High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing tobacco-related human oral carcinoma in India

Saranath, Dhananjaya; Chang, Sidney E.; Bhoite, Leena T.; Panchal, Rekha G.; Kerr, I. B.; Mehta, A. R.; Johnson, N. W.; Deo, M. G.

doi:10.1038/bjc.1991.133

Cited by 221 publications

(132 citation statements)

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“…Previous studies have identified a number of genetic abnormalities in HNSCC, including nonrandom cytogenetic aberrations (Cowan et al, 1992;Heo et al, 1989), mutation or overexpression of the H-ras gene (Saranath et al, 1991) and p53 gene (Brennan et al, 1995;Field et al, 1992), and overexpression of epidermal growth factor receptor (Grandis et al, 1998a(Grandis et al, , 1998b. Inactivation of p16 gene (CDKN2), a G1 cyclindependent kinase inhibitor and DCC (deletion in colon cancer) gene, has also been reported (Reed et al, 1996).…”

Section: Discussionmentioning

confidence: 99%

“…In addition, despite the great emphasis on early detection and the efforts to improve multimodality treatment management, 5-year survival rate for HNSCC patients does not exceed 50% (Ries et al, 1990). The pressing epidemiologic problem and the lack of effective management for patients with HNSCC thus strengthen the need for more extensive research on HNSCC at the molecular and genetic levels.Previous studies have identified a number of genetic abnormalities in HNSCC, including nonrandom cytogenetic aberrations (Cowan et al, 1992;Heo et al, 1989), mutation or overexpression of the H-ras gene (Saranath et al, 1991) and p53 gene (Brennan et al, 1995;Field et al, 1992), and overexpression of epidermal growth factor receptor (Grandis et al, 1998a(Grandis et al, , 1998b. Inactivation of p16 gene (CDKN2), a G1 cyclindependent kinase inhibitor and DCC (deletion in colon cancer) gene, has also been reported (Reed et al, 1996).…”

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confidence: 99%

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Frequent Allelic Imbalance and Loss of Protein Expression of the DNA Repair Gene hOGG1 in Head and Neck Squamous Cell Carcinoma

Fan

Liu

Huang

et al. 2001

Laboratory Investigation

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SUMMARY:Reactive oxygen species produced by aerobic cellular metabolism or through exposure to environmental carcinogens can cause oxidative DNA damage by generating DNA base lesions and strand breakage. Prime among these base lesions is the conversion of guanine to 8-oxoguanine. Among 20 or so oxidative DNA base lesions, 8-oxoguanine is the most abundant and is critical in terms of mutagenesis because it is capable of mispairing with adenine, which, if not sufficiently repaired, may lead to G:C to T:A transversion upon DNA replication. The gene encoding human 8-oxoguanine DNA glycosylase 1 (hOGG1), capable of excision repair of 8-oxoguanine, has been recently cloned, characterized, and mapped to the short arm of chromosome 3 (3p25-26), a region showing frequent loss of heterozygosity (LOH) in head and neck squamous cell carcinoma (HNSCC). In the present study, we developed a tissue microdissection approach designed for use with formalin-fixed, paraffin-embedded specimens which is capable of detecting and characterizing the hOGG1 allelic loss using two highly informative, intragenic single nucleotide polymorphisms. Among 45 cases of HNSCC, 18 cases were informative. We analyzed these 18 cases and found that 11 showed evidence of hOGG1 allelic loss. By immunohistochemical staining on a total of 71 HNSCC cases using a commercially available anti-hOGG1 antibody, we showed that hOGG1 gene expression was markedly suppressed in up to 38% of the cases. The frequent allelic imbalance and suppression of the hOGG1 gene thus imply that repair for oxidative DNA damages may be relevant in future studies on head and neck squamous carcinogenesis. (Lab Invest 2001, 81:1429 -1438.H ead and neck tumors are a heterogeneous group of neoplasms that display a wide range of biologic behaviors. In the United States, excluding those from skin, central nervous system, eye, thyroid and lymph nodes, tumors of the head and neck account for 5% of the total cancer burden.Of all head and neck tumors, 80% to 90% are squamous cell carcinoma (SCC). The strong association with tobacco and alcohol use makes head and neck squamous cell carcinoma (HNSCC) one of the most preventable malignant diseases (Blot et al, 1988;Franceschi et al, 1990). Basic research on HNSCC has been largely neglected because of the tumor's rarity. However, there are approximately 50,000 new cases of HNSCC in the United States annually (Vokes et al, 1993) and the incidence is expected to climb as a result of the increasing number of female and adolescent smokers (Centers for Disease Control, 1990). In addition, despite the great emphasis on early detection and the efforts to improve multimodality treatment management, 5-year survival rate for HNSCC patients does not exceed 50% (Ries et al, 1990). The pressing epidemiologic problem and the lack of effective management for patients with HNSCC thus strengthen the need for more extensive research on HNSCC at the molecular and genetic levels.Previous studies have identified a number of genetic abnormalities in HNSCC, including no...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Frequent Allelic Imbalance and Loss of Protein Expression of the DNA Repair Gene hOGG1 in Head and Neck Squamous Cell Carcinoma

Fan

Liu

Huang

et al. 2001

Laboratory Investigation

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“…In the Western world, ras mutations in SCCHN are very rare (< 5%), whereas in India 35% of SCCHN patients harbour a mutation in H-ras, and this has been associated with tobacco chewing (Saranath et al, 1991). In Taiwan, 18% of oral cancer patients investigted were found to have a K-ras mutation, and these patients chew betel quid but do not use tobacco (Kuo et al, 1994).…”

Section: Redsmentioning

confidence: 99%

“…Loss of heterozygosity (LOH) of the H-ras locus has been reported in a number of carcinomas (Shiraishi et al, 1987;Garcia et al, 1989;Vachtenheim et al, 1994), including SCCHN (Howell et al, 1989;Sheng et al, 1990;Kiaris et al, 1994), and it has been proposed that the normal H-ras gene may possess tumour-suppressor as well as oncogene functions . Recently, we reported that genetic instability of a repetitive element which is located within intron 1 of H-ras is associated with the nodal status of patients with SCCHN (Saranath et al, 1991) and is most likely to be associated with the chewing of tobacco. Although ras mutations are considered to be rare events in the Western world (Field, 1992, for a review), overexpression of ras family genes has been reported by a number of investigators.…”

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confidence: 99%

Mutations, expression and genomic instability of the H-ras proto-oncogene in squamous cell carcinomas of the head and neck

Kiaris

Spandidos²,

Jones³

et al. 1995

Br J Cancer

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S_mimary Mutation and overexpression are the main activating mechanisms for the ras family of genes in human cancer and the variable tandem repeat (VTR) located at the 3' end of H-ras has been associated with this risk. In the present study, we have analysed the relative levels of expression of H-ras mRNA in 26 samples of squamous cell carcinomas of the head and neck (SCCHN) by competitive reverse transcription-polymerase chain reaction (competitive RT-PCR) and also investigated whether there is an association between ras expression and alterations in the 3'-VTR region. In addition, we have studied the incidence of point mutations in codon 12 of H-ras, codons 12 and 13 of K-ras and codon 61 of N-ras in 120 SCCHN samples. Our results indicate that only two samples carry mutations, both of which are located in codon 12 of K-ras, but that overexpression of the H-ras proto-oncogene is a frequent event in SCCHN [54% (14/26)] and is associated with a favourable prognosis: 3 of 14 patients with H-ras overexpression have died, whereas 9 of 12 patients with low levels of H-ras expression have died. We have also undertaken an analysis of these results together with our previous investigations on microsatellite instability and loss of heterozygosity in SCCHN, but no associations were found. We therefore conclude that ras mutations are an infrequent event in the progression of the SCCHN in the Western world, whereas overexpression of the H-ras proto-oncogene is a common event.

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“…Mutant ras is also found in high proportions of carcinogen-induced cancers including lung and bladder cancers (Mirvish, 1995). Although ras mutations have been reported in 35% of oral cancers in India and Southeast Asia where betel nut chewing and reverse smoking are prevalent, ras mutations in oral cancers are quite rare in patients in the Western Hemisphere (Clark et al, 1993;Saranath et al, 1991;Jordan and Daley, 1997). It is thus likely that activation of other ras-like proteins may play a role in oral carcinogenesis because SMGs are integral members of the growth factor signaling pathways (Bokoch, 1993).…”

Section: Introductionmentioning

confidence: 99%

Rap1A and rap1B ras-family proteins are prominently expressed in the nucleus of squamous carcinomas: nuclear translocation of GTP-bound active form

et al. 2003

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We recently showed that rap1 regulates growth and proliferation in normal keratinocytes, which provoked us to investigate its expression and regulation in malignant cells. Rap1 is variably expressed in whole cell lysates of squamous cell carcinoma (SCC) cell lines. Immunoblot analysis of nuclear and cytosolic fractions and immunohistochemistry revealed that in addition to cytoplasmic expression, SCC cells also exhibit prominent punctate rap1 expression in the nucleus. This unexpected nuclear distribution was confirmed by the evaluation of human oral cancer specimens by immunohistochemistry, which showed both nuclear and cytoplasmic localization. Cytoplasmic rap1 expression was observed mostly in large differentiated cells, whereas nuclear localization was found in morphologically less differentiated cells. Quantitative reverse transcriptase polymerase chain reaction and Northern blot analysis showed that both rap1A and rap1B are expressed in SCC cell lines although rap1B signals are more prominent. Transfection with enhanced GFP-tagged constitutively active and inactive forms of rap1B demonstrated that the active GTP-bound form translocates to the nucleus whereas inactive rap1B GDP is retained in the cytoplasm, much of which is in a perinuclear distribution. Furthermore, growth factors induce nuclear translocation of rap1 in oral cancer cells. This novel discovery that active, GTP-bound rap1 translocates to the nucleus makes it only the second of over 100 small GTP-binding proteins to be identified in the nucleus, and the striking prominence of rap1 expression in the nucleus of SCC cells suggests that activated rap1 plays a role in the malignant process.

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High frequency mutation in codons 12 and 61 of H-ras oncogene in chewing tobacco-related human oral carcinoma in India

Abstract: Summary 57 primary tumour samples from Indian oral cancer patients with a 5-15 year tobacco chewing habit, were examined for mutational activation in codons 12, 13 and 61 of the H-ras, K-

Cited by 221 publications

References 26 publications

Frequent Allelic Imbalance and Loss of Protein Expression of the DNA Repair Gene hOGG1 in Head and Neck Squamous Cell Carcinoma

Frequent Allelic Imbalance and Loss of Protein Expression of the DNA Repair Gene hOGG1 in Head and Neck Squamous Cell Carcinoma

Mutations, expression and genomic instability of the H-ras proto-oncogene in squamous cell carcinomas of the head and neck

Rap1A and rap1B ras-family proteins are prominently expressed in the nucleus of squamous carcinomas: nuclear translocation of GTP-bound active form

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