Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer

Abstract

Importance: 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.

Objectives: 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.

Main outcomes and measures: 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).

Results: 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.

Conclusions and relevance: 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.

Figure 1.. Prevalence of Germline Alterations by Percentage

GEJ indicates gastroesophageal junction; LP/P, likely pathogenic or pathogenic. ^aPresent as homozygous variants: NBN c.481-2A>T and recurrent MUTYH germline variant c.536A>G (p.Tyr179Cys), respectively. ^bAPC c.3920T>A (p.Ile1307Lys), common founder variant among the Ashkenazi Jewish population, considered to be of low penetrance. ^cCHEK2 c.470T>C (p.Ile157Thr), considered to be of uncertain clinical actionability. ^dVHL c.598C>T (p.Arg200Trp) germline variant associated with recessive Chuvash type polycythemia and not with von Hippel Lindau syndrome and therefore not categorized as high penetrance. ^eEPCAM c. 325C>T (p.Gln109*) germline variants not reported in the literature; EPCAM loss-of-function variants (other than 3′EPCAM deletions associated with Lynch syndrome) have been associated with autosomal recessive congenital tufting enteropathy.

Figure 2.. Pedigrees of Selected Patients With Germline Alterations

A, ATM pathogenic alteration in a 29-year-old woman with stage IV gastric signet ring cell adenocarcinoma treated with folinic acid, fluorouracil, and oxaliplatin (FOLFOX) with treatment discontinued after 6 months because of toxic effects. Overall survival was 9.5 months. The identification of an ATM pathogenic alteration represented an incidental finding in a relative with familial gastric cancer. B, BRCA2 alteration in a 35-year-old woman with stage IV gastric cardia cancer to the lymph nodes with complete response to epirubicin, oxaliplatin, and capecitabine chemotherapy that lasted for 16 months. Overall survival was 53.5 months. In addition to the germline BRCA2 alteration, a somatic BRCA2 alteration was also identified, presumed to be the second hit in the context of a cancer caused by the germline mutation. C, Germline CDH1 alteration in a 45-year-old man with stage IV gastric signet ring cell carcinoma treated with FOLFOX for 9 months before progression. He remained alive 10.4 months into treatment. A germline CDH1 alteration, presumably inherited from the paternal lineage without familial gastric cancer, was identified. Because he did not meet genetic testing criteria for CDH1, it is considered an incidental finding. Square indicates male; circle, female; bracket around a circle, adopted individual; slash, deceased; black upper left portion of a square or circle, cancer-affected individual; arrowhead, a family member who underwent matched tumor and germline sequencing; black asterisk, germline-positive status; blue asterisk, presence of a second somatic alteration; pink asterisk, obligate carrier; and gold asterisk, confirmed germline-negative status.