Abstract
BackgroundAdenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. There are few data directly comparing the frequencies of single nucleotide mutations in cancer-related genes between the two sites. Sequencing of targeted gene panels may be useful in uncovering multiple genomic aberrations using a single test.MethodsDNA from 92 gastroesophageal junction and 75 gastric adenocarcinoma resection specimens was extracted from formalin-fixed paraffin-embedded tissue. Targeted deep sequencing of 46 cancer-related genes was performed through emulsion PCR followed by semiconductor-based sequencing. Gastroesophageal junction and gastric carcinomas were contrasted with respect to mutational profiles, immunohistochemistry and in situ hybridization, as well as corresponding clinicopathologic data.ResultsGastroesophageal junction carcinomas were associated with younger age, more frequent intestinal-type histology, more frequent p53 overexpression, and worse disease-free survival on multivariable analysis. Among all cases, 145 mutations were detected in 31 genes. TP53 mutations were the most common abnormality detected, and were more common in gastroesophageal junction carcinomas (42% vs. 27%, p = 0.036). Mutations in the Wnt pathway components APC and CTNNB1 were more common among gastric carcinomas (16% vs. 3%, p = 0.006), and gastric carcinomas were more likely to have ≥3 driver mutations detected (11% vs. 2%, p = 0.044). Twenty percent of cases had potentially actionable mutations identified. R132H and R132C missense mutations in the IDH1 gene were observed, and are the first reported mutations of their kind in gastric carcinoma.ConclusionsPanel sequencing of routine pathology material can yield mutational information on several driver genes, including some for which targeted therapies are available. Differing rates of mutations and clinicopathologic differences support a distinction between adenocarcinomas that arise in the gastroesophageal junction and those that arise in the stomach proper.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1021-7) contains supplementary material, which is available to authorized users.
Highlights
Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival
Cases of gastric carcinoma were retrieved from departmental archives from the British Columbia Cancer Agency (BCCA), a provincial referral center
Clinicopathologic differences between gastroesophageal junction (GEJ) and gastric carcinomas The clinicopathologic features of these cases are summarized in Table 1 and anonymized clinical data is provided in a supplemental file (Additional file 2: Table S2)
Summary
Adenocarcinomas of both the gastroesophageal junction and stomach are molecularly complex, but differ with respect to epidemiology, etiology and survival. Carcinomas of the gastroesophageal junction (GEJ) have been grouped with gastric carcinomas in cancer registries and in clinical trials for targeted therapies [3], lesions at these two sites have distinct clinical features. Adenocarcinomas of the stomach proper are primarily caused by Helicobacter pylori infection [4] and are decreasing in incidence worldwide [1]. GEJ cancers are most associated with gastroesophageal reflux disease [2,3,4,5] and obesity [6], and the incidence of GEJ carcinomas has remained stable over the past 20 years [7]. Recognizing the distinction between carcinomas of the GEJ, esophagus, and stomach may enhance the collection of meaningful epidemiologic data and result in increased management precision [9]
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