KRAS mutations in microsatellite instable gastric tumours: impact of targeted treatment and intratumoural heterogeneity

Queiros, P Ribeiro; Pinheiro, Hugo; Carvalho, Joana; Oliveira, Patrícia; Gullo, Irene; Carneiro, Fátima; Almeida, Gabriela M.; Oliveíra, Carla

doi:10.1007/s00428-015-1823-7

Cited by 6 publications

(5 citation statements)

References 27 publications

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“…Histological phenotyping was performed on a single slide. Given the high frequency of intra-tumoural morphological heterogeneity in this study and the previously reported intra-tumoural heterogeneity in KRAS mut status in GC [54], the sensitivity of some of the techniques used in the current study may not be sufficient to detect KRAS activation in subclones of tumour cells. As we did not perform microdissection of tumour subregions, we cannot comment on KRAS status heterogeneity within the same tumour.…”

Section: Discussionmentioning

confidence: 90%

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

et al. 2019

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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.Electronic supplementary materialThe online version of this article (10.1007/s10120-019-00972-6) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 90%

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

et al. 2019

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“…Thus, KRAS belongs to a family of oncogenes that have the potential to cause normal cells to become cancerous. Abnormal expression and somatic activating mutations in KRAS are extensively found in various human cancers, including CRC, pancreatic cancer, gastric cancer, breast cancer and lung cancer891011. Furthermore, activating oncogenic KRAS mutations are frequently associated with the resistance to chemotherapy and targeted therapies1213141516.…”

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confidence: 99%

Deregulation of the miR-16-KRAS axis promotes colorectal cancer

You

Liang

Sun

et al. 2016

Sci Rep

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KRAS plays a significant role in the etiology and progression of colorectal cancer (CRC), but the mechanism underlying this process has not been fully elucidated. In this study, we found that the KRAS protein levels were higher in CRC tissues than in the normal adjacent tissues, whereas its mRNA levels varied irregularly, suggesting that a post-transcriptional mechanism is involved in the regulation of KRAS. Then, we performed bioinformatic analyses to search for miRNAs that potentially target KRAS. We predicted and experimentally validated that miR-16 directly recognizes the 3′-UTR of the KRAS transcript and regulates KRAS expression. Furthermore, the in vitro results showed that the repression of KRAS by miR-16 suppressed the proliferation and invasion and induced the apoptosis of CRC cells, and the in vivo results revealed that miR-16 exerted a tumor-suppressive effect by negatively regulating KRAS in xenograft mice. Taken together, our findings provide evidence supporting the role of miR-16 as a tumor suppressor in CRC by targeting KRAS.

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“…However, due to intratumoral heterogeneity [ 4 – 6 ] KRAS mutation heterogeneity within different areas of the tumor might be a potential concern as recently reported at least for selected patients [ 7 , 8 ]. A phenomenom that is not only restricted to colorectal cancer as shown by Queirós et al [ 9 ]. Differences in the KRAS mutation status between primary tumor and distant metastases [ 7 , 10 ].…”

Section: Introductionmentioning

confidence: 99%

Heterogeneity of KRAS Mutation Status in Rectal Cancer

Jo¹,

König²,

Schirmer³

et al. 2016

PLoS ONE

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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.

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KRAS mutations in microsatellite instable gastric tumours: impact of targeted treatment and intratumoural heterogeneity

Cited by 6 publications

References 27 publications

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

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

Deregulation of the miR-16-KRAS axis promotes colorectal cancer

Heterogeneity of KRAS Mutation Status in Rectal Cancer

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