hMLH1 and hMSH2 expression correlates with allelic imbalance on chromosome 3p in non-small cell lung carcinomas.

DNA mismatch repair genes have been implicated in the pathogenesis and predisposition of certain malignancies through a mutator phenotype. In this study, we investigated, in 150 non-small cell lung carcinomas, the expression levels of hMLH1 and hMSH2 proteins in relation to loss of heterozygosity on chromosomes 3p and 2p, the mutational status of these genes' promoters and the hot spot exons. We have demonstrated that 88 of 150 (58.6%) tumor specimens had reduced expression levels of the hMLH1 protein, whereas 85 of 147 (57.8%) specimens had reduced expression levels of the hMSH2 protein. Reduced expression levels of both proteins were observed in 51 of 150 (34%) specimens. In adenocarcinomas, the reduction of hMSH2 expression was more frequently observed than that of hMLH1 (P<0.003), whereas in squamous cell carcinoma of the lung hMLH1 expression was more frequently reduced than hMSH2 (P<0.006). Reduced expression of hMLH1correlated with allelic imbalance on loci D3S1289 (P<0.0002) and D2S391 (P<0.05). It is of note that an inverse correlation was found between hMSH2 reduced expression and loss of heterozygosity at locus D3S1300 (P = 0.016). In addition, hMLH1 reduced expression was more frequently associated with heavy smokers, assessed by daily tobacco uptake (P = 0.018) and total smoking exposure (pack-years; P<0.05). In addition, a correlation between hMLH1 reduced expression and nodal metastasis in squamous cell carcinoma of the lung was observed (P = 0.015). No mutations were identified in the promoters or exons examined in these two genes. These findings indicate that hMLH1 and hMSH2 gene inactivation is a common event in the development of non-small cell lung carcinoma and allelic loss seems to be a major genetic event involved in hMLH1 silencing. In addition, we propose that a putative negative regulator of hMSH2 gene may be located at the locus 3p14.

[1]  F. Guadagni,et al.  Unbalanced germ-line expression of hMLH1 and hMSH2 alleles in hereditary nonpolyposis colorectal cancer. , 1999, Cancer research.

[2]  N. Russell,et al.  Microsatellite instability and p53 mutations are associated with abnormal expression of the MSH2 gene in adult acute leukemia. , 1999, Blood.

[3]  A. Thorburn,et al.  Apoptosis induced by overexpression of hMSH2 or hMLH1. , 1999, Cancer research.

[4]  J. Palazzo,et al.  MLH1 promoter methylation and gene silencing is the primary cause of microsatellite instability in sporadic endometrial cancers. , 1999, Human molecular genetics.

[5]  E. Gabrielson,et al.  Absence of intragenic mismatch mutations in small cell lung cancers with microsatellite instability , 1999, International journal of cancer.

[6]  J. Herman,et al.  Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. , 1999, Cancer research.

[7]  D. Labuda,et al.  Frequent loss of heterozygosity at the DNA mismatch-repair loci hMLH1 and hMSH3 in sporadic breast cancer , 1999, British Journal of Cancer.

[8]  Y. Yatabe,et al.  Frameshift mutations in TGFbetaRII, IGFIIR, BAX, hMSH3 and hMSH6 are absent in lung cancers. , 1999, Carcinogenesis.

[9]  Manel Esteller,et al.  MLH1 promoter hypermethylation is associated with the microsatellite instability phenotype in sporadic endometrial carcinomas , 1998, Oncogene.

[10]  D. Labuda,et al.  Allelic losses and DNA methylation at DNA mismatch repair loci in sporadic colorectal cancer. , 1998, Carcinogenesis.

[11]  J. Minna,et al.  Progress in understanding the molecular pathogenesis of human lung cancer. , 1998, Biochimica et biophysica acta.

[12]  S N Thibodeau,et al.  Hypermethylation of the hMLH1 promoter in colon cancer with microsatellite instability. , 1998, Cancer research.

[13]  D. Labuda,et al.  High resolution deletion mapping reveals frequent allelic losses at the DNA mismatch repair loci hMLH1 and hMSH3 in non‐small cell lung cancer , 1998, International journal of cancer.

[14]  Sajeev P. Cherian,et al.  Microsatellite instability and loss of heterozygosity at DNA mismatch repair gene loci occurs during hepatic carcinogenesis , 1998, Hepatology.

[15]  J. Herman,et al.  Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[16]  B. Levin,et al.  Reduced expression of mismatch repair genes in colorectal cancer patients in Egypt. , 1998, International journal of oncology.

[17]  A. Kristjuhan,et al.  Oligomerization of p53 is necessary to inhibit its transcriptional transactivation property at high protein concentration , 1998, Oncogene.

[18]  M. Spitz,et al.  Reduced expression of hMLH1 and hGTBP/hMSH6: a risk factor for head and neck cancer. , 1998, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[19]  Y. Bang,et al.  Mutational analysis of the hMSH2 gene in a wide variety of tumors. , 1997, International Journal of Oncology.

[20]  J. Bruner,et al.  Reduced expression of mismatch repair genes measured by multiplex reverse transcription-polymerase chain reaction in human gliomas. , 1997, Cancer research.

[21]  D. Spandidos,et al.  p53 gene aberrations in non-small-cell lung carcinomas from a smoking population. , 1997, British Journal of Cancer.

[22]  M. Loda,et al.  Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. , 1997, Cancer research.

[23]  S. Thibodeau,et al.  Altered expression of hMSH2 and hMLH1 in tumors with microsatellite instability and genetic alterations in mismatch repair genes. , 1996, Cancer research.

[24]  T. Liloglou,et al.  Allelotype of non-small cell lung cancer. , 1996, International Journal of Oncology.

[25]  R. Kolodner,et al.  Biochemistry and genetics of eukaryotic mismatch repair. , 1996, Genes & development.

[26]  S. Dooley,et al.  Specific in vitro binding of p53 to the promoter region of the human mismatch repair gene hMSH2. , 1996, Biochemical and biophysical research communications.

[27]  M. S. Rhyu.  Molecular mechanisms underlying hereditary nonpolyposis colorectal carcinoma. , 1996, Journal of the National Cancer Institute.

[28]  A. Cats,et al.  Majority of hMLH1 mutations responsible for hereditary nonpolyposis colorectal cancer cluster at the exonic region 15-16. , 1996, American journal of human genetics.

[29]  G. Ellison,et al.  Detection of k-ras mutations in nonsmall cell lung-carcinoma. , 1995, International journal of oncology.

[30]  J. Field,et al.  Loss of heterozygosity at 9p23 defines a novel locus in non-small cell lung cancer. , 1995, Oncogene.

[31]  Y. Nakamura,et al.  Allelotype of non-small cell lung carcinoma--comparison between loss of heterozygosity in squamous cell carcinoma and adenocarcinoma. , 1992, Cancer research.

[32]  P. Maloney,et al.  Sensitivity and limitations of high throughput fluorescent microsatellite analysis for the detection of allelic imbalance: application in lung tumors. , 2000, International journal of oncology.

[33]  L. Loeb,et al.  Cancer cells exhibit a mutator phenotype. , 1998, Advances in cancer research.

[34]  K. Shin,et al.  Absence or decreased levels of the hMLH1 protein in human gastric carcinoma cell lines: implication of hMLH1 in alkylation tolerance , 1998, Journal of Cancer Research and Clinical Oncology.

[35]  T. Liloglou,et al.  Molecular Pathological Mechanisms in NSCLC and the Assessment of Individuals with a High Risk of Developing Lung Cancer , 1998 .

[36]  A. de la Chapelle,et al.  Mutations predisposing to hereditary nonpolyposis colorectal cancer. , 1997, Advances in cancer research.

[37]  Peter Beighton,et al.  de la Chapelle, A. , 1997 .

[38]  I. Wieland,et al.  Microsatellite instability and loss of heterozygosity at the hMLH1 locus on chromosome 3p21 occur in a subset of nonsmall cell lung carcinomas. , 1996, Oncology Research.