Abstract
BackgroundGastric cancer (GC) is histologically a very heterogeneous disease, and the temporal development of different histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation (KRASact) can influence histological phenotype. KRASact likely results from KRAS mutation (KRASmut) or KRAS amplification (KRASamp). The aim of the study was to investigate whether KRASmut and/or KRASamp are related to the histological phenotype in GC.MethodsDigitized haematoxylin/eosin-stained slides from 1282 GC resection specimens were classified according to Japanese Gastric Cancer Association (JGCA) and the Lauren classification by at least two observers. The relationship between KRAS status, predominant histological phenotype and clinicopathological variables was assessed.ResultsKRASmut and KRASamp were found in 68 (5%) and 47 (7%) GCs, respectively. Within the KRASmut and KRASamp cases, the most frequent GC histological phenotype was moderately differentiated tubular 2 (tub2) type (KRASmut: n = 27, 40%; KRASamp: n = 21, 46%) or intestinal type (KRASmut: n = 41, 61%; KRASamp: n = 23, 50%). Comparing individual histological subtypes, mucinous carcinoma displayed the highest frequency of KRASmut (JGCA: n = 6, 12%, p = 0.012; Lauren: n = 6, 12%, p = 0.013), and KRASamp was more frequently found in poorly differentiated solid type (n = 12, 10%, p = 0.267) or indeterminate type (n = 12, 10%, p = 0.480) GC. 724 GCs (57%) had intratumour morphological heterogeneity.ConclusionsThis is the largest GC study investigating KRAS status and histological phenotype. We identified a relationship between KRASmut and mucinous phenotype. The high level of intratumour morphological heterogeneity could reflect KRASmut heterogeneity, which may explain the failure of anti-EGFR therapy in GC.
Highlights
Gastric cancer (GC) is histologically a very heterogeneous disease, and this is reflected in the numerous proposed histological classification schemes [1]
Two GCs from the The Cancer Genome Atlas (TCGA) cohort had a concurrent Kirsten Rat Sarcoma Viral Oncogene Homolog (KRAS) amplification (KRASamp) and KRAS mutation (KRASmut); one was a mucinous GC, the other was a por2 GC according to Japanese Gastric Cancer Association (JGCA) classification. This is the largest multicentre study to date to investigate the relationship between KRAS activation by mutation and/ or amplification and histological phenotype in GC
The frequency of KRASamp (7%) was slightly higher than that of KRASmut (5%) which is consistent with other GC studies [10, 11, 37]
Summary
Gastric cancer (GC) is histologically a very heterogeneous disease, and this is reflected in the numerous proposed histological classification schemes [1]. Mutations in KRAS have been identified in many human cancers and result in the constitutive activation of KRAS and the receptor tyrosine kinase (RTK) pathway [4]. Gastric cancer (GC) is histologically a very heterogeneous disease, and the temporal development of different histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation (KRASact) can influence histological phenotype. KRASact likely results from KRAS mutation (KRASmut) or KRAS amplification (KRASamp). Mucinous carcinoma displayed the highest frequency of KRASmut (JGCA: n = 6, 12%, p = 0.012; Lauren: n = 6, 12%, p = 0.013), and KRASamp was more frequently found in poorly differentiated solid type (n = 12, 10%, p = 0.267) or indeterminate type (n = 12, 10%, p = 0.480) GC. The high level of intratumour morphological heterogeneity could reflect KRASmut heterogeneity, which may explain the failure of anti-EGFR therapy in GC
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