Topographical distribution of allelic loss in individual lung adenocarcinomas with lymph node metastases

Abstract

Adenocarcinomas of the lung are characterized by morphological heterogeneity, and since carcinogenesis has been suggested to be a multistep process involving sequential accumulation of multiple genetic alterations, the morphological heterogeneity may represent a cross-sectional view of genetic alterations within individual tumors. Therefore, to elucidate whether, and which, genetic alterations accumulated in relation to morphological cancer progression, we examined 56 microdissected sites for topographical distribution of loss of heterozygosity (LOH) in 12 adenocarcinomas of the lung with bronchioloalveolar (BA) and invasive components in their primary tumors and metastases to lymph nodes. The morphological changes from noninvasive BA lesions to invasive and metastatic components were characterized by a significant rise in the prevalence of allelic losses (Po0.05). Individually, eight cases (67%) showed accumulation of genetic alterations from BA lesions to metastases. LOHs in multiple foci in one case were compared to determine whether they were shared at all tumor sites as an early event or localized in metastases as an additional event.LOHs at 5q and 17p may be crucial steps in the early phase of development to metastasis, while 18q loss may be an additional step. These findings suggested that the cancer cells in some pulmonary adenocarcinomas evolved from the BA lesions to the invasive and metastatic lesions.

Clonality status of multifocal lung adenocarcinomas based on the mutation patterns of EGFR and K-ras

“…We classified this patient as having tumors exhibiting the same clonality (pattern D), which corresponds to PM according to the EGFR mutation status. Because lung adenocarcinoma is morphologically and genetically heterogenous [11], we considered that a clone with the L858R mutation metastasized to three secondary tumors from a primary tumor with genetic heterogeneity. Twenty-three (50%) secondary tumors were categorized into pattern A, B or C and were regarded as exhibiting a different clonality.…”

Genetic relationship among atypical adenomatous hyperplasia, bronchioloalveolar carcinoma and adenocarcinoma of the lung

“…These markers were selected because their LOH was frequently found in lung cancer and in AAH [21][22][23][24][25][26][31][32][33][34]. In our cases the most frequent lost loci were D3S1478 at 3p21 (closed to SEMA3B), and D3S1300 at 3p14.2 (close to FHIT) [26].…”

“…The markers were selected because their LOH was repeatedly found in AAH, BAC and AC [21][22][23][24][25][26]. PCR primer sets for specific allele loci were obtained from MWGBiotech (Ebersberg, Germany).…”

The Role of DNA Methylation in the Development and Progression of Lung Adenocarcinoma

“…LOH continues to become more evident. An analysis of adenocarcinomas with BAC component (used because true non-invasive BAC is rare) showed frequent 5q and 17p losses in what would be considered the lowest grade sections of the tumors [153]. A detailed investigation of loci associated with LOH, using BACs and small adenocarcinomas, showed localized loss of 5q(APC), 9p(CDKN2A), 13q(RB1), 17p(TP53) and 18q(SMAD4) in BAC, while LOH of 3p(FHIT) and 11q(INT2) did not become prominent until invasion [154], consistent with the observed persistence of FHIT protein expression in AAH and BAC but loss of expression in invasive disease [124].…”