To study the involvement of DNA mismatch repair genes in non-small cell lung cancer, matched normal and tumoral DNA samples from 31 patients were analyzed for both LOH and microsatellite instability with 34 markers at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32), and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found to be hemizygously deleted in 55% and 42% of the patients, respectively. Sixty five percent of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlap for 3p21 and 5q11-q13 deletions delimited by D3S1561/D3S1612 and D5S2107/ D5S624, respectively, were restricted to genetic distances of only 1 cM. Currently, the hMLH1 (3p21) and hMSH3 (5q11-q13) genes are the only known candidates located within these regions. The mutational analysis of hMLH1 and hMSH3 in hemizygously deleted patients led to the detection of 2 new polymorphisms in hMSH3. The consequence of these allelic losses remains unclear, but the lack of inactivating mutation might explain that replication error, the hallmark of mismatch repair genes inactivation in cancer cells, was quasiabsent in tumors. We suggest that hMLH1 and hMSH3 genes could be involved in lung tumorigenesis through dosage effect in cellular functions other than replication error correction. Int. J. Cancer 77:173-180, 1998. Wiley-Liss, Inc.Lung cancer is the leading cause of death from cancer worldwide with a survival rate as low as 10% despite intensive treatment. About 75% of all cases fall into the broad category of non-small cell lung cancer (NSCLC) which includes squamous cell carcinoma, adenocarcinoma and large cell carcinoma (Carney and de Leij, 1988). Lung carcinomas are characterized by multiple genetic alterations, which include the activation of oncogenes and the loss or inactivation of tumor suppressor genes (reviewed by Gazdar et al., 1994). Mutations in the p53 gene , as well as deletions at chromosome 3p (Chiba et al., 1990) appear to constitute the most common alterations involved in lung carcinogenesis. Frequent allelic losses affecting several chromosomal arms also strongly suggest the involvement of other yet unknown tumor suppressor genes (Petersen et al., 1997).Another type of genetic alteration, revealed as microsatellite instability in tumors (reviewed by Speicher, 1995), was reported in up to 45% of small cell lung cancers (Merlo et al., 1994) and in up to 66% of NSCLC (Pifarre et al., 1997). In hereditary nonpolyposis colon cancer (HNPCC) this type of genetic instability underlies defects in replication errors correction due to inactivation of mismatch repair genes (reviewed by Peltomäki and de la Chapelle, 1997). Does the deficiency in DNA repair contribute to lung carcinogenesis? Like suppressor genes, inactivation of mismatch repair genes appears to occur in two steps. The first mutational event is either somatic (sporadic cancer) or germinal (hereditary cancer) followed by somatic mutations of the second allele. This second step may be revealed as LOH,...

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SummaryTo study the involvement of DNA mismatch-repair genes in sporadic breast cancer, matched normal and tumoral DNA samples of 22 patients were analysed for genetic instability and loss of heterozygosity (LOH) with 42 microsatellites at or linked to hMLH1 (3p21), hMSH2 (2p16), hMSH3 (5q11-q13), hMSH6 (2p16), hPMS1 (2q32) and hPMS2 (7p22) loci. Chromosomal regions 3p21 and 5q11-q13 were found hemizygously deleted in 46% and 23% of patients respectively. Half of the patients deleted at hMLH1 were also deleted at hMSH3. The shortest regions of overlapping (SRO) deletions were delimited by markers D3S1298 and D3S1266 at 3p21 and by D5S647 and D5S418 at 5q11-q13. Currently, the genes hMLH1 (3p21) and hMSH3 (5q11-q13) are the only known candidates located within these regions. The consequence of these allelic losses is still unclear because none of the breast cancers examined displayed microsatellite instability, a hallmark of mismatch-repair defect during replication error correction. We suggest that hMLH1 and hMSH3 could be involved in breast tumorigenesis through cellular functions other than replication error correction.

Normal and tumor DNA samples of 35 patients with sporadic colorectal carcinoma were analyzed for microsatellite alterations at 12 markers linked to mismatch repair loci: hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2. Remarkably, no correlation was observed between the replication error phenotype (RER+) and allelic losses at these loci. Hemizygous deletions, seen in 6/35 (17%) informative cases at hMLH1, 4/27 (15%) at hMSH2/hMSH6 and 6/34 (18%) at hMSH3, were rarely found in RER+ tumors. Since mismatch repair protein components act in molecular complexes of defined stoichiometry we propose that hemizygous deletion of the corresponding loci may be involved in colorectal tumorigenesis through defects in cellular functions other than replication error correction. The analysis of the methylation status of the promoter region of hMLH1 revealed that methylation might be an important mechanism of this locus inactivation in RER+ sporadic colorectal cancer.