K-ras gene mutations in adenomas and carcinomas of the colon

doi:10.1016/0960-7404(92)90088-3

Surgical Oncology

Volume 1, Issue 4, August 1992, Pages 275-282

https://doi.org/10.1016/0960-7404(92)90088-3 Get rights and content

Abstract

DNA extracted from 29 colorectal carcinomas and 40 sporadic adenomas was amplified by the polymerase chain reaction (PCR) and analysed for the presence of K-ras gene mutations at codon 12 using a panel of synthetic oligonucleotide probes specific for normal and mutated sequences. The presence of mutations was correlated with various histopathological and clinical data. Ten carcinomas (34.5%) and 14 sporadic adenomas (35%) showed K-ras mutations at codon 12. In the carcinoma group, no apparent correlation was found between the presence of mutant oncogenes and the degree of histological differentiation. Dukes' staging or the development of distant metastasis. In the adenoma group, the frequency of mutations increased with the size of the adenoma and the severity of the dysplastic changes. This study confirms that ras gene mutations are common and early events in colon carcinogenesis. They appear to give a selective growth advantage to those polyps with mutations which leads to their increase in size and thus possibly prepare the ground for malignant transformation.

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Oxaliplatin-based chemotherapy might provide longer progression-free survival in KRAS mutant metastatic colorectal cancer
2013, Translational Oncology
The identification of better regimens in currently available chemotherapeutic agents is crucial for treating patients with KRAS mutant metastatic colorectal cancer (mCRC). Records of mCRC patients who received first-line oxaliplatin- based or irinotecan-based regimens were reviewed retrospectively. Clinicopathologic features and treatment outcome of patients with first-line progression-free survival (PFS) and overall survival (OS) in association with KRAS mutation status were analyzed using the Cox proportional hazard model. Between 2007 and 2010, a total of 118 mCRC patients were enrolled. Among them, 67 were males and 51 were females. In patients who received first-line oxaliplatin-based regimens, the PFS was significantly longer in KRAS mutant patients (N = 32) than that in KRAS wild-type patients (N = 51). The median PFS was 8.5 months in KRAS mutant versus 5.8 months in KRAS wild-type patients (P = .008). In contrast, in patients who received first-line irinotecan-based regimens, the PFS was shorter in KRAS mutant patients (N = 15) than that in KRAS wild-type patients (N = 20). Median PFS was 3.9 months in KRAS mutant versus 6.0 months in KRAS wild-type patients (P = .23). Median OS between KRAS mutant and wild-type patients was not significantly different in both oxaliplatin-based and irinotecan-based regimens. In multivariate analyses, KRAS mutation remains an independent predictive factor for longer PFS in first-line oxaliplatin-based regimens. In conclusion, oxaliplatin-based chemotherapy in KRAS mutant mCRC might result in longer PFS than in KRAS wild-type mCRC.
Tumor-infiltrating lymphocytes and dendritic cells in human colorectal cancer: Their relationship to KRAS mutational status and disease recurrence
2011, Human Immunology
Citation Excerpt :
It has been reported that KRAS mutations occur early in colorectal carcinogenesis, often before the development of polyps [3,17,18]. The percentage of CRC patients with mutations in KRAS varies from 30 to 50%, most likely depending on the different techniques used for detection [7–9]. In our cohort of patients, we identified KRAS mutations in 45.5% of tumors, including 65% in codon 12 and 35% in codon 13, which agrees with previous studies [9,10].
The prognosis of newly diagnosed colorectal cancer patients relies mostly on tumor-node metastasis classification. However, analyses of tumor-infiltrating lymphocytes and several molecular markers have also shown promising prognostic value. Mutations in the proto-oncogene KRAS, which occur early in colorectal carcinogenesis, have been demonstrated to be common in human colorectal cancer (CRC); however, their prognostic significance remains controversial. We examined the correlations between KRAS mutational status and tumor-infiltrating immune cells with respect to CRC recurrence. Mutations in KRAS were identified in 45.5% of the primary carcinomas in our cohort of patients: 65% in codon 12 and 35% in codon 13. Although codon 13 KRAS mutations were associated with disease relapse, they were present in both disease-free and relapsed patients. However, disease-free and relapsed patients differed markedly in their patterns of tumor-infiltrating immune cells. There was a trend toward decreased density of tumor-infiltrating lymphocytes (TILs) within the group of relapsed cases. In addition, relapsed patients with codon 13 mutations had markedly lower levels of tumor-infiltrating mature DC-LAMP⁺ dendritic cells (DCs) and higher frequency of CD1a⁺ cells compared with disease-free patients. Our data suggest that CRC patients with low levels of TILs, a high CD1a⁺/DC-LAMP⁺ tumor-infiltrating DC ratio, and a KRAS mutation in codon 13 are at a high risk of disease recurrence.
Sensitive detection of KRAS mutations in archived formalin-fixed paraffin-embedded tissue using mutant-enriched PCR and reverse-hybridization
2009, Journal of Molecular Diagnostics
Recently, evidence has emerged indicating that assessment of KRAS mutations before anti-epidermal growth factor receptor therapy improves outcome in patients with metastatic colorectal cancer (CRC). We report here a novel reverse-hybridization (RH) assay to screen for KRAS mutations in formalin-fixed paraffin-embedded colorectal tissue samples. We combined mutant-enriched PCR based on peptide nucleic acid clamping and RH of amplification products to nitrocellulose test strips that contained a parallel array of oligonucleotide probes targeting 10 frequent mutations in codons 12 and 13 of the KRAS gene. DNA mixing experiments, which included eight different tumor cell lines with known KRAS mutations, were performed to examine the sensitivity of mutation detection. All KRAS mutations present in tumor cell lines were unambiguously identified by the RH assay with 1% of each cell line DNA diluted in normal DNA. RH was then used to screen for KRAS mutations in 74 colorectal tumor and 4 normal control samples. Twenty-six (35%) of the 74 tumor samples showed KRAS mutations. No mutation was found in the four samples of normal colorectal tissue. DNA sequencing without previous mutant enrichment, however, failed to detect four (15%) out of 26 KRAS-positive formalin-fixed paraffin-embedded samples (FFPE). This finding suggests that even after microdissection, mutant sequences in a given DNA isolate can be rare and more sensitive methods are needed for mutation analysis.
The relationships of OSBPL3 expression with KI-67 expression and KRAS mutations in CRC: implications for diagnosis and prognosis
2022, BMC Medical Genomics
The respective relations of expression of OSBPL3 with Ki-67 expression and KRAS mutation in CRC for diagnosis and prognosis
2022, Research Square
Copy number variation and rearrangements assessment in cancer: Comparison of droplet digital pcr with the current approaches
2021, International Journal of Molecular Sciences

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^‡: Present address: Department of Surgery, University of Liverpool, UK.

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Surgical Oncology

Abstract

References (18)

Purifiction of DNA from formaldehyde fixed and paraffin embedded human tissue

Biochem. Biophys Res Commun

Specific synthesis of DNA in vitro via a polymerase catalysed chain reaction

Meth Enzymol

Improved technique utilizing non fat dry milk for analysis of proteins and nucleic acids transferred to nitrocellulose

Gene Analyt Tech

Most human carcinomas of the exocrine pancreas contain mutant c1-K-ras genes

Cell

A genetic model for colorectal tumourigenesis

Cell

The evolution of cancer of the colon and rectum

Cancer

Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects

Cancer Res

Incidence of synchronous and metachondrous colorectal carcinoma

Br J Surg

Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers

N Engl J Med

Cited by (50)

Oxaliplatin-based chemotherapy might provide longer progression-free survival in KRAS mutant metastatic colorectal cancer

Tumor-infiltrating lymphocytes and dendritic cells in human colorectal cancer: Their relationship to KRAS mutational status and disease recurrence

Sensitive detection of KRAS mutations in archived formalin-fixed paraffin-embedded tissue using mutant-enriched PCR and reverse-hybridization

The relationships of OSBPL3 expression with KI-67 expression and KRAS mutations in CRC: implications for diagnosis and prognosis

The respective relations of expression of OSBPL3 with Ki-67 expression and KRAS mutation in CRC for diagnosis and prognosis

Copy number variation and rearrangements assessment in cancer: Comparison of droplet digital pcr with the current approaches

Original articleK-ras gene mutations in adenomas and carcinomas of the colon

Abstract

Biochem. Biophys Res Commun

Meth Enzymol

Gene Analyt Tech

Cell

Cell

The evolution of cancer of the colon and rectum

Cancer

Biomarkers of increased susceptibility to gastrointestinal cancer: new application to studies of cancer prevention in human subjects

Cancer Res

Incidence of synchronous and metachondrous colorectal carcinoma

Br J Surg

Common inheritance of susceptibility to colonic adenomatous polyps and associated colorectal cancers

N Engl J Med

Original article
K-ras gene mutations in adenomas and carcinomas of the colon