Background. In lung adenocarcinoma, the frequency of KRAS mutations is ethnicity dependent with a higher proportion in African Americans and white Caucasians than in Asians. The prevalence of these mutations among North Africans patients is unknown. The objective of this study was to report the frequency and spectrum of KRAS mutations in a group of Moroccan lung adenocarcinoma patients. Methods. Tumor specimens from 117 Moroccan patients with lung adenocarcinoma were selected to determine frequency and spectrum of KRAS mutations. KRAS mutations in codons 12 and 13 of exon 2 were analyzed using conventional DNA sequencing. Results. The overall frequency of the KRAS mutations was 9% (11/117). In the population with KRAS mutations, there was a trend towards more male ( ) and more smokers ( ) compared to patients with wild type KRAS. KRAS mutations were located at codon 12 in 10 out of 11 patients (91%). The G12C mutation was the most frequent KRAS mutation (73%). Conclusion. This is the first study to date examining the frequency and spectrum of KRAS mutations in lung adenocarcinomas in North African and Arab populations. KRAS mutation frequency in Moroccan patients was comparable with the frequency observed in East-Asian population. KRAS mutations are more likely observed in males and smokers and to be transversions. Further studies, in larger numbers of patients, are needed to confirm these findings. 1. Introduction Lung cancer is one of the most common cancers in Morocco and in the world and is the leading cause of cancer mortality in both males and females [1, 2]. During the last few years, improvement in the knowledge of lung cancer molecular biology led to identification of several biological events crucial for tumor cell survival. In nonsmall-cell lung cancer (NSCLC), one of the most commonly genetic aberrations is conversion of the protooncogene KRAS to its activated oncogenic form. KRAS encodes low molecular weight GTPase binding proteins that regulate cell growth, differentiation, and apoptosis. Mutations of KRAS are associated with impaired GTPase activity, causing increased mitogenic RAS signaling [3]. Mutations in KRAS gene occur more frequently (20–30%) in adenocarcinoma and less frequently (about 7%) in squamous-cell carcinoma and are usually associated with a history of smoking [4]. The incidence of KRAS mutation is ethnicity dependent with a higher proportion in African Americans and white Caucasians (20–30%) than in Asians (5–20%) [5–7]. However, such information is still lacking in some other races, such as North African patients.
References
[1]
R. Siegel, D. Naishadham, and A. Jemal, “Cancer statistics, 2013,” CA Cancer Journal for Clinicians, vol. 63, pp. 11–30, 2012.
[2]
The Grand Casablanca cancer registry, 2007.
[3]
S. L. Campbell, R. Khosravi-Far, K. L. Rossman, G. J. Clark, and C. J. Der, “Increasing complexity of Ras signaling,” Oncogene, vol. 17, no. 11, pp. 1395–1413, 1998.
[4]
S. Forbes, J. Clements, E. Dawson et al., “Cosmic 2005,” British Journal of Cancer, vol. 94, no. 2, pp. 318–322, 2006.
[5]
M. Suzuki, H. Shigematsu, T. Iizasa et al., “Exclusive mutation in epidermal growth factor receptor gene, HER-2, and KRAS, and synchronous methylation of nonsmall cell lung cancer,” Cancer, vol. 106, no. 10, pp. 2200–2207, 2006.
[6]
R. Califano, L. Landi, and F. Cappuzzo, “Prognostic and predictive value of K-RAS mutations in non-small cell lung cancer,” Drugs, vol. 72, no. 1 supplement, pp. 28–36, 2012.
[7]
G. J. Riely, M. G. Kris, D. Rosenbaum et al., “Frequency and distinctive spectrum of KRAS mutations in never smokers with lung adenocarcinoma,” Clinical Cancer Research, vol. 14, no. 18, pp. 5731–5734, 2008.
[8]
J. L. Bos, “Ras oncogenes in human cancer: a review,” Cancer Research, vol. 49, no. 17, pp. 4682–4689, 1989.
[9]
L. Ding, G. Getz, D. A. Wheeler et al., “Somatic mutations affect key pathways in lung adenocarcinoma,” Nature, vol. 455, no. 7216, pp. 1069–1075, 2008.
[10]
S. Schubbert, K. Shannon, and G. Bollag, “Hyperactive Ras in developmental disorders and cancer,” Nature Reviews Cancer, vol. 7, no. 4, pp. 295–308, 2007.
[11]
A. J. Smits, J. A. Kummer, J. W. Hinrichs et al., “EGFR and KRAS mutations in lung carcinomas in the Dutch population: increased EGFR mutation frequency in malignant pleural effusion of lung adenocarcinoma,” Cellular Oncology, vol. 35, no. 3, pp. 189–196, 2012.
[12]
C. Boch, J. Kollmeier, A. Roth et al., “The frequency of EGFR and KRAS mutations in non-small cell lung cancer (NSCLC): routine screening data for central Europe from a cohort study,” BMJ Open, vol. 3, no. 4, Article ID e002560, 2013.
[13]
J. M. Reinersman, M. L. Johnson, G. J. Riely et al., “Frequency of EGFR and KRAS mutations in lung adenocarcinomas in African Americans,” Journal of Thoracic Oncology, vol. 6, no. 1, pp. 28–31, 2011.
[14]
J. D. Hunt, A. Strimas, J. E. Martin et al., “Differences in KRAS mutation spectrum in lung cancer cases between African Americans and Caucasians after occupational or environmental exposure to known carcinogens,” Cancer Epidemiology Biomarkers and Prevention, vol. 11, no. 11, pp. 1405–1412, 2002.
[15]
R. S. Leidner, P. Fu, B. Clifford et al., “Genetic abnormalities of the EGFR pathway in African American patients with non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 27, no. 33, pp. 5620–5626, 2009.
[16]
H. Sasaki, K. Okuda, O. Kawano et al., “Nras and Kras mutation in Japanese lung cancer patients: genotyping analysis using LightCycler,” Oncology Reports, vol. 18, no. 3, pp. 623–628, 2007.
[17]
Y. T. Kim, T.-Y. Kim, D. S. Lee et al., “Molecular changes of epidermal growth factor receptor (EGFR) and KRAS and their impact on the clinical outcomes in surgically resected adenocarcinoma of the lung,” Lung Cancer, vol. 59, no. 1, pp. 111–118, 2008.
[18]
H. Akamatsu, K. Kaira, H. Murakami et al., “The impact of clinical outcomes according to EGFR mutation status in patients with locally advanced lung adenocarcinoma who recieved concurrent chemoradiotherapy,” American Journal of Clinical Oncology, 2012.
[19]
S. Y. Lee, M. J. Kim, G. Jin et al., “Somatic mutations in epidermal growth factor receptor signaling pathway genes in non-small cell lung cancers,” Journal of Thoracic Oncology, vol. 5, no. 11, pp. 1734–1740, 2010.
[20]
K. Takamochi, S. Oh, and K. Suzuki, “Differences in EGFR and KRAS mutation spectra in lung adenocarcinoma of never and heavy smokers,” Oncology Letters, vol. 6, no. 5, pp. 1207–1212, 2013.
[21]
S. A. Ahrendt, P. A. Decker, E. A. Alawi et al., “Cigarette smoking is strongly associated with mutation of the K-ras gene in patients with primary adenocarcinoma of the lung,” Cancer, vol. 92, no. 6, pp. 1525–1530, 2001.
[22]
C. Mao, L.-X. Qiu, R.-Y. Liao et al., “KRAS mutations and resistance to EGFR-TKIs treatment in patients with non-small cell lung cancer: a meta-analysis of 22 studies,” Lung Cancer, vol. 69, no. 3, pp. 272–278, 2010.
[23]
T. S. Mok, Y.-L. Wu, S. Thongprasert et al., “Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma,” The New England Journal of Medicine, vol. 361, no. 10, pp. 947–957, 2009.
[24]
J. M. Siegfried, A. T. Gillespie, R. Mera et al., “Prognostic value of specific KRAS mutations in lung adenocarcinomas,” Cancer Epidemiology Biomarkers and Prevention, vol. 6, no. 10, pp. 841–847, 1997.
[25]
S. S. Hecht, “Tobacco smoke carcinogens and lung cancer,” Journal of the National Cancer Institute, vol. 91, no. 14, pp. 1194–1210, 1999.
[26]
P. Martin, N. B. Leighl, M. S. Tsao, and F. A. Shepherd, “KRAS mutations as prognostic and predictive markers in non-small cell lung cancer,” Journal of Thoracic Oncology, vol. 8, no. 5, pp. 530–542, 2013.
