Adenoma and carcinoma components in colonic tumors show discordance for KRAS mutation

Hershkovitz, Dov; Simon, Einav; Bick, Tova; Prinz, Elad; Noy, Shawna; Sabo, Edmond; Ben‐Izhak, Ofer

doi:10.1016/j.humpath.2014.05.005

Cited by 17 publications

(18 citation statements)

References 32 publications

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“…It has been shown that CRC develops from an accumulation of genetic aberrations that can begin in the normal colon and progresses through an adenomatous polyp to cancer . Currently, molecular features that characterize these precursor polyps as being at high risk for malignant transformation are currently limited, and LOH and CNV analyses are particularly limited in polyps that are associated with cancer …”

Section: Introductionmentioning

confidence: 99%

“…2,25,26 Currently, molecular features that characterize these precursor polyps as being at high risk for malignant transformation are currently limited, and LOH and CNV analyses are particularly limited in polyps that are associated with cancer. [27][28][29][30][31] We infer from these pioneering works that a broad spectrum of genetic aberrations may exist in morphologically and histologically non-malignant (either normal or polyp) colon tissue in sporadic CRC patients. Therefore, a more comprehensive evaluation of these aberrations is warranted.…”

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confidence: 99%

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Early genetic aberrations in patients with sporadic colorectal cancer

Druliner

Ruan

Sicotte

et al. 2017

Molecular Carcinogenesis

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Chromosome instability (CIN) is widely observed in both sporadic and hereditary colorectal cancer (CRC). Defects in APC and WNT signaling are primarily associated with CIN in hereditary CRC, but the genetic causes for CIN in sporadic CRC remain elusive. Using high‐density SNP array and exome data from The Cancer Genome Atlas (TCGA), we characterized loss of heterozygosity (LOH) and copy number variation (CNV) in the peripheral blood, normal colon, and corresponding tumor tissue in 15 CRC patients with proficient mismatch repair (MMR) and 24 CRC patients with deficient MMR. We found a high frequency of 18q LOH in tumors and arm‐specific enrichment of genetic aberrations on 18q in the normal colon (primarily copy neutral LOH) and blood (primarily copy gain). These aberrations were specific to the sporadic, pMMR CRC. Though in tumor samples genetic aberrations were observed for genes commonly mutated in hereditary CRC (eg, APC, CTNNB1, SMAD4, BRAF), none of them showed LOH or CNV in the normal colon or blood. DCC located on 18q21.1 topped the list of genes with genetic aberrations in the tumor. In an independent cohort of 13 patients subjected to Whole Genome Sequencing (WGS), we found LOH and CNV on 18q in adenomatous polyp and tumor tissues. Our data suggests that patients with sporadic CRC may have genetic aberrations preferentially enriched on 18q in their blood, normal colon epithelium, and non‐malignant polyp lesions that may prove useful as a clinical marker for sporadic CRC detection and risk assessment.

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Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

Early genetic aberrations in patients with sporadic colorectal cancer

Druliner

Ruan

Sicotte

et al. 2017

Molecular Carcinogenesis

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“…If both adenoma and carcinoma tissues were combined for testing, discordant RAS mutation status between adenoma and carcinoma components of a tumour could lead to incorrect classification of the carcinoma's RAS status, and incorrect treatment. Discordant KRAS status between adenoma and carcinoma components of colorectal tumours was reported in 23% of cases in one study,7 and the authors suggested RAS testing should be limited to the invasive component of a colorectal tumour. In the future, testing of ctDNA for RAS and other mutations may help address the challenges of tumour heterogeneity 15…”

Section: Discussionmentioning

confidence: 97%

“…However, there have been several publications ascribing distinct roles for mutations in KRAS and NRAS during oncogenesis4 5 and speculation that KRAS and NRAS mutations are perhaps not mutually exclusive. Following from this, a CRC cohort study from China reported the detection of KRAS and NRAS mutations in the same patient, although detailed data were not presented,6 and other sporadic reports of the presence of mutations in both genes were attributed to differences in the adenoma and carcinoma portions of the lesion 7. However, a recent case report showed the presence of KRAS G12V and NRAS G12S mutations in both the adenoma and carcinoma portions of the same colorectal tumour, and the authors claimed that the most likely explanation was co-occurring mutations, although further investigations to support this claim, such as laser capture microdissection of the tumour, were not performed 8…”

Section: Introductionmentioning

confidence: 94%

Intratumorous heterogeneity for RAS mutations in a treatment-naïve colorectal tumour

et al. 2017

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Activating mutations in and genes in patients with colorectal cancer (CRC) are associated with a lack of response to treatment with anti-epidermal growth factor receptor (EGFR) therapies. Mutations in these genes are thought to be mutually exclusive, however reports have described CRCs with two activating rat sarcoma (RAS) mutations. This has fuelled discussion about whether these mutations are the result of intratumorous heterogeneity, or if they are co-occurring in the same cancer cell clone. We present a case of a colorectal tumour with three RAS mutations detected during routine diagnostic testing. Further detailed analysis with laser capture microdissection and next generation sequencing excluded the possibility of all three mutations being present in the same clone, presenting the highest resolution evidence of intratumorous heterogeneity of RAS mutations to date.

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“…In advanced stages of the colon carcinoma, there was a relative homogeneity with regard to KRAS mutation 28 ; however, investigation of earlier malignant lesions that were present within adenoma found a substantial heterogeneity between the adenoma and carcinoma components. 29 Interestingly, as the tumor progressed, the frequency of this heterogeneity decreased. This suggests similar dynamics of KRAS mutation in colon and pancreatic cancers.…”

Section: Discussionmentioning

confidence: 99%