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

ABSTRACT: 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 (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. 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: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 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. CONCLUSIONS:This 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.

SUBMITTER: Hewitt LC

PROVIDER: S-EPMC6811379 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature

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

Hewitt Lindsay C LC Saito Yuichi Y Wang Tan T Matsuda Yoko Y Oosting Jan J Silva Arnaldo N S ANS Slaney Hayley L HL Melotte Veerle V Hutchins Gordon G Tan Patrick P Yoshikawa Takaki T Arai Tomio T Grabsch Heike I HI

Gastric cancer : official journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association 20190520 6

<h4>Background</h4>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). The aim of the study was to investigate whether KRASmut and/or KRASamp are related to the histological phenotype in GC.<h4>Met ...[more]

PMID: 31111275

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Project description:IntroductionAnti-EGFR targeted therapy is of increasing importance in advanced colorectal cancer and prior KRAS mutation testing is mandatory for therapy. However, at which occasions this should be performed is still under debate. We aimed to assess in patients with locally advanced rectal cancer whether there is intra-specimen KRAS heterogeneity prior to and upon preoperative chemoradiotherapy (CRT), and if there are any changes in KRAS mutation status due to this intervention.Materials and methodsKRAS mutation status analyses were performed in 199 tumor samples from 47 patients with rectal cancer. To evaluate the heterogeneity between different tumor areas within the same tumor prior to preoperative CRT, 114 biopsies from 34 patients (mean 3 biopsies per patient) were analyzed (pre-therapeutic intratumoral heterogeneity). For the assessment of heterogeneity after CRT residual tumor tissue (85 samples) from 12 patients (mean 4.2 tissue samples per patient) were analyzed (post-therapeutic intratumoral heterogeneity) and assessment of heterogeneity before and after CRT was evaluated in corresponding patient samples (interventional heterogeneity). Primer extension method (SNaPshot™) was used for initial KRAS mutation status testing for Codon 12, 13, 61, and 146. Discordant results by this method were reevaluated by using the FDA-approved KRAS Pyro Kit 24, V1 and the RAS Extension Pyro Kit 24, V1 Kit (therascreen® KRAS test).ResultsFor 20 (43%) out of the 47 patients, a KRAS mutation was detected. With 12 out of 20, the majority of these mutations affected codon 35. We did not obtained evidence that CRT results in changes of the KRAS mutation pattern. In addition, no intratumoral heterogeneity in the KRAS mutational status could be proven. This was true for both the biopsies prior to CRT and the resection specimens thereafter. The discrepancy observed in some samples when using the SNaPshot™ assay was due to insufficient sensitivity of this technique upon massive tumor regression by CRT as application of the therascreen® KRAS test revealed concordant results.ConclusionOur results indicate that the KRAS mutation status at the primary tumor site of rectal cancer is homogenous. Its assessment for therapeutic decisions is feasible in pre-therapeutic biopsies as well as in post-therapeutic resected specimens. The amount of viable tumor cells seems to be an important determinant for assay sensitivity and should thus be considered for selection of the analytical method.

Dataset Information

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

Publications

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

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