），而发病年龄>50 岁的患者（52 [13.8%]；95%CI，10.5%-17.7%；P=0.046）。6 名（4.3%）早发性食管胃癌症患者存在 ATM LP/P 变体，而 5 名（1.3%）晚发性食管胃癌症患者存在 ATM LP/P 变体（95%CI，1.6%-9.1%；vs 0.4%-3.1%；P=0.08）。
这些结果表明，致病性种系变体在胃和早发性食管胃癌症中更为丰富，这些人群应考虑进行种系检测。ATM 改变在食管胃癌症风险中的作用值得进一步研究。
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