Loss of Fragile Histidine Triad Gene Expression in Advanced Lung Cancer Is Consequent to Allelic Loss at 3p14 Locus and Promoter Methylation

Wali, Anjlina; Srinivasan, Radhika; Shabnam, Mir Snober; Majumdar, S.; Joshi, Kusum; Behera, Digambar

doi:10.1158/1541-7786.mcr-05-0070

Cited by 15 publications

(13 citation statements)

References 31 publications

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“…In lung squamous cell carcinomas and breast tumors, an association between methylation of FHIT promoter and protein expression was reported, confirming a previous study that showed a significant association between FHIT methylation status and loss of FHIT expression by Northern Blot and immunostaining in lung and breast cancer cell lines and primary tumors (10). In a small study of 30 locally advanced (stage III) lung carcinomas, no association was observed between FHIT LOH and loss of FHIT mRNA and protein expression, whereas methylation of the FHIT promoter correlated significantly with loss of FHIT expression at the transcript level (22).…”

Section: Discussionmentioning

confidence: 90%

Fragile Histidine Triad Gene Inactivation in Lung Cancer

Verri

Roz

Conte

et al. 2009

Am J Respir Crit Care Med

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Rationale: Fragile histidine triad (FHIT) is a tumor suppressor gene involved in the pathogenesis of lung cancer. Objectives: The purpose of this study was to investigate the different molecular alterations leading to the inactivation of FHIT gene function and to validate their use as biomarkers of risk for progression of the disease in patients belonging to the multicentric European study for the Early detection of Lung Cancer (EUELC) who were resected for early-stage lung tumors. Methods: FHIT immunostaining was performed on 305 tumor samples. The methylation status of FHIT promoter was assessed by nested methylation-specific polymerase chain reaction (MSP-PCR) in 232 tumor and 225 normal lung samples of which a subset of 187 patients had available normal/tumor DNA pairs. Loss of heterozygosity (LOH) at the FHIT locus was analyzed in 202 informative cases by D3S1300 and D3S1234 microsatellite markers. Measurements and Main Results: Lost or reduced FHIT expression was found in 36.7 and 75.7% of the tumor samples, respectively. Methylation of the FHIT promoter was found in 36.7% of tumor and 32.7% of normal lung samples, whereas LOH was detected in 61.9% of the tumors. A strong association with complete loss of FHIT expression was present when methylation and LOH were analyzed together (P 5 0.0064). Loss of FHIT protein expression was significantly more frequent in squamous cell carcinoma histotype (P , 0.0001) and in smokers (P 5 0.008). FHIT methylation in normal lung was associated with an increased risk of progressive disease (OR, 2.27; P 5 0.0415). Conclusions: Our results indicate that different molecular mechanisms interplay to inactivate FHIT expression and support the proposition that FHIT methylation in normal lung tissue could represent a prognostic marker for progressive disease.Keywords: lung cancer; FHIT gene; methylation; prognostic biomarker Lung cancer is one of the most common malignancies in the world and represents the leading cause of cancer-related deaths in industrialized countries. The overall 5-year survival rate for lung cancer is less then 15% largely due to the late stage at which most patients are diagnosed. Because survival of patients surgically resected for early-stage lung cancer is variable, the detection of additional prognostic parameters could be of importance to better predict the outcome of the disease and to offer the optimal therapeutic treatment to the patients.Fragile histidine triad (FHIT) is a tumor suppressor gene that spans the FRAB3B common fragile site at chromosome 3p14.2 and is frequently altered in lung cancer (1). Restoration of FHIT expression in cell lines lacking endogenous protein restrains tumor formation in vivo and in vitro through induction of apoptosis and inhibition of cell cycle progression (2). Homozygous deletions and loss of heterozygosity (LOH) at the FHIT locus have been frequently reported in lung cancer cell lines and primary tumors (3-7); aberrant FHIT mRNA transcripts have been detected in 40 to 80% of tumor samples (8), whereas mutations a...

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Section: Discussionmentioning

confidence: 90%

Fragile Histidine Triad Gene Inactivation in Lung Cancer

Verri

Roz

Conte

et al. 2009

Am J Respir Crit Care Med

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“…[37][38][39] Further studies have reported loss of Fhit not due to altered transcript but to promoter hypermethylation of the FHIT gene in breast, gallbladder and NSCL cancers. 36,[40][41][42] On the other hand, we recently showed that downregulation of Fhit protein recently showed that downregulation of Fhit protein levels in the presence of a normal mRNA can occur through Fhit protein posttranslational modification. 43 Our work began based on the observation that Fhit can be phosphorylated by Src on tyrosine 114.…”

Section: E S B I O S C I E N C E D O N O T D I S T R I B U T Ementioning

confidence: 99%

Fhit Expression Protects Against HER2-Driven Breast tumor Development: Unraveling the Molecular Interconnections

et al. 2007

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“…Large deletions within FHIT transcripts occur frequently in multiple malignancies [10]. Most of the deletions in FHIT gene involve loss of one or more coding exons and lead to absence or reduction of protein expression [10][11][12][13]. Loss of FHIT protein expression and abnormal FHIT transcripts have been found in a variety of human cancers and cancer cell lines, including those of lung, breast, stomach, kidney and head and neck [12,[14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

“…Most of the deletions in FHIT gene involve loss of one or more coding exons and lead to absence or reduction of protein expression [10][11][12][13]. Loss of FHIT protein expression and abnormal FHIT transcripts have been found in a variety of human cancers and cancer cell lines, including those of lung, breast, stomach, kidney and head and neck [12,[14][15][16][17][18]. Studies indicated that alteration of FHIT expression is an early and frequent event in lung cancer and correlates with disease advanced stage in breast cancer [10,15].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic value of the FHIT and p16 mRNA loss and the K-ras gene mutation in pleural fluids for malignant pleural effusion

Bao

Wang

et al. 2013

CBM

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Inactivation of the tumor suppressor genes and activation of oncogenes are involved in the development of cancer. The aim of this study was to evaluate the diagnostic value of the fragile histidine triad (FHIT) and p16 mRNA loss and the K-ras gene mutation in distinguishing malignant from benign pleural effusion. A total of 50 patients with malignant pleural effusion and 30 patients with benign pleural effusion were enrolled in this study. All pleural fluid specimens were evaluated in parallel by cytology, reverse transcriptase-PCR for the loss of FHIT and p16 mRNA, and PCR-SSCP (single-stranded conformation polymorphism) for the mutation of K-ras gene. The detection rates of FHIT and p16 mRNA loss were significantly higher in malignant than in benign pleural effusion (P < 0.001 and P = 0.001). The K-ras mutations were more frequent in malignant than benign pleural effusion (P = 0.006). The sensitivity and specificity were 58% and 93% for FHIT loss, 48% and 90% for p16 loss, and 44% and 87% for the K-ras mutation, respectively. In combined evaluation with both FHIT and p16 loss, the sensitivity was 68%, and specificity was 90%. The combination of the three molecular markers reached 74% sensitivity, whereas the combined use of the cytology and the three markers increased the diagnostic yield of the former by 38%. More than one third of cytology negative malignant pleural effusion could be identified by at least one of the three markers. These results suggest that the detection of FHIT and p16 mRNA loss and the k-ras gene mutation in pleural fluid could be helpful adjunct to cytology in the diagnosis of malignant pleural effusion.

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Loss of Fragile Histidine Triad Gene Expression in Advanced Lung Cancer Is Consequent to Allelic Loss at 3p14 Locus and Promoter Methylation

Cited by 15 publications

References 31 publications

Fragile Histidine Triad Gene Inactivation in Lung Cancer

Fragile Histidine Triad Gene Inactivation in Lung Cancer

Fhit Expression Protects Against HER2-Driven Breast tumor Development: Unraveling the Molecular Interconnections

Diagnostic value of the FHIT and p16 mRNA loss and the K-ras gene mutation in pleural fluids for malignant pleural effusion

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