Original ArticleIs Alpha-B Crystallin an Independent Marker for Prognosis in Lung Cancer?
Introduction
Malignancies of the lung, particularly non-small cell lung cancer (NSCLC), remain the most common cause of death from cancer and have a ratio of mortality-to-incidence of 0.87 [1]. It has been suggested that the future of treatment of lung cancer lies in the greater prognostic specificity that can be afforded by molecular analysis based staging [2]. Molecular analysis may allow subtyping of patients with what have traditionally been thought of as low grade tumours, thus prompting more aggressive treatment in the first instance to prevent recurrence and nodal spread [3]. It is proposed that clinical practice will soon entail integration of molecular analysis with traditional clinical features as outlined in the TNM system. Additionally, our knowledge of the prognostic impact of additional clinical factors, in particular pre-morbid performance scores, age and gender [4], [5], continues to grow, allowing greater prognostic accuracy in conjunction with the current TNM system.
Alpha B-crystallin (CRYAB) is a molecule involved in a wide range of human epithelial malignancies. There is increasing understanding of the normal and pathological role this molecular chaperone and member of the small heat shock protein (sHSP) family plays. There appears to be oncogenic transformation associated up-regulation of CRYAB expression in certain tumours. Current data suggest that it may be a prognostic marker in breast, renal, thyroid, head and neck, nasopharyngeal, hepatocellular and potentially lung cancers. Further, there is now a solid understanding of the role of CRYAB as an anti-apoptotic molecule, accounting for its apparent oncogenicity.
At present, knowledge of specific molecular markers of prognosis in lung cancer is limited. We have explored the prognostic impact of CRYAB in a series of early stage NSCLC patients by investigating the role of CRYAB as a marker of recurrence (R) and mortality (M).
Section snippets
Patients
Between 2002 and 2006, 48 patients were treated by the multidisciplinary Lung Cancer Unit at Princess Alexandra Hospital in Brisbane, Australia. We excluded any patient with malignancies other than NSCLC. Histological or cytological diagnosis was available for all patients, with pertinent radiological findings from computed tomography.
We resected 50 NSCLC specimens from 48 patients. Patients underwent wedge resection, lobectomy or pneumonectomy following clinical staging. Following resection of
Methods
Following approval by our institutional Human Research and Ethics Committee, we used previously obtained specimens for immunohistochemical analysis. The required tissue blocks were retrieved and sections (5 μm) of formalin-fixed and paraffin-embedded tissues were dewaxed, and incubated with a rabbit anti-αB crystallin polyclonal antibody (Stressgen Biotechnologies, Ann Arbor, MI) at 1:250 dilution overnight at room temperature. Normal serum was used as a negative control and all slides were then
Statistics
Analyses were primarily descriptive in view of the limited number of patients, particularly the limited number of patients with positive staining. Chi-square or Fisher's exact tests were used to analyse differences between groups. Only univariate analyses were performed. Time to mortality and time to recurrence were performed as time-to-event analyses using the Kaplan–Meier method incorporating univariate Cox proportional hazards method to calculate the unadjusted hazard ratio associated with
Results
Based on previous histological assessment, there were known to be 32 adenocarcinomas and 18 squamous cell carcinomas (SCC). Synchronous tumours were found in three patients, one of whom had a synchronous metastatic cancer to the lung, which was not included in the study. Based on TNM staging, median tumour size was T2. Nodal deposits were detected in 10 (21%) patients. The median tumour grade was grade 2 (moderately differentiated).
From the 50 samples, 92% were T1 or T2 (17 T1, 29 T2).
Discussion
Our understanding of the molecular basis of tumourigenesis, the mechanism of action of anti-cancer drugs, and in particular, an appreciation for the impact of a variety of mutations commonly encountered in human cancers on treatment response has rapidly expanded in the last decade. There has been a corresponding increase in the cancer literature describing genetic, and protein based markers which have prognostic potential and are predictive of responses to specific agents. The further
Conclusion
It seems likely that CRYAB interacts with such redundancy with the machinery of cell death that the influence of its presence or absence may depend on other molecular characteristics of particular tumour cells. At present, attempts to identify over-expression of CRYAB as a potential prognostic marker are the main thrust of various studies, however the potential for these death-preventing proteins to become the targets of therapy remains to be demonstrated.
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