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BCL2L12: a multiply spliced gene with independent prognostic significance in breast cancer

  • Athina Kladi-Skandali , Diamantis C. Sideris and Andreas Scorilas ORCID logo EMAIL logo
Published/Copyright: October 16, 2018
Clinical Chemistry and Laboratory Medicine (CCLM)
From the journal Clinical Chemistry and Laboratory Medicine (CCLM) Volume 57 Issue 2

Abstract

Background

Alternative splicing is a key process in carcinogenesis and, from a clinical aspect, holds great promises, as alternatively spliced variants have emerged as an untapped source of diagnostic and prognostic markers. Our aim was to assess the prognostic value of three recently recognized splice variants of the apoptosis-related gene, BCL2L12, in breast cancer (BC).

Methods

Total RNA was extracted from breast samples (150 BC and 80 tumor-adjacent normal tissues) and, following cDNA synthesis, a variant-specific qPCR was performed for the expressional quantification of BCL2L12 v.1, v.2 and v.4 transcript variants. Extensive statistical analysis, including bootstrap resampling and internal validation, was conducted in order to evaluate the associations of v.1, v.2 and v.4 expression with patients’ clinopathological and survival data.

Results

All examined BCL2L12 variants were significantly upregulated in BC specimens compared to their non-cancerous counterpart (v.1, p<0.001; v.2, p=0.009; v.4, p=0.004). Increased BCL2L12 v.4 mRNA expression was associated with markers of unfavorable prognosis namely, advanced tumor grade (p=0.002), ER- (p=0.015)/PR- (p<0.001) negativity, Ki-67-positivity (p=0.007) and high NPI (Nottingham prognostic index) score (p=0.033). Moreover, v.4 was significantly overexpressed in women with triple negative BC (TNBC) and HER2-positive tumors compared to those harboring luminal tumors (p<0.001). Survival analysis disclosed that BCL2L12 v.2 overexpression, as a continuous variable ([HR]=0.45, 95% CI=0.17–0.82, p=0.010), is a strong and independent marker of favorable prognosis for BC patients. Interestingly, v.2 retains its prognostic value in patients with Grade II/III ([HR]=0.21, 95% CI=0.05–0.57, p=0.006) or HER2-positive/TNBC tumors ([HR]=0.25, 95% CI=0.05–0.74, p=0.042).

Conclusions

BCL2L12 v.1, v.2, v.4 are aberrantly expressed in BC. Their expressional analysis by cost-effective molecular methods could provide a novel molecular tool for BC management.

Keywords: apoptosis; BCL-2 family; breast cancer; breast cancer prognosis; molecular tumor markers
Corresponding author: Dr. Andreas Scorilas, Department of Biochemistry and Molecular Biology, Faculty of Biology, National and Kapodistrian, University of Athens, 15701 Panepistimiopolis, Athens, Greece, Phone: +30-210-727-4306, Fax: +30-210-727-4158

Acknowledgments

We thank Prof. A. Ardavanis (First Department of Oncology, “St. Savvas” Anticancer Hospital, Athens, Greece) for kindly providing breast tissue samples along with detailed patient characteristics, tumor clinical and histopathological features and for his thorough revision of our manuscript.

  1. Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

  2. Research funding: None declared.

  3. Employment or leadership: None declared.

  4. Honorarium: None declared.

  5. Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.

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Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/cclm-2018-0272).

Received: 2018-03-14
Accepted: 2018-09-06
Published Online: 2018-10-16
Published in Print: 2018-12-19

©2019 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2018-0272
Keywords for this article
apoptosis; BCL-2 family; breast cancer; breast cancer prognosis; molecular tumor markers

Articles in the same Issue

  1. Frontmatter
  2. Obituary
  3. Jillian Russyll (AKA Jill) Tate
  4. Editorial
  5. The long way to standardization of practices: HbA1c as archetypal example
  6. Reviews
  7. Secretory tumors of the pituitary gland: a clinical biochemistry perspective
  8. Thalassemia in the laboratory: pearls, pitfalls, and promises
  9. Opinion Paper
  10. Diagnostic biomarkers of muscle injury and exertional rhabdomyolysis
  11. General Clinical Chemistry and Laboratory Medicine
  12. Patient’s knowledge and awareness about the effect of the over-the-counter (OTC) drugs and dietary supplements on laboratory test results: a survey in 18 European countries
  13. National surveys on 15 quality indicators for the total testing process in clinical laboratories of China from 2015 to 2017
  14. Urinary albumin strip assay as a screening test to replace quantitative technology in certain conditions
  15. Cerebrospinal fluid free kappa light chains and kappa index perform equal to oligoclonal bands in the diagnosis of multiple sclerosis
  16. Different immunoreactivity of monomers and dimers makes automated free light chains assays not equivalent
  17. The utility of saliva testing in the estimation of uremic toxin levels in serum
  18. Determination of cannabinoids in oral fluid and urine of “light cannabis” consumers: a pilot study
  19. Moving from the second to the third generation Roche PTH assays: what are the consequences for clinical practice?
  20. Baseline hepcidin measurement in the differential diagnosis of anaemia for elderly patients and its correlation with the increment of transferrin saturation following an oral iron absorption test
  21. Reference Values and Biological Variations
  22. A multicenter study for the evaluation of the reference interval for TSH in Italy (ELAS TSH Italian Study)
  23. Cancer Diagnostics
  24. Urinary measurement of circulating tumor DNA for treatment monitoring and prognosis of metastatic colorectal cancer patients
  25. BCL2L12: a multiply spliced gene with independent prognostic significance in breast cancer
  26. Diabetes
  27. The global impact of the International Federation of Clinical Chemistry and Laboratory Medicine, Education and Management Division: engaging stakeholders and assessing HbA1c quality in a multicentre study across China
  28. The frequency of testing for glycated haemoglobin, HbA1c, is linked to the probability of achieving target levels in patients with suboptimally controlled diabetes mellitus
  29. Letters to the Editor
  30. Response to article by Caponi et al. about serum free light chains
  31. Response to Letter to the Editor about immunochemical measurement of urine free light chains
  32. Estimated GFR-specific 99th percentiles for high-sensitive cardiac troponin T based on the adjusted analytical change limit (adjACL) in hospitalized patients
  33. Perioperative heart-type fatty acid binding protein concentration cutoffs for the identification of severe acute kidney injury in patients undergoing cardiac surgery
  34. A peculiar reaction curve with dual spikes in absorbance during a total bilirubin assay in spite of accurate results induced by high M-protein concentration
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  36. A single-center performance evaluation of the fully automated iFlash anti-Müllerian hormone immunoassay
  37. Genetic polymorphisms and variants in the LDL receptor associated with familial hypercholesterolemia: cascade screening and identification of the variants 666C>A, 862G>A, 901G>A, and 919G>A of a Brazilian family
  38. Undetected paraganglioma by functional imaging techniques: case report
  39. A particular case of AML patient with the polymorphism G105G (rs11554137) and the missense mutation R132C in IDH1 gene
  40. Atypical “hairy cell-like” presentation of leukemic mantle cell lymphoma
  41. Evaluation of a rapid centrifugation step (4500 g for 2 min) in coagulation assays to monitor direct oral anticoagulants
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