KRAS status is related to histological phenotype in gastric cancer: results from a large multicentre study

Background Gastric cancer (GC) is histologically a very heterogeneous disease, and the temporal development of diferent histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation (KRASact) can infuence histological phenotype. KRASact likely results from KRAS mutation (KRASmut) or KRAS amplifcation (KRASamp). The aim of the study was to investigate whether KRASmut and/or KRASamp are related to the histological phenotype in GC. Methods Digitized haematoxylin/eosin-stained slides from 1282 GC resection specimens were classifed according to Japanese Gastric Cancer Association (JGCA) and the Lauren classifcation by at least two observers. The relationship between KRAS status, predominant histological phenotype and clinicopathological variables was assessed. Results KRASmut 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 diferentiated 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 diferentiated 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. Conclusions This is the largest GC study investigating KRAS status and histological phenotype. We identifed a relationship between KRASmut and mucinous phenotype. The high level of intratumour morphological heterogeneity could refect KRASmut heterogeneity, which may explain the failure of anti-EGFR therapy in GC.

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