Localization of chromosome 8p regions involved in early tumorigenesis of oral and laryngeal squamous carcinoma

We analysed 30 primary invasive oral and laryngeal squamous carcinomas (SC), with concurrent dysplastic lesions, for genetic alterations at 15 microsatellite loci on the short arm of chromosome 8. Overall, loss of heterozygosity (LOH) was observed, in at least one informative locus, in 27% of the dysplastic lesions and in 67% of the invasive carcinomas. The highest frequency of allele losses in dysplasia (20% and 17%), and invasive carcinoma (40% and 48%) were detected in the same D8S298 and LPL-tet loci located on chromosomes 8p21 and 8p22 respectively. The minimal region with LOH was limited to 4.6 megaBases (mBs) at 8p22 and 7.1 mBs at 8p21. In addition, allelic losses in both dysplastic and corresponding invasive specimens were noted at the same loci in some tumors suggesting their emergence from a common preneoplastic clone. Allele losses correlated significantly with male gender, oral and laryngeal sites and high proliferative index. The data suggest that inactivation of tumor suppressor gene(s), within these loci, may constitute an early event in the evolution of oral and laryngeal SC.     

Detection of loss of heterozygosityat microsatellite loci in esophageal squamous-cell carcinoma

Microsatellite alterations at 3 genetic loci (chromosomes 2p, 3p and 17p) were analyzed in 25 tumors (20 primary tumors and 5 metastatic lymph nodes) from 20 patients after surgical treatment for esophageal cancer. DNA samples from tumors were compared with control DNA from lymphocytes obtained from the peripheral blood of the individual patients. Microsatellite alterations [microsatellite instability (MSI) and loss of heterozygosity (LOH)] were detected in 15% of 20 primary tumors with marker D2S123 (chromosome 2p), 55% with marker D3S1067 (chromosome 3p) and 50% with marker TP53 (chromosome 17p). The 3-year disease-free survival rate of the 10 patients who had tumors without alterations or with an alteration at only 1 of 3 microsatellite loci was 75% and it was better than that of the 10 patients who had tumors with alterations at 2 or 3 microsatellite loci (48%, p = 0.049). This finding suggests that esophageal cancer with alterations at multiple microsatellite loci might have strong malignant potential. However, MSI was only detected in one of 20 patients, which suggests that MSI might not play an important role in the development of this cancer. Three of 5 metastatic lymph nodes showed no LOH even though primary tumors of these patients exhibited LOH with 1 or 2 markers, and 1 metastatic lymph node had LOH that was detected with D3S1067 even though the primary tumor of this patient had no LOH with all markers. Thus, clonal heterogeneity might exist in esophageal squamous-cell carcinomas.     

Respiratory symptoms and spirometry in experienced coal miners: effects of both distant and recent coal mine dust exposures

Loss of heterozygosity (LOH) on 3p is frequent in human renal cell carcinomas, lung cancers, and breast cancers. To define the region(s) on 3p that harbor presumptive tumor suppressor gene(s) for breast cancer, we examined 196 primary breast tumors for their patterns of LOH at 22 microsatellite marker loci distributed along this chromosome arm. Allelic loss at one or more loci was observed in 101 (52%) of these tumors. Detailed deletion mapping identified two distinct commonly deleted regions; one was localized to a 2-cM interval flanked by D3S1547 and D3S1295 at 3p14.3-21.1, and the other to a 5-cM interval flanked by D3S1286 and D3S1585 at 3p24.3-25.1. The FHIT gene lies in the vicinity of the proximal commonly deleted region. Attempts to correlate LOH on 3p to clinicopathological parameters detected an association with the absence of the progesterone receptor (P = 0.0096). The results suggest that inactivation of unidentified tumor suppressor genes on 3p plays a role in the mechanism whereby hormone dependency is lost in the course of breast carcinogenesis.     

Frequent allelic losses on chromosome 13q in human male breast carcinomas

Loss of genetic material on chromosomes 13q and 17 has been suggested to be of importance in the initiation and progression of female breast cancer, but their involvement is less well illustrated in male breast carcinomas. The present study was designed to investigate the incidence of allelic loss and microsatellite instability for chromosomes 13q, 17p and 17q in 13 sporadic male breast carcinomas using matched normal-tumour DNA samples and seven polymorphic microsatellite markers. Genetic imbalance was found in one or more informative markers in 85% of the patients, with more frequent loss of heterozygosity and microsatellite instability at loci on chromosome 13q. Thus, a high incidence of allelic losses was observed at the retinoblastoma gene (4/6) and likewise at the D13S263 locus (7/12), which also exhibited the highest frequency of microsatellite instability. The intragenic microsatellite in intron 1 of the TP53 gene on chromosome 17p revealed loss of heterozygosity in 3 of 8 informative patients. The investigated proximal region of chromosome 13q is postulated to harbour several potential tumour suppressor genes associated with female breast cancer. The high incidence of allelic losses at the D13S263 microsatellite, located distal to both the BRCA2 and the Brush-1 loci but proximal to the retinoblastoma gene, possibly indicates the presence of an additional tumour suppressor gene which may be involved in male breast carcinomas. However, this hypothesis needs verification in an extended study of male breast carcinomas.     

Haemodynamic changes in patients undergoing high-risk PTCA under protection of transfemoral heart- lung machine support with centrifugal pumps

Deletions, mutations and the functional inactivation of tumor suppressor gene p16 are involved in the genesis of different neoplasias. Little is known about the role of p16 gene alterations in the genesis of gastric carcinomas. This study aimed to detect genetic alterations of the p16 gene in gastric carcinomas. We analyzed p16 gene mutations and the frequency of loss of heterozygosity (LOH) at the p16 locus in 43 gastric carcinomas. PCR-SSCP analysis of exons 1 and 2 revealed only one gene mutation in a carcinoma of the diffuse type. Besides carcinomas of the diffuse, intestinal and the mixed type, we also investigated a small-cell primary gastric carcinoma, which was the only one to show a deletion in the p16 gene. LOH analysis was performed using two polymorphic markers located near the p16 gene (D9S171, D9S162) and a sequence-tagged-site marker (c5.1). Allelic loss was noted in two carcinomas of the diffuse type and in one carcinoma of the intestinal type. Allelic instabilities were found in one tumor of the intestinal type and diffuse type each. Although only five of 43 (11.6%) gastric carcinomas had p16 alterations, tumors of the diffuse type tend to show a higher number of genetic alterations near the p16 locus.     

Loss of heterozygosity at chromosome 6q in preinvasive and early invasive breast carcinomas

We have used polymerase chain reaction (PCR) analysis to study the incidence of allelic imbalance at four polymorphic microsatellite markers on chromosome 6q25.1-27, three dinucleotide repeats and one trinucleotide repeat, for microdissected tumour foci from a group of 75 'early' breast carcinomas. The tumours comprised 16 preinvasive cases of ductal carcinoma in situ (DCIS) and 59 mammographically detected early invasive carcinomas. Loss of heterozygosity (LOH) was detected at all four loci and in all types and grade of disease. The frequency of LOH ranged from 23% to 50% depending on the marker studied. The highest frequency of LOH was observed at the D6S186 locus for the cases of DCIS and at the oestrogen receptor locus for the invasive carcinomas. These data suggest that the inactivation of tumour-suppressor genes within this region on chromosome 6q is important for the development of these early lesions.     

Cysteine proteases of Trichomonas vaginalis degrade secretory leukocyte protease inhibitor

Loss of heterozygosity (LOH) of chromosomal arm 8p has been reported to occur at high frequency for a number of common forms of human cancer, including breast cancer. The objectives of this study were to define the regions on this chromosomal arm that are likely to contain breast cancer tumor suppressor genes and to determine when loss of chromosomal arm 8p occurs during breast cancer progression. For mapping the tumor suppressor gene loci, we evaluated 60 cases of infiltrating ductal cancer for allelic loss using 14 microsatellite markers mapped to this chromosomal arm and found LOH of 8p in 36 (60%) of the tumors. Whereas most of these tumors had allelic loss at all informative markers, five tumors had partial loss of 8p affecting two nonoverlapping regions. LOH for all but one of the tumors with 8p loss involved the region between markers D8S560 and D8S518 at 8p21.3-p23.3, suggesting that this is the locus of a breast cancer tumor suppressor gene. We then studied LOH of 8p in 38 cases of ductal carcinoma in situ (DCIS) with multiple individually microdissected tumor foci evaluated for each case. LOH of 8p was found in 14 of the DCIS cases (36%), including 6 of 16 cases of low histological grade and 8 of 22 cases of intermediate or high histological grade. In four of these DCIS cases, 8p LOH was seen in some but not all of the multiple tumor foci examined. These data suggest that during the evolution of these tumors, LOH of 8p occurred after loss of other chromosomal arms that were lost in all tumor foci. Thus, LOH of 8p, particularly 8p21.3-p23, is a common genetic alteration in infiltrating and in situ breast cancer. Although 8p LOH is common even in low histological grade DCIS, this allelic loss often appears to be preceded by loss of other alleles in the evolution of breast cancer.     

Mechanism of proton translocation by the respiratory oxidases. The histidine cycle

The short area of chromosome 17 is a frequent target for deletions in human tumors, including breast cancer. We have investigated by restriction fragment polymorphism analysis the pattern of loss of heterozygosity (LOH) at four loci on 17p13.1-17pter in a panel of 110 primary human breast carcinomas. A copy of the p53 gene was lost in 23% of the informative cases. Point mutations in the p53 gene were statistically associated with LOH at the same locus (p = 0.003) but not at other loci on 17p13.3-17pter. A second region bordered by the loci D17S5/D17S28 (17p13.3) and D17S34 (17pter) is also affected by LOH, independent of point mutations in the p53 gene. We propose the presence of a second tumor suppressor gene within this region. In support of this hypothesis is the significant association (p = 0.005) between LOH at the D17S5/D17S28, but not at the TP53 or D17S34 loci, and tumors having a high S-phase index.     

Management of upper urinary tract calculi with ureteroscopic techniques

Frequent loss of heterozygosity on chromosome 8p in a variety of human malignancies, including head and neck cancers, has suggested the presence of a tumor suppressor gene (or genes) associated with the pathogenesis of these cancers. To test the role of genetic alterations at 8p23 in oral carcinogenesis, we studied 51 squamous cell carcinomas of the head and neck and 29 oral squamous cell carcinoma cell lines for allelic loss using 7 microsatellite markers spanning approximately 5 cM of chromosome band 8p23. Twenty-three of 51 tumors (45%) and 23 of 29 cell lines (79%) showed allelic loss at 1 or more loci. Three cell lines showed homozygous deletion of loci within a 3 cM region defined by the markers D8S1781 and D8S262. Our results suggest that a tumor suppressor gene (or genes) is located in 8p23 and is associated with the development and/or progression of oral carcinomas.     

Frequent microsatellite instability and loss of heterozygosity in the region including BRCA1 (17q21) in young patients with gastric cancer

It is known that nearly 5% of gastric carcinomas arise under the age of 40. To elucidate genetic alterations in these patients, we performed studies using microsatellite assay in 27 gastric cancers under 35 years of age, composed of 5 well and 22 poorly differentiated adenocarcinomas. We detected replication errors (RERs) in 18 (67%) of 27 tumors, but no germline mutation in DNA mismatch repair genes (hMLH1 and hMSH2), except fory 3 somatic mutations in the hMLH1 gene. Loss of heterozygosity (LOH) at D17S855, located on chromosome 17q21 (BRCA1), was detected in 8 (40%) of 20 informative cases. In 12 (44%) of 27 cases, LOH on chromosome 17q12-21 including the BRCA1 was found in several neighboring markers in this region, while no mutation was found in the BRCA1 gene. Four (40%) of 10 scirrhous type gastric cancers exhibited wide allelic deletions on chromosome 17q12-21. These results overall suggest that young gastric cancer patients display highly frequent micro-satellite instability that might be due to defect of DNA repair system rather than hMLH1 and hMSH2. In addition, chromosome 17q12-21 including BRCA1 locus may contain a candidate for tumor suppressor gene, particularly in scirrhous type gastric cancers arising in young patients.     

Loss of heterozygosity on the long arm of human chromosome 7 in sporadic renal cell carcinomas

Cytogenetic and molecular analysis of DNA sequences with highly polymorphic microsatellite markers have implicated allele loss in several chromosomal regions including 3p, 6p, 6q, 8p, 9p, 9q, 11p and 14q in the pathogenesis of sporadic renal cell carcinomas (RCCs). Deletions involving the long arm of chromosome 7 have not been described in RCCs although they have been seen in several other tumor types. However, there have been no detailed analysis of loss of heterozygosity (LOH) of 7q sequences in sporadic RCCs. We therefore studied LOH for DNA sequences on 7q with 10 highly polymorphic markers in 92 matched normal/tumor samples representing sporadic RCCs including papillary, nonpapillary, and oncocytomas in order to determine whether allelic loss could be detected in a tumor type with no visible 7q rearrangements at the cytogenetic level. We found chromosome 7q allele loss in 59 of 92 cases (64%) involving one, two, or more microsatellite markers. The most common allele loss included loci D7S522 (24%) and D7S649 (30%) at 7q31.1-31.2, a region that contains one of the common fragile sites, FRA7G. By comparative multiplex PCR analysis, we detected a homozygous deletion of one marker in the 7q 31.1-31.2 region in one tumor, RC21. These results support the idea that a tumor suppressor gene in 7q31 is involved in the pathogenesis of sporadic renal cell carcinomas.     

A case of double primary adenocarcinoma of the lung with multiple atypical adenomatous hyperplasia

A case of double primary adenocarcinoma of the lung with multiple atypical adenomatous hyperplasia (AAH) in a 77-year-old woman is reported. Histopathologically, in the resected left upper lobe of the lung, both cancers were diagnosed as well-differentiated papillary adenocarcinoma, and 161 lesions of AAH were also found. Both the cancer lesions and six AAH (greater than 3 mm in diameter) were examined with regard to immunoreactivity of carcinoembryonic antigen (CEA) and p53 gene product, microsatellite instability (MI) and loss of heterozygosity (LOH) on chromosome 9q and 17q by polymerase chain reaction (PCR). Although both cancers expressed CEA, they did not show clonal immunoreactivity for the p53 gene product. Atypical adenomatous hyperplasia expressed CEA weakly and showed no immunoreactivity for p53 gene protein. Both carcinomas showed LOH on chromosome 17q, and one of them showed LOH on chromosome 9q. In six AAH, LOH on chromosome 17q was detected in two tumors, and one of them also showed LOH on chromosome 9q. One AAH, which was negative for LOH on chromosome 17q and 9q, showed MI at D17S791. These results indicated that AAH is a clonal neoplastic lesion with genetic abnormalities and should be called intraepithelial pneumocyte neoplasia, and that each of the numerous papillary lesions in this case was considered to be an independent lesion.     

Allelotype analysis of oesophageal adenocarcinoma: loss of heterozygosity occurs at multiple sites

Deletions of tumour-suppressor genes can be detected by loss of heterozygosity (LOH) studies, which were performed on 23 cases of adenocarcinoma of the oesophagus, using 120 microsatellite primers covering all non-acrocentric autosomal chromosome arms. The chromosomal arms most frequently demonstrating LOH were 3p (64% of tumours), 5q (45%), 9p (52%), 11p (61%), 13q (50%), 17p (96%), 17q (55%) and 18q (70%). LOH on 3p, 9p, 13q, 17p and 18q occurred mainly within the loci of the VHL, CDKN2, Rb, TP53 and DCC tumour-suppressor genes respectively. LOH on 5q occurred at the sites of the MSH3 mismatch repair gene and the APC tumour-suppressor gene. 11p15.5 and 17q25-qter represented areas of greatest LOH on chromosomes 11p and 17q, and are putative sites of novel tumour-suppressor genes. LOH on 9p was significantly associated with LOH on 5q, and tumours demonstrating LOH at both the CDKN2 (9p21) and MSH3 (5q11-q12) genes had a significantly higher fractional allele loss than those retaining heterozygosity at these sites. Six of nine carcinomas displaying microsatellite alterations also demonstrated LOH at CDKN2, which may be associated with widespread genomic instability. Overall, there are nine sites of LOH associated with oesophageal adenocarcinoma.     

Can knee joint proprioception by reconstruction of the anterior cruciate ligament be restored? A prospective longitudinal study

BACKGROUND: Usual ductal hyperplasia (UDH), atypical ductal hyperplasia (ADH), and ductal carcinoma in situ (DCIS) are risk factors for invasive breast cancer (IBC), suggesting that these lesions may be direct precursors of IBC. To identify genetic changes that may be important in the early development of precursor lesions and their progression to malignant or invasive disease, we examined 399 putative precursors (211 UDH, 51 ADH, 81 non-comedo DCIS, and 56 comedo DCIS) for loss of heterozygosity (LOH) at 15 polymorphic genetic loci known to exhibit high rates of loss in IBC. We also assessed the sharing of LOH by putative precursors and synchronous cancers. METHODS: The polymerase chain reaction was used to analyze DNA from microdissected archival specimens. RESULTS AND CONCLUSIONS: In hyperplasias from noncancerous breasts (i.e., without DCIS and/or IBC in analyses of hyperplasias), LOH at any given locus was rare (range, 0%-15%), although 37% of UDH and 42% of ADH lesions showed loss for at least one locus, suggesting that the development of hyperplasias can involve many different tumor suppressor genes. In DCIS from noncancerous breasts (i.e., without IBC in analyses of DCIS), LOH was common, with 70% of noncomedo lesions and 79% of comedo lesions showing at least one loss. In DCIS, substantial rates of loss (up to 37%) were observed at loci on chromosomes 16q, 17p, and 17q, suggesting that inactivated tumor suppressor genes in these regions may be important in the development of noninvasive breast cancer. When DCIS lesions from cancerous and noncancerous breasts were compared, substantially more LOH was observed in the cancerous breasts at a few loci (on chromosomes 2p, 11p, and 17q), suggesting that genetic alterations in these regions may be important in the progression to invasive disease. Among specimens harvested from cancerous breasts, 37% of UDH, 45% of ADH, 77% of noncomedo DCIS, and 80% of comedo DCIS lesions shared LOH with synchronous cancers at one locus or more, supporting the idea that the putative precursors and the cancers are genetically related.     

Sequential molecular abnormalities are involved in the multistage development of squamous cell lung carcinoma

To understand the molecular pathways involved in the pathogenesis of squamous cell lung carcinoma, we obtained DNA from 94 microdissected foci from 12 archival surgically resected tumors including histologically normal epithelium (n=13), preneoplastic lesions (n=54), carcinoma is situ (CIS) (n=15) and invasive tumors (n=12). We determined loss of heterozygosity (LOH) at 10 chromosomal regions (3p12, 3p14.2, 3p14.1-21.3, 3p21, 3p22-24, 3p25, 5q22, 9p21, 13q14 RB, and 17p13 TP53) frequently deleted in lung cancer, using 31 polymorphic microsatellite markers, including 24 that spanned the entire 3p arm. Our major findings are as follows: (1) Thirty one percent of histologically normal epithelium and 42% of mildly abnormal (hyperplasia/metaplasia) specimens had clones of cells with allelic loss at one or more regions; (2) There was a progressive increase of the overall LOH frequency within clones with increasing severity of histopathological changes; (3) The earliest and most frequent regions of allelic loss occurred at 3p21, 3p22-24, 3p25 and 9p21; (4) The size of the 3p deletions increased with progressive histologic changes; (5) TP53 allelic loss was present in many histologically advanced lesions (dysplasia and CIS); (6) Analyses of 58 normal and non-invasive foci having any molecular abnormality, indicated that 30 probably arose as independent clonal events, while 28 were potentially of the same clonal origin as the corresponding tumor; (7) Nevertheless, when the allelic losses in the 30 clonally independent lesions and their clonally unrelated tumors were compared the same parental allele was lost in 113 of 125 (90%) of comparisons. The mechanism by which this phenomenon (known as allele specific mutations) occurs is unknown; (8) Four patterns of allelic loss in clones were found. Histologically normal or mildly abnormal foci had a negative pattern (no allelic loss) or early pattern of loss while all foci of CIS and invasive tumor had an advanced pattern. However dysplasias demonstrated the entire spectrum of allelic loss patterns, and were the only histologic category having the intermediate pattern. Our findings indicate that multiple, sequentially occurring allele specific molecular changes commence in widely dispersed, apparently clonally independent foci, early in the multistage pathogenesis of squamous cell carcinomas of the lung.     

Altered microsatellites in incomplete-type intestinal metaplasia adjacent to primary gastric cancers

AIM: To investigate the presence of genetic instability in precancerous lesions of the stomach. METHODS: Fifteen cases of sporadic gastric cancers with a background of intestinal metaplasia were studied by microsatellite assay at nine loci. Altered metaplastic mucosa was microdissected, reconstructed topographically, and examined immunohistochemically with an anti-p53 antibody, comparing its positive area with foci of microsatellite instability in each individual. RESULTS: Alterations at one or more loci were observed in seven of 15 cancers (46.7%) and four of 15 intestinal metaplasias (26.7%). Two cases of replication error positive phenotype had no microsatellite alterations in their metaplastic mucosa. All the microsatellite alterations in the metaplastic mucosa were restricted to incomplete-type intestinal metaplasia around the respective cancers. Moreover, in one case, an identical pattern of microsatellite alteration was detected in the cancer tissue and in the adjacent metaplastic mucosa, suggesting the sequential development of gastric cancer from intestinal metaplasia. Frequent alteration was found at the locus D1S191 (1q), indicating that this locus might be altered early in the development of intestinal-type gastric cancer. No significant association between microsatellite instability and p53 immunoreactivity was observed in the cases examined. CONCLUSION: These results indicate that microsatellite instability may be an early event in stomach carcinogenesis, especially in intestinal-type cancers.     

Poly(ADP-ribose) polymerase and aging

The activation of oncogenes and the inactivation of tumour suppressor genes play a critical role in laryngeal tumorigenesis. Recent investigations revealed that 8p, 9p and 17q arms of human chromosomes harbour tumour suppressor genes (TSGs) such as p16 and BRCA1 with an important role in the multistage carcinogenesis of the larynx. In order to investigate the implication of these novel TSGs in the development of laryngeal neoplasia we performed a loss of heterozygosity (LOH) analysis using a bank of 15 polymorphic microsatellite markers (4 at 8p21, 7 at 9p21 arm and 4 at 17q arm surrounding the BRCA1 region) in a series of 32 cytological specimens (19 squamous cell carcinoma, 13 benign lesions of the larynx). Both benign and malignant specimens exhibited genetic alterations with at least one microsatellite marker. Fifteen (47%) out of the 32 specimens exhibited LOH at 8p21, 25/32 (78%) showed LOH at 9p21 and 18/32 (56%) displayed LOH at 17q21. Genetic alterations were detected in both benign and malignant lesions for all the loci tested suggesting an important role of these regions in the development of laryngeal neoplasia. This is the first report of detection of microsatellite alterations not only in solid tumours of the larynx but in laryngeal cytological specimens, suggesting that microsatellite analysis may be a useful tool in the primary diagnosis of the disease.     

A method of dynamic foot-pressure measurement for the evaluation of pediatric orthopaedic foot deformities

We analysed 42 differentiated thyroid tumors including 15 follicular adenomas (FA), 13 papillary thyroid cancers (PTC) and 14 follicular thyroid carcinomas (FTC) with 13 microsatellite markers specific for the long arm of human chromosome 7 within 7q31; this region is deleted frequently in several other tumor types. Overall, 20 of the 42 samples analysed (48%) displayed LOH with one or more of the markers tested. LOH was detected most frequently (78%) in FTC, the most malignant of the thyroid tumors. A smallest common deleted region (SCDR) was defined in this tumor type flanked by markers D7S480 and D7S490. This SCDR is distinct from D7S522, the most commonly deleted locus in many other tumors, which was deleted in only one FTC. D7S522 did show LOH in two of six informative PTCs. None of the PTC and only two of the FAs showed LOH in the FTC SCDR. Since FA is considered a premalignant stage of FTC, our results suggest that inactivation of a putative tumor suppressor at 7q31.2 may be acquired during adenoma to carcinoma progression. The absence of LOH at this locus amongst PTC suggests that inactivation of this tumor suppressor is specific for FTC. In conclusion, LOH at 7q31 is a frequent event in differentiated thyroid cancer, and we have defined a 2 cM SCDR specific for FTC.     

Molecular support for field cancerization in the head and neck

BACKGROUND: Two competing concepts, field cancerization and micrometastatic lesions, have been postulated to account for the high frequency of second primary tumors and multicentric dysplasia in patients with head and neck carcinoma. METHODS: To provide insight into this process, the authors examined histologically normal mucosa and dysplastic tissue adjacent to invasive tumor for loss of heterozygosity (LOH) at three commonly deleted loci. Tissues from 21 patients with carcinoma of the oral cavity and oropharynx were identified and verified by a pathologist to contain histologically normal mucosa, dysplasia, and adjacent invasive squamous cell carcinoma. Each specimen was analyzed for LOH at D9S171 (9p21), D3S1007 (3p21.3-22), and D3S1228 (3p14). RESULTS: Of the 21 patients, 19 had adequate DNA for analysis. Seventeen patients were heterozygous at one or both of the 3p sites and LOH occurred in 6 of 17 invasive tumor specimens, 1 of 17 dysplasia specimens, and in none of the mucosal specimens. LOH at 9p21 occurred in 11 of 13 informative specimens of invasive tumor, 8 of 13 dysplasia specimens, and 6 of 13 normal mucosa specimens. However, one case that did not have 9p deletion in the tumor demonstrated LOH in the mucosa and two cases had LOH in both the tumor and mucosa but with deletion of the opposite allele. CONCLUSIONS: These data suggest that 9p21 but not 3p14 or 3p21 deletions occur in the absence of histologic changes. In two cases preinvasive and invasive lesions that apparently were an example of histologic progression contained disparate genetic events, calling into question the use of adjacent dysplasia as a model for premalignant lesions.