BIRC5 promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients

Our plain-English summary of BIRC5 promoter SNPs do not affect nuclear survivin expression and survival of malignant pleural mesothelioma patients, by J. Hmeljak, N. Erčulj, V. Dolžan, et al (Journal of Cancer Research and Clinical Oncology, 2011).

The study

• Authors: J. Hmeljak, N. Erčulj, V. Dolžan, I. Kern, A. Cör
• Journal: Journal of Cancer Research and Clinical Oncology
• Published: 2011;137(11):1641-51
• Cited by: 16 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

Abstract

Purpose: Malignant pleural mesothelioma is an incurable, asbestos-associated cancer. Its incidence is rapidly increasing and survival remains short. Apoptosis deregulation is an important feature of cancer and survivin, a member of the inhibitor-of-apoptosis-protein family encoded by the BIRC5 gene, has been suggested to have a role in the development and progression of several cancers. Genetic variability, in particular single nucleotide polymorphisms in the BIRC5 promoter, may affect the protein's expression levels. The aim of our study was to elucidate the effects of BIRC5 promoter single nucleotide polymorphisms on survivin expression, patient survival and age at diagnosis in malignant pleural mesothelioma.

Methods: Archival mesothelioma samples from 101 Slovenian patients were immunohistochemically analysed for survivin expression. DNA was extracted from tumour samples and genotyped for three BIRC5 promoter single nucleotide polymorphisms (-31G > C, -241C > T and -625G > C). Genotypes were associated with nuclear survivin expression. Nuclear survivin expression, genotypes, haplotypes, histological type, gender and asbestos exposure were included in univariate Cox survival analyses.

Results: Survivin expression was detected in both tumour cell nuclei and cytoplasms in all analysed samples. No association between BIRC5 promoter polymorphism genotypes or haplotypes and nuclear survivin expression was found. Polymorphism -241C > T affected patients' age at diagnosis. Survival analysis confirmed that younger age at diagnosis and epitheloid histological type improved survival, but no significant effects of nuclear survivin expression or genotype/haplotype on overall survival were observed.

Conclusion: Our findings indicate no relationship between BIRC5 genotypes and survivin expression or overall survival in mesothelioma patients. We observed that BIRC5 -241C > T polymorphism had a significant effect on patient age at diagnosis.

In plain English

This study examined archived tumour samples from 101 patients diagnosed with malignant pleural mesothelioma between 1996 and 2006 at a clinic in Golnik, Slovenia. The authors stained the tissue for survivin, a protein that helps cells avoid programmed cell death. They also tested tumour DNA from 96 patients for three variants in the promoter of the BIRC5 gene, which codes for survivin: -31G>C, -241C>T and -625G>C. The -31G>C test failed in one sample. Survivin was found in every sample. None of the variants was significantly linked to the share of tumour cell nuclei containing survivin. Neither the variants nor nuclear survivin expression was significantly linked to overall survival. Patients with the -241CC genotype were younger at diagnosis than carriers of at least one -241T allele (P = 0.028). Asbestos exposure was recorded in interviews at diagnosis and was not significantly related to survival. Epitheloid tumours and younger age were linked to longer survival. The authors concluded that BIRC5 genotypes showed no relationship with survivin expression or survival, and that the age finding needs further validation.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective genotype and protein-expression association study of archival tumour tissue, with univariate Cox survival analysis
• Who was studied: 101 patients diagnosed with malignant pleural mesothelioma between 1996 and 2006 at the University Clinic for Pulmonary and Allergic Diseases in Golnik, Slovenia (65 male, 36 female; median age at diagnosis 62 years). 96 entered the genotyping analysis, and the -31G>C test failed in one of these. Survival data were available for 98.
• Exposure: The main factors studied were three BIRC5 promoter variants and nuclear survivin expression. Asbestos exposure, determined in clinical interviews at diagnosis, was included in the survival analysis: occupational 50 (49.6%), environmental 7 (6.9%), sporadical 6 (5.9%), unexposed 31 (30.7%), undefined 7 (6.9%). No fiber types, products or doses are given.
• Main results:
  • Survivin was expressed in all analysed tumour samples. The median percentage of survivin-positive tumour cell nuclei was 67.3% (range 9.7 to 94.9%).
  • Genotyping succeeded in all samples except one, in which the -31G>C variant did not amplify.
  • None of the three BIRC5 promoter variants significantly influenced the percentage of survivin-positive nuclei. The -625GG genotype showed a borderline lower percentage compared with carriers of at least one -625C allele (P = 0.062).
  • Patients with the -241CC genotype were significantly younger at diagnosis (mean 61.0, SD 12.0 years) than carriers of at least one -241T allele (mean 65.7, SD 5.9 years).
  • In the haplotype analysis, the CCG haplotype (H3) showed a borderline association with a higher percentage of survivin-positive nuclei compared with the wild-type haplotype (P = 0.050). Carriers of the GTG haplotype (H4) were significantly older at diagnosis than wild-type haplotype carriers (P = 0.025).
  • The percentage of survivin-positive nuclei, as a continuous measure, was not significantly related to overall survival: HR 0.995 (95% CI 0.987 to 1.005; P = 0.295).
  • For patients with an above-median percentage of survivin-positive nuclei compared with below-median, the HR for overall survival was 1.402 (95% CI 0.934 to 2.104; P = 0.103). This was not significant.
  • None of the BIRC5 promoter genotypes had a significant effect on overall survival.
  • Asbestos exposure did not significantly affect overall survival. For example, the HR for professional (occupational) exposure compared with unexposed patients was 1.112 (95% CI 0.692 to 1.786; P = 0.660).
  • Compared with epitheloid mesothelioma, overall survival was shorter for biphasic (HR 3.054, 95% CI 1.841 to 5.140) and sarcomatoid (HR 4.647, 95% CI 2.216 to 9.745) types. Older age was also associated with shorter survival (HR 1.023 per year, 95% CI 1.004 to 1.043; P = 0.019).
• The authors' conclusion: The authors concluded that their findings indicate no relationship between BIRC5 genotypes and survivin expression or overall survival in mesothelioma patients. They found that the -241C>T variant may affect age at diagnosis, but stated that this effect, although statistically significant, needs further validation.
• Limitations the authors state:
  • The genotype frequencies for -241C>T did not follow Hardy-Weinberg equilibrium. The authors suggested this could reflect the patients' restricted geographic origin or loss of heterozygosity in tumour tissue.
  • No corrections for multiple testing were made, because the study was exploratory and the sample was small.
  • Data on patient performance status and tumour stage could not be obtained, so these were not included in the survival estimates.
  • Patients were not stratified by treatment, because no standard treatment protocol existed in Slovenia at the time.
  • Only nuclear survivin was analysed. Cytoplasmic survivin scoring was dropped because of large discrepancies between investigators.
  • Immunohistochemistry is considered a rather coarse method of measuring protein expression.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Mesothelioma.

Medical terms in this study, explained in our Lexicon: Pleural Mesothelioma, Apoptosis, Mesothelioma, Asbestos Exposure, Overall Survival.

Related studies

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• Low Merlin expression and high Survivin labeling index are indicators for poor prognosis in patients with malignant pleural mesothelioma — M. Meerang, K. Bérard, et al. (2016)
• Serum Survivin Levels and Outcome of Chemotherapy in Patients with Malignant Mesothelioma — K. Goričar, V. Kovač, et al. (2015)
• Methylation of MGMT in malignant pleural mesothelioma occurs in a subset of patients and is associated with the T allele of the rs16906252 MGMT promoter SNP — L.S. Kristensen, H.M. Nielsen, et al. (2011)
• Preclinical development of HIvax: Human survivin highly immunogenic vaccines — P.R. Hoffmann, M. Panigada, et al. (2015)
• Survivin is a negative prognostic factor in malignant pleural effusion — E. Arellano-Orden, B. Romero-Romero, et al. (2018)

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