Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck

Kisielewski, Anne; Xiao, Guang-Hui; Liu, S C; Klein‐Szanto, Andres J.; Novara, Maria Eugenia; Sina, Joseph F.; Bleicher, Kimberly B.; Yeung, Raymond S.; Goodrow, Tamra

doi:10.1038/sj.onc.1201910

Cited by 31 publications

(29 citation statements)

References 14 publications

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“…Our findings on 3p are consistent with those of previous studies. Based on discrete regions of deletion on the 3p arm in a variety of human cancers, several candidate TSGs were suggested, including VHL, FHIT, RASSF1, and H37 (Dammann et al, 2000;Kisielewski et al, 1998;Latif et al, 1993;Oh et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas

Beder

Gündüz

Ouchida

et al. 2003

Laboratory Investigation

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SUMMARY:Head and neck squamous cell carcinoma (HNSCC) is a frequent malignancy with a poor survival rate. Identifying the tumor suppressor gene (TSG) loci by genomic studies is an important step to uncover the molecular mechanisms involved in HNSCC pathogenesis. We therefore performed comprehensive analyses on loss of heterozygosity (LOH) using a genome-wide panel of 191 microsatellite markers in 22 HNSCC samples. We found 53 markers with significantly high LOH (Ͼ30%) on 21 chromosomal arms; the highest values of those were observed on 3p, 9p, 13q, 15q, and 17p, corresponding to D3S2432 (67%), D9S921-D9S925 (67%) and GATA62F03 (86%), D13S1493 (60%), D15S211 (62%), and D17S1353 (88%), respectively. Fifteen hot spots of LOH were defined in 13 chromosomal arms: 2q22-23, 4p15.2, 4q24-25, 5q31, 8p23, 9p23-24, 9q31.3, 9q34.2, 10q21, 11q21-22.3, 14q11-13, 14q22.3, 17p13, 18q11, and 19q12 as loci reported previously in HNSCCs. Furthermore, we identified five novel hot spots of LOH on three chromosomal arms in HNSCC at 2q33 (D2S1384), 2q37 (D2S125), 8q12-13 (D8S1136), 8q24 (D8S1128), and 15q21 (D15S211). In conclusion, our comprehensive allelotype analyses have unveiled and confirmed a total of 20 possible TSG loci that could be involved in the development of HNSCC. These results provide useful clues for identification of putative TSGs involved in HNSCC by fine mapping of the suspected regions and subsequent analysis for functional genes. (Lab Invest 2003, 83:99 -105). Head and neck squamous cell carcinomas (HNSCCs) are a diverse group of cancers and are frequently aggressive in their biologic behavior. They account for 1% to 2% of all cancer deaths in both the United States and Japan. Most patients with this malignancy have advanced disease at presentation, with regional disease in 43% and distant metastases in 10% (Pfister et al, 1997). The overall survival rate for this disease group remains poor, largely because of the high incidence of recurrent disease at the primary site or in the regional lymph nodes. Patients presenting with HNSCC also demonstrate a high incidence of second primary tumors in the upper aerodigestive tract, which may be synchronous or metachronous.In neoplastic progression, most of the sporadic solid tumors result from a multistep process of accumulated genetic and epigenetic alterations (Renan, 1993). Among these changes, inactivation of the tumor suppressor genes (TSGs) is one of the most critical steps. In this process, the deletion of targeted chromosomal regions eliminates the one allele, while inactivating events (mutation, deletion, or promoter hypermethylation) affect the other allele of the concerning TSG (Knudson, 1971). The detection of frequent loss of heterozygosity (LOH) in a chromosomal locus is considered to be critical evidence for the localization of a TSG. Large-scale genomic studies identified the chromosomal locations of several different human TSGs. A substantial number of TSGs involved in the genesis of several cancer types, including HNSCCs, have already been discovered. ...

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Section: Discussionmentioning

confidence: 99%

Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas

Beder

Gündüz

Ouchida

et al. 2003

Laboratory Investigation

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“…Indeed p16 on 9p21 and TP53 on 17p21 demonstrated either promoter hypermethylation or mutations as a second hit of inactivation (Cabelguenne et al, 2000;ElNaggar et al, 1997). Concerning chromosome 3p, several genes have been suspected and studied as TGFbRII (Garrigue-Antar et al, 1995), OGG1 (Blons et al, 1999b), and FHIT (Kisielewski et al, 1998;Mao et al, 1996) but their roles are still not ascertained. TSG implicated in HNSCC carcinogenesis and located on chromosomes 8p and 18q remain to be identified.…”

Section: Introductionmentioning

confidence: 99%

Delineation and candidate gene mutation screening of the 18q22 minimal region of deletion in head and neck squamous cell carcinoma

et al. 2002

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The 18q chromosome arm is frequently lost in advanced head and neck squamous cell carcinoma. Twenty-four microsatellite markers located on chromosome 18q were genotyped in 145 primary tumors and 10 cell lines in order to identify putative tumor suppressor genes implicated in tumor progression. Two different minimal common regions of loss (MCRL) were identified at 18q22 and 18q23 respectively. To refine and delineate boundaries of an homozygous deletion found in one cell line, 44 extra markers located at 18q22 were analysed and the homozygous deletion was precisely defined within a critical region of 4.9 Mb. Four known genes (CDH7, CDH19, DNAM-1, FLJ23594) located in this critical region and two EST clusters (Hs.96900, Hs.98628) were selected for further investigations. For these six genes, genomic structures were established, somatic mutations were screened in 20 HNSCC and 10 cell lines and transcription levels were determined in eight cell lines. No somatic mutations were found in any of the candidate genes analysed (57 coding exons). However, differential transcription levels were observed for CDH19 and Hs.96900 in head and neck cancer cell lines supporting their putative involvement through down regulation mechanisms in head and neck cancer progression.

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“…We also do not know if the overexpression of FHIT seen in our study reflects wild type or a splice variant mRNA. Kisielewski et al 19 have reported expression of a putative truncated FHIT protein in 3/9 cell lines by Western blot and also found overexpression of a truncated FHIT protein in a primary carcinoma.…”

Section: Discussionmentioning

confidence: 99%

FHIT mRNA and protein expression in hepatocellular carcinoma

et al. 2004

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Loss of fragile histidine triad (FHIT) gene expression is seen in approximately 50% of hepatocellular carcinomas in China. However, little information is available on FHIT expression in hepatocellular carcinoma in the United States, where carcinogen exposure is generally lower. Investigations of FHIT mRNA in hepatocellular neoplasms and paired non-neoplastic tissues demonstrated normal-sized FHIT transcripts in all non-neoplastic tissues and in all neoplasms including 11 hepatocellular carcinomas, two fibrolamellar carcinomas, and four benign proliferative lesions. In addition, all but one malignant and all benign neoplasms showed aberrant smaller transcripts. The smaller aberrant transcripts were overexpressed in 6/11 hepatocellular carcinomas and 1/2 fibrolamellar carcinomas. An additional 79 hepatocellular carcinomas, 12 fibrolamellar carcinomas and 15 hepatic adenomas were examined for FHIT expression by immunohistochemistry. No loss of immunostaining was seen in 67/79 (85%) of hepatocellular carcinomas, while a moderate or marked decrease was seen in 12/79 (15%). Fibrolamellar carcinomas and hepatic adenomas showed no loss of FHIT expression. In conclusion, hepatocellular carcinomas retained expression of normal FHIT mRNA transcripts, but also showed universal expression of smaller sized aberrant transcripts and commonly overexpressed these aberrant transcripts. Loss of FHIT protein expression is relatively uncommon in this cohort from the United States, where exposure to hepatic carcinogens is generally low.

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Analysis of the FHIT gene and its product in squamous cell carcinomas of the head and neck

Cited by 31 publications

References 14 publications

Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas

Genome-Wide Analyses on Loss of Heterozygosity in Head and Neck Squamous Cell Carcinomas

Delineation and candidate gene mutation screening of the 18q22 minimal region of deletion in head and neck squamous cell carcinoma

FHIT mRNA and protein expression in hepatocellular carcinoma

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