Frequency and clinicopathologic correlates of KRAS amplification in non-small cell lung carcinoma
Introduction
In a wide variety of human cancers, activating mutations in RAS oncogenes contribute to tumorigenesis by promoting cellular proliferation in the absence of normal stimuli for growth and replication. The oncogenic effects of RAS proteins are manifested when specific codons (12, 13 and 61) are mutated such that their gene products are no longer susceptible to counter-regulatory signals, rendering them constitutively active. The myriad downstream effects of dysregulated RAS activity facilitate unchecked cell division and the accumulation of additional oncogenic mutations. In lung cancer, this chain of events is well characterized, and KRAS mutations are associated with a discrete subset of tumors defined by a strong association with tobacco exposure, locally advanced disease, limited prognosis, and poor response rates to tyrosine kinase inhibitors [1].
By contrast, the role of RAS gene amplification as an oncogenic mechanism remains relatively undefined. A number of recent studies employing high-resolution techniques to map human tumor genomes have consistently identified copy number gains at 12p12.1, including the KRAS gene, in a wide spectrum of malignancies, including lung cancer [2], [3], [4], [5], [6], [7], [8]. Using fluorescence in situ hybridization, we previously confirmed the presence of KRAS amplification in a minority of non-small cell lung carcinomas (NSCLCs), and demonstrated an association between KRAS amplification and increased expression of the p21 gene product [3], [4], [5], [6], [7], [8], [9], [10], [11], [22]. In a similar report, Modrek et al., detected copy number gains of KRAS in ∼17% of NSCLCs and found that amplification was more likely in patients with activating KRAS mutations [12]. These authors established a strong correlation between KRAS amplification and increased KRAS mRNA levels.
On the basis of these findings, evidence for a clear relationship among KRAS gene amplification, activating mutation and protein expression has emerged. However, the clinicopathologic significance of these findings remains unknown. In order to better define the relationship between KRAS amplification and activating mutation, and to investigate the clinical relevance of KRAS amplification, we determined its frequency in two large cohorts of NSCLC, utilizing fluorescence in situ hybridization. We then correlated KRAS amplification status with the presence of KRAS activating mutations, standard clinicopathologic features, and outcome data.
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Patients and tumor samples
The University of Zurich cohort is a population based cohort of 538 patients with NSCLC who underwent surgery between January 1993 and December 2002 at the University Hospital Zurich and surrounding referral hospitals, and has been previously described [13], [14]. Histologic tumor types included in the cohort were adenocarcinoma, squamous cell carcinoma, and adenosquamous carcinoma, while large cell carcinoma, neuroendocrine carcinoma, sarcomatoid carcinoma, and metastases from primaries other
Frequency of KRAS amplification
Frequency of KRAS amplification was ascertained in two independent cohorts of patients. Among the first cohort of 538 tumors (University of Zurich), 445 had sufficient tissue for FISH evaluation. Evidence of KRAS amplification was seen in 61 cases (13.7%), with high-level amplification occurring in 10 tumors (2.2%) and low-level amplification in 51 (11.5%). The second cohort (Cornell) contained 385 evaluable tumors with sufficient tissue for FISH analysis, with KRAS amplification present in 58
Discussion
Conventionally, the process of epithelial carcinogenesis has been understood in terms of small-scale events that lead to altered function of oncoproteins or tumor suppressor proteins, as exemplified by activating point mutations affecting KRAS. Larger-scale alterations, such as gene amplification or translocation, were not well described in epithelial cancers in spite of their recognized significance in the pathogenesis of hematologic malignancies and sarcomas. More recently, the influence of
Conclusions
KRAS amplification occurs in approximately 15% of NSCLCs, and is associated with increased KRAS expression even when copy number gains are modest. Concomitant amplification and mutation of KRAS may enhance the aggressiveness of NSCLC relative to tumors with KRAS mutation alone. While KRAS amplification is associated with histologic indicators of locally aggressive disease, future studies will be necessary to determine its importance in predicting response to therapy and overall prognosis.
Conflict of interest statement
There are no conflicts of interest to report.
References (22)
- et al.
Prognostic and therapeutic implications of EGFR and KRAS mutations in resected lung adenocarcinoma
J Thorac Oncol
(2008) - et al.
Investigation of c-myc and K-ras amplification in renal clear cell adenocarcinoma
Cancer Lett
(1997) - et al.
EML4-ALK fusion lung cancer: a rare acquired event
Neoplasia
(2008) - et al.
EML4-ALK fusion is linked to histological characteristics in a subset of lung cancers
J Thorac Oncol
(2008) - et al.
Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer
Cell
(2007) - et al.
Comparative genomic hybridization analysis detects frequent, often high-level, overrepresentation of DNA sequences at 3q, 5p, 7p, and 8q in human non-small cell lung carcinomas
Cancer Res
(1997) - et al.
Somatic mutations affect key pathways in lung adenocarcinoma
Nature
(2008) - et al.
RAS/RAF pathway activation in gliomas: the result of copy number gains rather than activating mutations
Acta Neuropathol.
(2007 Aug) - et al.
Gains, losses, and amplifications of genomic materials in primary gastric cancers analyzed by comparative genomic hybridization
Genes Chromosomes Cancer
(1999) - et al.
Amplification of protooncogenes in surgical specimens of human lung carcinomas
Cancer Res
(1989)
Characterizing the cancer genome in lung adenocarcinoma
Nature
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Current address: Institute of Pathology, University Hospital Bonn, Bonn, Germany.