Significant frequency of allelic imbalance in 3p region covering RARβ and MLH1 loci seems to be essential in molecular non-small cell lung cancer diagnosis

Abstract

The aim of the study was to investigate the influence of allelic imbalance (AI) in several loci of tumor suppressor genes in 3p region on the non-small cell lung cancer (NSCLC) development. We evaluated the frequency of loss of heterozygosity and/or microsatellite imbalance (LOH/MSI) and assessed their association with patients’ characteristics (age, gender, tobacco addiction) and NSCLC classification according to TNM/AJCC staging. To analyze the potential role of AI involved in NSCLC pathogenesis, we allelotyped a group of 74 NSCLC patients using 7 microsatellite markers. The highest frequency of LOH/MSI, however, not statistically significant, was observed in RARβ and MLH1 (p = 0.104 and p = 0.216, respectively) loci. The association between high LOH/MSI frequency in 3p region with male gender (p = 0.041) as well as with age (especially >60 years) for RARβ and MLH1 genes (p = 0.0001 and p = 0.020, respectively) was documented. Statistically significant increased frequency of MLH1 allelic loss in squamous cell carcinoma (SCC) versus non-squamous cell carcinoma (non-SCC) was observed (p = 0.01). Significant increase in LOH/MSI frequency in 3p region (mainly in FHIT and MLH1loci) in correlation with cigarette addiction in a lifetime (≥40 years and ≥40 Pack Years) was also documented (p < 0.05). The highest LOH/MSI was revealed in RARβ locus in IA tumors (p = 0.0001), while the similarly high allelic loss of MLH1 correlated with III A/B tumors (p = 0.0002), according to AJCC staging. The obtained results demonstrate that AI is influenced by tobacco smoking and seems to be vital in the molecular diagnosis of NSCLC, especially of SCC subtype.

The clinicopathological significance of <em>hMLH1</em> hypermethylation in non-small-cell lung cancer: a meta-analysis and literature review

“…However, studies indicate that hMLH1 expression is under regulation by different methods. Homozygous deletions, allelic deletion, and point mutations have also been found to attenuate hMLH1 expression 44–46. Specifically, hMLH1 protein acting as a part of DNA repair pathways undergoes hypoxia regulation via epigenetic modulation as well as transcriptional and translational regulation 45…”

“…Antczak et al44 reported that reduced hMLH1 expression due to allelic imbalance combined with epigenetic alteration was more frequently associated with heavy smokers; however, a correlation could not be determined between hMLH1 methylation and the smoking characteristic (smoking history) of the individuals with NSCLC due to lack of quantitative data.…”

Identifying Genetic Variants for Addiction via Propensity Score Adjusted Generalized Kendall’s Tau

“…Very recently, FHIT has been documented to be in correlation with lifetime cigarette addiction (Antczak et al, 2013). This existing result, combined with our finding that FHIT is associated with alcohol dependence, partially supports the hypothesis that common genes underlie the comorbidity of multiple substance dependencies.…”

Alterations in Retinoic Acid Receptors in Non-Small Cell Lung Cancer and Their Clinical Implications

“…Multiple impaired expression of the RARs and RXRs can occur through genetic events such as epigeneticchanges, homozygous deletion, intragenic mutation, rearrangement of chromosomal material and loss of heterozygosity (LOH) followed by a second hit, which plays a major role in cancer initiation and progression [35].…”

“…The LOH has been identified as the initial event in lung carcinogenesis, and it is recognized in multiple chromosomal regions [35] [47] [48]. Frequently the 3p21 region contains a distinct locus that is sensitive to loss from the action of tobacco smoke carcinogens and has been reported as a biomarker in the genetic classification of pathological stages of NSCLC [48]- [50].…”