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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 the protein expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) p53R2, (e) TUBB3, (f) BRCA1, and (g) RRM1 in the overall population.
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fig3: Kaplan-Meier estimates of overall survival according to the protein expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) p53R2, (e) TUBB3, (f) BRCA1, and (g) RRM1 in the overall population.

Mentions: Among the investigated associations between IHC expression of biomarkers, patients, and clinicopathologic features, only subunit p53R2 was found to be significantly associated with histotype (p < 0.001) with more p53R2-positive cases in nonsquamous than in squamous cancer (data not shown). The associations between patient and cancer characteristics, biological markers expression, and OS are shown in Table 3. Among all patients, a total of 37 (45%) deaths were observed during follow-up. The probability of surviving at 1 year and 2, 3, 4, and 5 years was 89%, 73%, 65%, 56%, and 54%, respectively. Pathological TNM was the only variable statistically associated with OS in univariate analysis (stage II, HR = 2.81, 95% CI = 1.18–6.69; stage III, HR = 4.44, 95% CI = 2.08–9.46, p < 0.001) (Table 3). K-M estimated mean survival time was 4.47 years for stage I patients (median survival time not reached), 3.12 years (median 2.69 years) for stage II patients, and 3.70 years (median 1.80 years) for stage III patients (data not shown). K-M analysis showed that despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ≤140) survived longer (HR = 1.84; 95% CI = 0.95–3.56) than patients with higher RRM2 expression (Table 3, Figure 3). The median survival was not reached for RRM2 ≤ 140 and was 3.7 years for RRM2 > 140. There was a trend towards longer survival for BRCA1-, ERCC1-, and TS-negative patients and for p53R2- and TUBB3-positive patients (Figure 3).


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 the protein expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) p53R2, (e) TUBB3, (f) BRCA1, and (g) RRM1 in the overall population.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Kaplan-Meier estimates of overall survival according to the protein expression levels of (a) RRM2, (b) TS, (c) ERCC1, (d) p53R2, (e) TUBB3, (f) BRCA1, and (g) RRM1 in the overall population.
Mentions: Among the investigated associations between IHC expression of biomarkers, patients, and clinicopathologic features, only subunit p53R2 was found to be significantly associated with histotype (p < 0.001) with more p53R2-positive cases in nonsquamous than in squamous cancer (data not shown). The associations between patient and cancer characteristics, biological markers expression, and OS are shown in Table 3. Among all patients, a total of 37 (45%) deaths were observed during follow-up. The probability of surviving at 1 year and 2, 3, 4, and 5 years was 89%, 73%, 65%, 56%, and 54%, respectively. Pathological TNM was the only variable statistically associated with OS in univariate analysis (stage II, HR = 2.81, 95% CI = 1.18–6.69; stage III, HR = 4.44, 95% CI = 2.08–9.46, p < 0.001) (Table 3). K-M estimated mean survival time was 4.47 years for stage I patients (median survival time not reached), 3.12 years (median 2.69 years) for stage II patients, and 3.70 years (median 1.80 years) for stage III patients (data not shown). K-M analysis showed that despite the lack of statistical significance, patients with lower RRM2 expression (i.e., ≤140) survived longer (HR = 1.84; 95% CI = 0.95–3.56) than patients with higher RRM2 expression (Table 3, Figure 3). The median survival was not reached for RRM2 ≤ 140 and was 3.7 years for RRM2 > 140. There was a trend towards longer survival for BRCA1-, ERCC1-, and TS-negative patients and for p53R2- and TUBB3-positive patients (Figure 3).

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