Context.—Odontogenic keratocysts (OKCs) are unique odontogenic lesions that have the potential to behave aggressively, that can recur, and that can be associated with the nevoid basal cell carcinoma syndrome. Whether they are developmental or neoplastic continues to be debated. Objectives.—To identify loss of heterozygosity of tumor suppressor genes in OKCs and to suggest a pathogenetic origin for these lesions. Design.—We examined 10 OKCs for loss of heterozygosity of tumor suppressor genes, using a microdissection and semiquantitative genotyping analysis. The genes analyzed included 10 common tumor suppressor genes, as well as the PTCH gene, which is mutated in nevoid basal cell carcinoma syndrome. Results.—Loss of heterozygosity was seen in 7 of 10 cases, with a frequency between 11% and 80% of the genes studied. The genes that exhibited the most frequent allelic losses were p16, p53, PTCH, and MCC (75%, 66%, 60%, and 60%, respectively). Daughter cysts were associated with a higher frequency of allelic loss (P = .02), but epithelial budding was not. Conclusions.—Our study indicates that a significant number of OKCs show clonal loss of heterozygosity of common tumor suppressor genes. The finding of clonal deletion mutations of genomic DNA in these cysts supports the hypothesis that they are neoplastic rather than developmental in origin.

Primary lymphoepithelioma-like carcinoma of the lung (LELC) shares some morphologic and clinical characteristics with malignancies associated with microsatellite instability (MSI). The aims of our study were to determine the MSI status in LELC and compare these findings with stage I non-small cell lung carcinoma (NSCLC) with marked lymphocytic host response (MLHR). We assessed MSI by a DNA-based polymerase chain reaction assay using mononucleotide (BAT25 and BAT26) and dinucleotide (D2S123, D5S346, and D17S250) repeats. MSI was detected in 2 (29%) of 7 LELC cases with only 1 marker (D17S250), and in 3 (19%) of 16 NSCLC cases with MLHR with only 2 markers (1D2S123 and 2 D17S250). Loss of heterozygosity (LOH) was detected at 1 or 2 of 3 dinucleotide repeats in 11 NSCLC cases (69%) with MLHR and 3 LELC cases (43%) (P = .36). The overall frequencies of LOH in NSCLC with MLHR were 29% and 19% in LELC (P = .55). MSI is very uncommon in LELC, indicating that MSI is not an important event in carcinogenesis for this tumor subtype. The presence of LOH suggests a probable role of tumor suppressor genes in LELC carcinogenesis.

To detect the possible genetic alterations characteristic of bronchioloalveolar carcinoma (BAC) and to study molecular genetic factors responsible for determining the biologic aggressiveness of pulmonary adenocarcinoma, comparative analysis of loss of heterozygosity (LOH) on 9 chromosomal regions was performed in 14 BACs and in 20 stage I adenocarcinomas (AD). The most frequently affected chromosome regions in BAC were 8q and 17p. In stage I AD, more than 60% of the cases showed LOH of 1p, 3p, 5q, 7q, 17p, and 18q loci, and LOH of 1p, 3p, 7q, and 18q was observed with greater frequency than in BAC (P < 0.05). Fractional allele loss (FAL) was significantly greater in stage I AD than in BAC (P < 0.001). In cases with microdissection of multiple sites, intratumoral heterogeneity of LOH status was observed in 73% of BAC and 94% of stage I AD, and homogeneous distribution of LOH of 9p was unique to BAC. The high FAL value was associated with a poor prognosis of BAC, but this trend did not reach statistical significance (P = 0.098). In stage I AD, no correlation was found between LOH of particular chromosomal region or FAL and clinical outcome. LOH of 1p, 3p, 7q, and 18q was associated with invasive properties of pulmonary AD and may be useful in identifying invasive adenocarcinoma when conventional histomorphological tools are not helpful.