Genomewide loss of heterozygosity and its clinical associations in non small cell lung cancer

Abstract

We extensively allelotyped a panel of 71 microdissected primary surgically resected non small cell lung cancer (NSCLC) tumors to identify chromosomal regions that are likely to contain tumor suppressor genes (TSGs) or associated with clinicopathologic and prognostic effects. Loss of heterozygosity (LOH) was detected by genotyping of 177 microsatellite markers and correlation of LOH with clinicopathologic parameters and prognosis was analyzed. Twenty markers showed an LOH frequency greater than 48%, and 8 of them (2p23.3, 2p24.3, 2q35, 6p22.2, 7p14.3, 7p22.2, 17q24.3 and 21q22.3) were novel in NSCLC. The high LOH regions were confirmed by further aligning continuous LOH regions from another set of 24 NSCLC tissues and defining 7 minimal deletion regions ranging from 1.29 to 12.26 cM. The aberrations of 8 markers showed a significant correlation with alteration of p16 and Rb proteins, suggesting the gene(s) located in the chromosomal loss that may interact with p16/Rb pathway. In addition, markers specifically associated with smoking, histology types and tumor stages were identified and the linked candidate TSGs were suggested. For example, marker D1S1612 closely linked with Mig-6 gene was associated with smoking patients, squamous cell carcinoma patients and late-stage patients. Furthermore, 3 markers, D2S2968, D6S2439 and D7S1818, were significantly associated with poor prognosis of NSCLC patients using both univariate and multivariate Cox's regression analyses (p 5 0.035, 0.022 and 0.006, respectively). These markers can potentially be used for early lung cancer detection, outcome measurement and the positional cloning of new TSGs whose loss of function contributes to NSCLC tumorigenesis. ' 2005 Wiley-Liss, Inc.Key words: non small cell lung cancer; loss of heterozygosity; tumor suppressor gene; prognosis Lung cancer is one of the most common malignancies in the world and is the leading cause of cancer deaths in industrialized countries.1 A number of factors, such as tumor staging based on the results of physical and surgical examinations, are known to influence prognosis.2 However, patients with the same stage often show varied prognoses. Furthermore, lung cancer classification based primarily on morphologic appearance of the tumor has limitations, because cancer is characterized by genotypic and phenotypic changes that result in a tremendous variability in clinical behavior. Therefore, genotypic detection methods could be used to identify patients at risk for disease metastasis and potentially improve survival of lung cancer. In addition, identification and characterization of the genetic changes that drive lung cancer development can shed light on the molecular mechanism involved in lung tumorigenesis.Human cancers develop through multistep processes involving mutations in several types of genes, including the activation of dominant oncogenes and the inactivating of recessive tumor suppressor genes (TSGs) and genes involved in DNA repair or replication.3 One allele of TSGs may be inactivated by point mutat...

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Screening of microsatellite markers in penile cancer reveals differences between metastatic and nonmetastatic carcinomas

“…LOH in 6p22-23-detected in more than 30% of penile carcinoma in this study-has also been shown in cervix carcinoma, 20,24 nonsmall cell lung cancer 25 or ovarian cancer, 26 although no correlations to advanced stages or survival could be established. LOH in microsatellite loci D6S260 and D6S1267 is in this study frequently associated with occurrence of metastases and poor prognosis.…”

Genetic and epigenetic changes in lung carcinoma and their clinical implications

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