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 different histological phenotypes remains unclear. Recent studies in lung and ovarian cancer suggest that KRAS activation ( KRAS act) can influence histological phenotype. KRAS act likely results from KRAS mutation ( KRAS mut) or KRAS amplification ( KRAS amp). The aim of the study was to investigate whether KRAS mut and/or KRAS amp are related to the histological phenotype in GC. Methods Digitized 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. Results KRAS mut and KRAS amp were found in 68 (5%) and 47 (7%) GCs, respectively. Within the KRAS mut and KRAS amp cases, the most frequent GC histological phenotype was moderately differentiated tubular 2 (tub2) type ( KRAS mut: n = 27, 40%; KRAS amp: n = 21, 46%) or intestinal type ( KRAS mut: n = 41, 61%; KRAS amp: n = 23, 50%). Comparing individual histological subtypes, mucinous carcinoma displayed the highest frequency of KRAS mut (JGCA: n = 6, 12%, p = 0.012; Lauren: n = 6, 12%, p = 0.013), and KRAS amp 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. Conclusions This is the largest GC study investigating KRAS status and histological phenotype. We identified a relationship between KRAS mut and mucinous phenotype. The high level of intratumour morphological heterogeneity could reflect KRAS mut heterogeneity, which may explain the failure of anti-EGFR therapy in GC.