The role of RAS oncogene in survival of patients with lung cancer: a systematic review of the literature with meta-analysis

C Mascaux, N Iannino, B Martin, M Paesmans, T Berghmans, M Dusart, A Haller, P Lothaire, A-P Meert, S Noel, J-J Lafitte, J-P Sculier, C Mascaux, N Iannino, B Martin, M Paesmans, T Berghmans, M Dusart, A Haller, P Lothaire, A-P Meert, S Noel, J-J Lafitte, J-P Sculier

Abstract

The proto-oncogene RAS, coding for a 21 kDa protein (p21), is mutated in 20% of lung cancer. However, the literature remains controversial on its prognostic significance for survival in lung cancer. We performed a systematic review of the literature with meta-analysis to assess its possible prognostic value on survival. Published studies on lung cancer assessing prognostic value of RAS mutation or p21 overexpression on survival were identified by an electronic search. After a methodological assessment, we estimated individual hazard ratios (HR) estimating RAS protein alteration or RAS mutation effect on survival and combined them using meta-analytic methods. In total, 53 studies were found eligible, with 10 concerning the same cohorts of patients. Among the 43 remaining studies, the revelation method was immunohistochemistry (IHC) in nine and polymerase chain reaction (PCR) in 34. Results in terms of survival were significantly pejorative, significantly favourable, not significant and not conclusive in 9, 1, 31, 2, respectively. In total, 29 studies were evaluable for meta-analysis but we aggregated only the 28 dealing with non-small-cell lung cancer (NSCLC) and not the only one dealing with small-cell-lung cancer (SCLC). The quality scores were not statistically significantly different between studies with or without significant results in terms of survival, allowing us to perform a quantitative aggregation. The combined HR was 1.35 (95% CI: 1.16-1.56), showing a worse survival for NSCLC with KRAS2 mutations or p21 overexpression and, particularly, in adenocarcinomas (ADC) (HR 1.59; 95% CI 1.26-2.02) and in studies using PCR (HR 1.40; 95% CI 1.18-1.65) but not in studies using IHC (HR 1.08; 95% CI 0.86-1.34). RAS appears to be a pejorative prognostic factor in terms of survival in NSCLC globally, in ADC and when it is studied by PCR.

Figures

Figure 1
Figure 1
Meta-analysis of studies assessing RAS with IHC in NSCLC. Hazard ratio (HR) and 95% confidence interval (CI) of survival in studies evaluating RAS-p21 status in NSCLC. HR>1 implies a survival disadvantage for the group with p21 expression. The square size is proportional to the number of patients included in the study. The center of the lozenge gives the combined HR of the meta-analysis and its extremities the 95% confidence interval. HR=1.08; CI 95% 0.86–1.34. Total number of patients: 989.
Figure 2
Figure 2
Meta-analysis of studies assessing RAS mutation with PCR in NSCLC. Hazard ratio (HR) and 95% confidence interval (CI) of survival in studies evaluating RAS-p21 status in NSCLC. HR>1 implies a survival disadvantage for the group with RAS mutation. The square size is proportional to the number of patients included in the study. The centre of the lozenge gives the combined HR of the meta-analysis and its extremities the 95% confidence interval. HR=1.40; CI 95% 1.18–1.65. Total number of patients: 2631.
Figure 3
Figure 3
Meta-analysis of studies assessing RAS mutation by PCR in adenocarcinomas. Hazard ratio (HR) and 95% confidence interval (CI) of survival in studies evaluating RAS-p21 status in NSCLC. HR>1 implies a survival disadvantage for the group with RAS mutation. The square size is proportional to the number of patients included in the study. The centre of the lozenge gives the combined HR of the meta-analysis and its extremities the 95% confidence interval. HR=1.50; CI 95% 1.26–1.80. Total number of patients: 1170.

References

    1. Ahrendt SA, Yang SC, Wu L, Roig CM, Russell P, Westra WH, Jen J, Brock MV, Heitmiller RF, Sidransky D (2002) Molecular assessment of lymph nodes in patients with resected stage I non-small cell lung cancer: preliminary results of a prospective study. J Thorac Cardiovasc Surg 123: 466–473
    1. Andjelic G, Magic Z, Bokun R, Stepic V (2001) Mutations in K-Ras oncogene and their influence on survival of patients with non-small cell lung cancer. J BUON 6: 61–66
    1. Broermann P, Junker K, Brandt BH, Heinecke A, Freitag L, Klinke F, Berdel WE, Thomas M (2002) Trimodality treatment in Stage III nonsmall cell lung carcinoma: prognostic impact of K-ras mutations after neoadjuvant therapy. Cancer 94: 2055–2062
    1. Cho JY, Kim JH, Lee YH, Chung KY, Kim SK, Gong SJ, You NC, Chung HC, Roh JK, Kim BS (1997) Correlation between K-ras gene mutation and prognosis of patients with nonsmall cell lung carcinoma. Cancer 79: 462–467
    1. De Gregorio L, Manenti G, Incarbone M, Pilotti S, Pastorino U, Pierotti MA, Dragani TA (1998) Prognostic value of loss of heterozygosity and KRAS2 mutations in lung adenocarcinoma. Int J Cancer 79: 269–272
    1. Delmotte P, Martin B, Paesmans M, Berghmans T, Mascaux C, Meert AP, Steels E, Verdebout JM, Lafitte JJ, Sculier JP (2002) VEGF and survival of patients with lung cancer: a systematic literature review and meta-analysis]. Rev Mal Respir 19: 577–584
    1. Dingemans AM, Witlox MA, Stallaert RA, van der Valk P, Postmus PE, Giaccone G (1999) Expression of DNA topoisomerase IIalpha and topoisomerase IIbeta genes predicts survival and response to chemotherapy in patients with small cell lung cancer. Clin Cancer Res 5: 2048–2058
    1. Dosaka-Akita H, Hu SX, Fujino M, Harada M, Kinoshita I, Xu HJ, Kuzumaki N, Kawakami Y, Benedict WF (1997) Altered retinoblastoma protein expression in non-small cell lung cancer: its synergistic effects with altered ras and p53 protein status on prognosis. Cancer 79: 1329–1337
    1. Fisher GH, Wellen SL, Klimstra D, Lenczowski JM, Tichelaar JW, Lizak MJ, Whitsett JA, Koretsky A, Varmus HE (2001) Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. Genes Dev 15: 3249–3262
    1. Fu XL, Zhu XZ, Shi DR, Xiu LZ, Wang LJ, Zhao S, Qian H, Lu HF, Xiang YB, Jiang GL (1999) Study of prognostic predictors for non-small cell lung cancer. Lung Cancer 23: 143–152
    1. Fujino M, Dosaka-Akita H, Harada M, Hiroumi H, Kinoshita I, Akie K, Kawakami Y (1995) Prognostic significance of p53 and ras p21 expression in nonsmall cell lung cancer. Cancer 76: 2457–2463
    1. Fukuyama Y, Mitsudomi T, Sugio K, Ishida T, Akazawa K, Sugimachi K (1997) K-ras and p53 mutations are an independent unfavourable prognostic indicator in patients with non-small-cell lung cancer. Br J Cancer 75: 1125–1130
    1. Graziano SL, Gamble GP, Newman NB, Abbott LZ, Rooney M, Mookherjee S, Lamb ML, Kohman LJ, Poiesz BJ (1999) Prognostic significance of K-ras codon 12 mutations in patients with resected stage I and II non-small-cell lung cancer. J Clin Oncol 17: 668–675
    1. Greatens TM, Niehans GA, Rubins JB, Jessurun J, Kratzke RA, Maddaus MA, Niewoehner DE (1998) Do molecular markers predict survival in non-small-cell lung cancer? Am J Respir Crit Care Med 157: 1093–1097
    1. Grossi F, Loprevite M, Chiaramondia M, Ceppa P, Pera C, Ratto GB, Serrano J, Ferrara GB, Costa R, Boni L, Ardizzoni A (2003) Prognostic significance of K-ras, p53, bcl-2, PCNA, CD34 in radically resected non-small cell lung cancers. Eur J Cancer 39: 1242–1250
    1. Harada M, Dosaka-Akita H, Miyamoto H, Kuzumaki N, Kawakami Y (1992) Prognostic significance of the expression of ras oncogene product in non-small cell lung cancer. Cancer 69: 72–77
    1. Hommura F, Dosaka-Akita H, Mishina T, Nishi M, Kojima T, Hiroumi H, Ogura S, Shimizu M, Katoh H, Kawakami Y (2000) Prognostic significance of p27KIP1 protein and ki-67 growth fraction in non-small cell lung cancers. Clin Cancer Res 6: 4073–4081
    1. Huang CL, Taki T, Adachi M, Konishi T, Higashiyama M, Kinoshita M, Hadama T, Miyake M (1998) Mutations of p53 and K-ras genes as prognostic factors for non-small cell lung cancer. Int J Oncol 12: 553–563
    1. Huncharek M, Muscat J, Geschwind JF (1999) K-ras oncogene mutation as a prognostic marker in non-small cell lung cancer: a combined analysis of 881 cases. Carcinogenesis 20: 1507–1510
    1. Kang YH, Kim KS, Yu YK, Lim SC, Kim YC, Park KO (2001) The relationship between microvessel count and the expression of vascular endothelial growth factor, p53, and K-ras in non-small cell lung cancer. J Korean Med Sci 16: 417–423
    1. Kanters SD, Lammers JW, Voest EE (1995) Molecular and biological factores in the prognosis of non-small cell lung cancer. Eur Respir J 8: 1389–1397
    1. Kashii T, Mizushima Y, Lima CE, Noto H, Sato H, Saito H, Kusajima Y, Kitagawa M, Yamamoto K, Kobayashi M (1995) Studies on clinicopathological features of lung cancer patients with K-ras/p53 gene alterations: comparison between younger and older groups. Oncology 52: 219–225
    1. Keohavong P, DeMichele MA, Melacrinos AC, Landreneau RJ, Weyant RJ, Siegfried JM (1996) Detection of K-ras mutations in lung carcinomas: relationship to prognosis. Clin Cancer Res 2: 411–418
    1. Keohavong P, Zhu D, Melacrinos AC, DeMichele MA, Weyant RJ, Luketich JD, Testa JR, Fedder M, Siegfried JM (1997) Detection of low-fraction K-ras mutations in primary lung tumors using a sensitive method. Int J Cancer 74: 162–170
    1. Kern JA, Slebos RJ, Top B, Rodenhuis S, Lager D, Robinson RA, Weiner D, Schwartz DA (1994) C-erbB-2 expression and codon 12 K-ras mutations both predict shortened survival for patients with pulmonary adenocarcinomas. J Clin Invest 93: 516–520
    1. Kim YC, Park KO, Kern JA, Park CS, Lim SC, Jang AS, Yang JB (1998) The interactive effect of Ras, HER2, P53 and Bcl-2 expression in predicting the survival of non-small cell lung cancer patients. Lung Cancer 22: 181–190
    1. Komiya T, Hosono Y, Hirashima T, Masuda N, Yasumitsu T, Nakagawa K, Kikui M, Ohno A, Fukuoka M, Kawase I (1997) p21 expression as a predictor for favorable prognosis in squamous cell carcinoma of the lung. Clin Cancer Res 3: 1831–1835
    1. Konishi T, Huang CL, Adachi M, Taki T, Inufusa H, Kodama K, Kohno N, Miyake M (2000) The K-ras gene regulates vascular endothelial growth factor gene expression in non-small cell lung cancers. Int J Oncol 16: 501–511
    1. Kwiatkowski DJ, Harpole Jr DH, Godleski J, Herndon JE, Shieh DB, Richards W, Blanco R, Xu HJ, Strauss GM, Sugarbaker DJ (1998) Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications. J Clin Oncol 16: 2468–2477
    1. Li ZH, Zheng J, Weiss LM, Shibata D (1994) c-k-ras and p53 mutations occur very early in adenocarcinoma of the lung. Am J Pathol 144: 303–309
    1. Martin B, Paesmans M, Berghmans T, Branle F, Ghisdal L, Mascaux C, Meert AP, Steels E, Vallot F, Verdebout JM, Lafitte JJ, Sculier JP (2003) Role of Bcl-2 as a prognostic factor for survival in lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 89: 55–64
    1. Meert AP, Martin B, Delmotte P, Berghmans T, Lafitte JJ, Mascaux C, Paesmans M, Steels E, Verdebout JM, Sculier JP (2002a) The role of EGF-R expression on patient survival in lung cancer: a systematic review with meta-analysis. Eur Respir J 20: 975–981
    1. Meert AP, Martin B, Paesmans M, Berghmans T, Mascaux C, Verdebout JM, Delmotte P, Lafitte JJ, Sculier JP (2003) The role of HER-2/neu expression on the survival of patients with lung cancer: a systematic review of the literature. Br J Cancer 89: 959–965
    1. Meert AP, Paesmans M, Martin B, Delmotte P, Berghmans T, Verdebout JM, Lafitte JJ, Mascaux C, Sculier JP (2002b) The role of microvessel density on the survival of patients with lung cancer: a systematic review of the literature with meta-analysis. Br J Cancer 87: 694–701
    1. Minamoto T, Mai M, Ronai Z (2000) K-ras mutation: early detection in molecular diagnosis and risk assessment of colorectal, pancreas, and lung cancers – a review. Cancer Detect Prev 24: 1–12
    1. Mitsudomi T, Steinberg SM, Oie HK, Mulshine JL, Phelps R, Viallet J, Pass H, Minna JD, Gazdar AF (1991) ras gene mutations in non-small cell lung cancers are associated with shortened survival irrespective of treatment intent. Cancer Res 51: 4999–5002
    1. Miyake M, Adachi M, Huang C, Higashiyama M, Kodama K, Taki T (1999) A novel molecular staging protocol for non-small cell lung cancer. Oncogene 18: 2397–2404
    1. Miyamoto H, Harada M, Isobe H, Akita HD, Haneda H, Yamaguchi E, Kuzumaki N, Kawakami Y (1991) Prognostic value of nuclear DNA content and expression of the ras oncogene product in lung cancer. Cancer Res 51: 6346–6350
    1. Moldvay J, Scheid P, Wild P, Nabil K, Siat J, Borrelly J, Marie B, Farre G, Labib T, Pottier G, Sesboue R, Bronner C, Vignaud JM, Martinet Y, Martinet N (2000) Predictive survival markers in patients with surgically resected non-small cell lung carcinoma. Clin Cancer Res 6: 1125–1134
    1. Nelson HH, Christiani DC, Mark EJ, Wiencke JK, Wain JC, Kelsey KT (1999) Implications and prognostic value of K-ras mutation for early-stage lung cancer in women. J Natl Cancer Inst 91: 2032–2038
    1. Nemunaitis J, Klemow S, Tong A, Courtney A, Johnston W, Mack M, Taylor W, Solano M, Stone M, Mallams J, Mues G (1998) Prognostic value of K-ras mutations, ras oncoprotein, and c-erb B-2 oncoprotein expression in adenocarcinoma of the lung. Am J Clin Oncol 21: 155–160
    1. Paesmans M, Sculier J-P, Lecomtre J, Thiriaux J, Libert P, Sergysels R, Bureau G, Dabouis G, Van Custem O, Mommen P, Ninane V, Klastersky J, for the European Lung Cancer Working Party (2000) Prognostic factors in patients with small cell lung cancer: analysis of a series of 763 patients included in four consecutive prospective trials and with a minimal 5-year follow-up duration. Cancer 89: 523–533
    1. Paesmans M, Sculier J-P, Libert P, Bureau G, Dabouis G, Thiriaux J, Michel J, Van Custem O, Sergysels R, Mommen P (1995) Prognostic factors for survival in advanced non-small cell lung cancer: univariate and multivariate analyses including recursive partitioning and amalgamation algorithms in 1052 patients. J Clin Oncol 13: 1221–1230
    1. Parmar MK, Torri V, Stewart L (1998) Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med 17: 2815–2834
    1. Pifarré A, Rosell R, Monzo M, De Anta JM, Moreno I, Sanchez JJ, Ariza A, Mate JL, Martinez E, Sanchez M (1997) Prognostic value of replication errors on chromosomes 2p and 3p in non-small-cell lung cancer. Br J Cancer 75: 184–189
    1. Ramirez JL, Sarries C, de Castro PL, Roig B, Queralt C, Escuin D, de Aguirre I, Sanchez JM, Manzano JL, Margeli M, Sanchez JJ, Astudillo J, Taron M, Rosell R (2003) Methylation patterns and K-ras mutations in tumor and paired serum of resected non-small-cell lung cancer patients. Cancer Lett 193: 207–216
    1. Rodenhuis S (1992) ras and human tumors. Semin Cancer Biol 3: 241–247
    1. Rodenhuis S, Boerrigter L, Top B, Slebos RJ, Mooi WJ, van't Veer L, van Zandwijk N (1997) Mutational activation of the K-ras oncogene and the effect of chemotherapy in advanced adenocarcinoma of the lung: a prospective study. J Clin Oncol 15: 285–291
    1. Rodenhuis S, Slebos RJ (1990) The ras oncogenes in human lung cancer. Am Rev Respir Dis 142: S27–S30
    1. Rodenhuis S, Slebos RJ, Boot AJ, Evers SG, Mooi WJ, Wagenaar SS, van Bodegom PC, Bos JL (1988) Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the human lung. Cancer Res 48: 5738–5741
    1. Rosell R, Li S, Skacel Z, Mate JL, Maestre J, Canela M, Tolosa E, Armengol P, Barnadas A, Ariza A (1993) Prognostic impact of mutated K-ras gene in surgically resected non-small cell lung cancer patients. Oncogene 8: 2407–2412
    1. Rosell R, Molina F, Moreno I, Martinez E, Pifarre A, Font A, Li S, Skacel Z, Gomez-Codina J, Camps C (1995a) Mutated K-ras gene analysis in a randomized trial of preoperative chemotherapy plus surgery vs surgery in stage IIIA non-small cell lung cancer. Lung Cancer 12(Suppl 1): S59–S70
    1. Rosell R, Monzo M, Molina F, Martinez E, Pifarre A, Moreno I, Mate JL, De Anta JM, Sanchez M, Font A (1995b) K-ras genotypes and prognosis in non-small-cell lung cancer. Ann Oncol 6(Suppl 3): S15–S20
    1. Rosell R, Monzo M, Pifarre A, Ariza A, Sanchez JJ, Moreno I, Maurel J, Lopez MP, Abad A, De Anta JM (1996) Molecular staging of non-small cell lung cancer according to K-ras genotypes. Clin Cancer Res 2: 1083–1086
    1. Rosell R, Pifarre A, Monzo M, Astudillo J, Lopez-Cabrerizo MP, Calvo R, Moreno I, Sanchez-Cespedes M, Font A, Navas-Palacios JJ (1997) Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors. Int J Cancer 74: 330–334
    1. Schiller JH, Adak S, Feins RH, Keller SM, Fry WA, Livingston RB, Hammond ME, Wolf B, Sabatini L, Jett J, Kohman L, Johnson DH (2001) Lack of prognostic significance of p53 and K-ras mutations in primary resected non-small-cell lung cancer on E4592: a Laboratory Ancillary Study on an Eastern Cooperative Oncology Group Prospective Randomized Trial of Postoperative Adjuvant Therapy. J Clin Oncol 19: 448–457
    1. Schneider PM, Praeuer HW, Stoeltzing O, Boehm J, Manning J, Metzger R, Fink U, Wegerer S, Hoelscher AH, Roth JA (2000) Multiple molecular marker testing (p53, C-Ki-ras, c-erbB-2) improves estimation of prognosis in potentially curative resected non-small cell lung cancer. Br J Cancer 83: 473–479
    1. Shoji T, Tanaka F, Takata T, Yanagihara K, Otake Y, Hanaoka N, Miyahara R, Nakagawa T, Kawano Y, Ishikawa S, Katakura H, Wada H (2002) Clinical significance of p21 expression in non-small-cell lung cancer. J Clin Oncol 20: 3865–3871
    1. Siegfried JM, Gillespie AT, Mera R, Casey TJ, Keohavong P, Testa JR, Hunt JD (1997) Prognostic value of specific KRAS mutations in lung adenocarcinomas. Cancer Epidemiol Biomarkers Prev 6: 841–847
    1. Silini EM, Bosi F, Pellegata NS, Volpato G, Romano A, Nazari S, Tinelli C, Ranzani GN, Solcia E, Fiocca R (1994) K-ras gene mutations: an unfavorable prognostic marker in stage I lung adenocarcinoma. Virchows Arch 424: 367–373
    1. Slebos RJ, Kibbelaar RE, Dalesio O, Kooistra A, Stam J, Meijer CJ, Wagenaar SS, Vanderschueren RG, van Zandwijk N, Mooi WJ (1990) K-ras oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J Med 323: 561–565
    1. Steels E, Paesmans M, Berghmans T, Branle F, Burniat A, Ghisdal L, Lafitte J-J, Lemaitre F, Mascaux C, Meert A-P, Vallot F, Sculier J-P (2001) Role of p53 on the survival of patients with lung cancer as assessed by a systematic review of the literature. Eur Respir J 18: 705–719
    1. Strauss GM (1997) Prognostic markers in resectable non-small cell lung cancer. Hematol Oncol Clin N Am 11: 409–434
    1. Sugio K, Ishida T, Yokoyama H, Inoue T, Sugimachi K, Sasazuki T (1992) ras gene mutations as a prognostic marker in adenocarcinoma of the human lung without lymph node metastasis. Cancer Res 52: 2903–2906
    1. Tomizawa Y, Kohno T, Kondo H, Otsuka A, Nishioka M, Niki T, Yamada T, Maeshima A, Yoshimura K, Saito R, Minna JD, Yokota J (2002) Clinicopathological significance of epigenetic inactivation of RASSF1A at 3p21.3 in stage I lung adenocarcinoma. Clin Cancer Res 8: 2362–2368
    1. Visscher DW, Yadrandji S, Tabaczka P, Kraut M, Sarkar FH (1997) Clinicopathologic analysis of k-ras, p53, and ERBB-2 gene alterations in pulmonary adenocarcinoma. Diagn Mol Pathol 6: 64–69
    1. Volm M, Drings P, Mattern J, Wodrich W (1993) Prognostic value of oncoproteins for the survival of patients with non-small cell lung carcinomas. Int J Oncol 2: 767–772
    1. Volm M, Koomagi R, Mattern J, Efferth T (2002) Expression profile of genes in non-small cell lung carcinomas from long-term surviving patients. Clin Cancer Res 8: 1843–1848
    1. Wang YC, Lee HS, Chen SK, Yang SC, Chen CY (1998) Analysis of K-ras gene mutations in lung carcinomas: correlation with gender, histological subtypes, and clinical outcome. J Cancer Res Clin Oncol 124: 517–522
    1. Westra WH, Slebos RJ, Offerhaus GJ, Goodman SN, Evers SG, Kensler TW, Askin FB, Rodenhuis S, Hruban RH (1993) K-ras oncogene activation in lung adenocarcinomas from former smokers. Evidence that K-ras mutations are an early and irreversible event in the development of adenocarcinoma of the lung. Cancer 72: 432–438
    1. Yusuf S, Peto R, Lewis J, Collins R, Sleight P (1985) Blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 27: 335–371

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