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Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I-III Non-Small Cell Lung Cancer.

Grossi F, Dal Bello MG, Salvi S, Puzone R, Pfeffer U, Fontana V, Alama A, Rijavec E, Barletta G, Genova C, Sini C, Ratto GB, Taviani M, Truini M, Merlo DF - Dis. Markers (2015)

Bottom Line: Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS).Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours.For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Unit, IRCCS A.O.U San Martino IST-Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genova, Italy.

ABSTRACT

Unlabelled: Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and q

Rt-pcr: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients.

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Related in: MedlinePlus

Kaplan-Meier estimates of overall survival according to gene expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) RRM1, (e) TUBB3, and (f) BRCA1 in Shedden 2008 [5] microarray dataset; N = 330 (adjuvant naïve patient only). Patients were categorised according to mRNA expression levels of each gene.
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fig5: Kaplan-Meier estimates of overall survival according to gene expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) RRM1, (e) TUBB3, and (f) BRCA1 in Shedden 2008 [5] microarray dataset; N = 330 (adjuvant naïve patient only). Patients were categorised according to mRNA expression levels of each gene.

Mentions: One hundred and seventy-four out of 330 patients were male (52.7%) and 156 (47.3%) were female. The median age at diagnosis was 65 years (range of 33–87). All of the patients had adenocarcinoma. Twenty-five (7.6%) patients were smokers, 182 (55.2%) former smokers, and 34 (10.3%) never-smokers. Smoking was missing for 89 (26.9%) subjects. Former and current smokers were grouped together in the statistical analysis (Table 6). At 5-year follow-up, a total of 121 (36.7%) deaths were observed. When patients were categorised into groups based on mRNA expression levels of each biomarker (i.e., negative, positive), three genes were found to be significantly associated with OS in univariate analyses (Table 6): BRCA1 (HR = 1.64, 95% CI = 1.12–2.39), TS (HR = 1.78, 95% CI = 1.24–2.56), and RRM2 (HR = 1.69, 95% CI = 1.17–2.44). The K-M survival curves for these genes are shown in Figure 5. Pathological TNM was a strong predictor of OS (HR = 3.19, 95% CI = 2.18–4.66 and HR = 6.45, 95% CI = 3.43–12.15 for stages II and III versus stage I, resp.) together with age at diagnosis (HR = 1.03, 95% CI = 1.01–1.04, and age = continuous) and gender (HR = 0.68, 95% CI = 0.47–0.98, females versus males). Cox multiple regression analyses (Table 6) identified age at diagnosis, pathological TNM, and TS (HR = 1.57, 95% CI: 1.08–2.28) as variables significantly associated with OS.


Expression of Ribonucleotide Reductase Subunit-2 and Thymidylate Synthase Correlates with Poor Prognosis in Patients with Resected Stages I-III Non-Small Cell Lung Cancer.

Grossi F, Dal Bello MG, Salvi S, Puzone R, Pfeffer U, Fontana V, Alama A, Rijavec E, Barletta G, Genova C, Sini C, Ratto GB, Taviani M, Truini M, Merlo DF - Dis. Markers (2015)

Kaplan-Meier estimates of overall survival according to gene expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) RRM1, (e) TUBB3, and (f) BRCA1 in Shedden 2008 [5] microarray dataset; N = 330 (adjuvant naïve patient only). Patients were categorised according to mRNA expression levels of each gene.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4664813&req=5

fig5: Kaplan-Meier estimates of overall survival according to gene expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) RRM1, (e) TUBB3, and (f) BRCA1 in Shedden 2008 [5] microarray dataset; N = 330 (adjuvant naïve patient only). Patients were categorised according to mRNA expression levels of each gene.
Mentions: One hundred and seventy-four out of 330 patients were male (52.7%) and 156 (47.3%) were female. The median age at diagnosis was 65 years (range of 33–87). All of the patients had adenocarcinoma. Twenty-five (7.6%) patients were smokers, 182 (55.2%) former smokers, and 34 (10.3%) never-smokers. Smoking was missing for 89 (26.9%) subjects. Former and current smokers were grouped together in the statistical analysis (Table 6). At 5-year follow-up, a total of 121 (36.7%) deaths were observed. When patients were categorised into groups based on mRNA expression levels of each biomarker (i.e., negative, positive), three genes were found to be significantly associated with OS in univariate analyses (Table 6): BRCA1 (HR = 1.64, 95% CI = 1.12–2.39), TS (HR = 1.78, 95% CI = 1.24–2.56), and RRM2 (HR = 1.69, 95% CI = 1.17–2.44). The K-M survival curves for these genes are shown in Figure 5. Pathological TNM was a strong predictor of OS (HR = 3.19, 95% CI = 2.18–4.66 and HR = 6.45, 95% CI = 3.43–12.15 for stages II and III versus stage I, resp.) together with age at diagnosis (HR = 1.03, 95% CI = 1.01–1.04, and age = continuous) and gender (HR = 0.68, 95% CI = 0.47–0.98, females versus males). Cox multiple regression analyses (Table 6) identified age at diagnosis, pathological TNM, and TS (HR = 1.57, 95% CI: 1.08–2.28) as variables significantly associated with OS.

Bottom Line: Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS).Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours.For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels.

View Article: PubMed Central - PubMed

Affiliation: Lung Cancer Unit, IRCCS A.O.U San Martino IST-Istituto Nazionale per la Ricerca sul Cancro, Largo Rosanna Benzi 10, 16132 Genova, Italy.

ABSTRACT

Unlabelled: Biomarkers can help to identify patients with early-stages or locally advanced non-small cell lung cancer (NSCLC) who have high risk of relapse and poor prognosis. To correlate the expression of seven biomarkers involved in DNA synthesis and repair and in cell division with clinical outcome, we consecutively collected 82 tumour tissues from radically resected NSCLC patients. The following biomarkers were investigated using IHC and q

Rt-pcr: excision repair cross-complementation group 1 (ERCC1), breast cancer 1 (BRCA1), ribonucleotide reductase subunits M1 and M2 (RRM1 and RRM2), subunit p53R2, thymidylate synthase (TS), and class III beta-tubulin (TUBB3). Gene expression levels were also validated in an available NSCLC microarray dataset. Multivariate analysis identified the protein overexpression of RRM2 and TS as independent prognostic factors of shorter overall survival (OS). Kaplan-Meier analysis showed a trend in shorter OS for patients with RRM2, TS, and ERCC1, BRCA1 overexpressed tumours. For all of the biomarkers except TUBB3, the OS trends relative to the gene expression levels were in agreement with those relative to the protein expression levels. The NSCLC microarray dataset showed RRM2 and TS as biomarkers significantly associated with OS. This study suggests that high expression levels of RRM2 and TS might be negative prognostic factors for resected NSCLC patients.

Show MeSH
Related in: MedlinePlus