Genetic Profile of Cumulative Mutational Damage Associated With Early Pulmonary Adenocarcinoma

Abstract

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.

Chromosome 1p and 19q status and p53 and p16 expression patterns as prognostic indicators of oligodendroglial tumors: A clinicopathological study using fluorescence in situ hybridization

“…However, changes that develop during tumor progression may show heterogeneous genetic alterations commensurate with new clone development. In various tumors, intratumoral LOH heterogeneity was observed, for example, 73% of bronchioloalveolar carcinomas and 94% of stage I adenocarcinomas show this effect 24 . Although chromosome 1p and 19q loss have been generally considered as early events in the pathogenesis of oligodendrogliomas, 1,25,26 there was no large‐scale study conducted on the regional heterogeneities of 1p and 19q loss using FISH.…”

Current Concepts in Bronchioloalveolar Carcinoma Biology

“…Although these studies provide some support for the progression of BAC to adenocarcinoma, they also point to the heterogeneity and complexity of the chromosomal alterations involved in lung cancer. In one study, 94% of adenocarcinomas had regions containing different chromosomal alterations when various histologic regions were laser capture microdissected and analyzed (32). The frequent clinical finding of AAH, BAC, and adenocarcinoma in the same lung cancer sample suggests that molecular events often occur heterogeneously, perhaps beginning with mutations in the bronchoalveolar stem cells, and that there might be multiple molecular pathways of progression to adenocarcinoma.…”

“…This finding suggests that there may be significant mutational heterogeneity early in invasive cancer until there is clonal selection of cells capable of metastasis. Allelic loss of 9p is commonly found in AAH and in early BAC, indicating that a gene in that region may be responsible for early changes associated with BAC formation (32,33). Cyclin-dependent kinase inhibitor 2a (p16), a tumor suppressor gene, is found in this region and has been an area of investigation.…”

“…Loss of heterozygosity of 8q and 17p, containing Myc and p53, respectively, are found more frequently in BAC compared with AAH, and still other allelic losses (1p, 3p, 7q, and 18q) are found more commonly in adenocarcinoma compared with BAC. Genes such as FHIT, MycL1, VHL, and DCC are found in these chromosomal regions, potentially representing genes related to the invasive properties of adenocarcinoma (31,32). The FHIT tumor suppressor gene located on 3p14 is important in a number of malignancies, and loss of expression by allelic loss or promoter hypermethylation is common and predicts poor prognosis in lung cancer (34).…”

Concordant and Discordant EGFR Mutations in Patients With Multifocal Adenocarcinomas: Implications for EGFR-Targeted Therapy

“…LOH of 1p, 3p, 7q, and 18q, as well as fractional allele loss (FAL) were more frequent in stage 1 adenocarcinomas than BAC. [27] While these genomic alterations are present in many precursor lesions, it is challenging to use LOH analysis to identified shared ancestry between independent lesions.…”