Cytogenetic findings in lung cancer that illuminate its biological history from adenomatous hyperplasia to bronchioalveolar carcinoma to adenocarcinoma: A case report (original) (raw)

Genetic changes in lung cancer

Journal of Cellular Biochemistry, 1993

In an attempt to define the type and temporal sequences of somatic genetic changes that precede the onset of invasive lung cancer, and to search for biological markers useful in screening multiple primary tumors of the upper aerodigestive tract, we have performed a cytogenetic and genetic study using normal bronchial epithelium and primary tumor specimens of 68 patients undergoing pulmonary resection for early stage lung cancer, and normal bronchial epithelium of 5 controls with metastatic sarcomas. Of the 68 lung cancer cases, 31 had a single tumor and 37 displayed multiple synchronous or metachronous tumors. Cytogenetic alterations were observed in 59% (23/39) of the evaluable tumor specimens with complex rearranged karyotypes, particularly involvingchromosomes 3 (70%), 17 (39%), 11 (26%), 8, 9, 12 (22%), and 7 (17%). Gene alterations were also detected including overexpression of epidermal growth factor receptor (EGFR) in 63% (36/57), HER2/NEU in 21% (12/56), and p53 mutations in 50% (12/24). The overall frequency of genetic changes (any type) in the tumors was 76% (52/68). In the normal bronchial mucosa, we identified a rearranged karyotype in 20% of the evaluable cases (13/63); particularly simple rearrangements involving chromosomes 3p (6 cases), 7 (6 cases), 17 (3 cases), 9, 11 (2 cases), 8 (1 case); as well as overexpression of EGFR in 39% (20/51) and of HER2/NEU in 14% (7/51). The overall frequency of genetic changes (any type) in the normal epithelium was 46% (30/65). The presence of a rearranged karyotype in the bronchial mucosa was associated with a rearranged karyotype in the tumor sample. Other statistically significant correlations were found between histopathologic and clinical features and the occurrence of the different cytogenetic and genetic changes both in tumors and in the normal bronchial mucosa. No genetic abnormalities were found in the bronchial epithelium of the 5 controls. 0 1993 Wiley-Liss, Inc. Lung cancer arises as the result of multiple genetic hits. Whereas a variety of morphological changes such as squamous metaplasia and bronchial dysplasia have been described in association with lung tumors, little is known about the Address correspondence to Ugo Pastorino, MD, Instituto Nazionale Tumori, Department of Thoracic Surgery, Via Venezian 1, Milano, Italy 20133. 0 1993 Wiley-Liss, Inc. occurrence and timing of genetic changes during the early, intermediate and late events of lung carcinogenesis. Knowledge of these factors would contribute t o the early diagnosis of precancerous lesions of the bronchial mucosa, t o the identification of patients at risk for multiple primary tumors of the lung, and t o a biological assessment of prognosis in invasive lung carcinoma. Cytogenetic studies have revealed a num-Incidence and possible clinical significance of K-ras oncogene activation in adenocarcinoma of the lung. Cancer Res 48:573%5741, 1988. Slebos RJC, Kibbelaar RE, Dalesio 0, Koolstra A, Stam J , Neifier CJLM, Wagenaar SS,Van der Schueren R, Van Zandwijk N, Mooi WJ, Bos JL, Rodenhuis S: K-rus oncogene activation as a prognostic marker in adenocarcinoma of the lung. N Engl J

Biochemical and cytogenetic studies of human lung cancers

The Journal of Thoracic and Cardiovascular Surgery, 1988

In ongoing studies, we have tested resected lung cancers from 41 men and 49 women; of those with primary lung cancer, 46 patients are free of disease and 35 have died of cancer or have persistent disease. Measurements andstudies were as foUows: total ceUular deoxyribonucleic acid content by image analysis (n = 77); total genomic deoxyribonucleic acid methylation state and banding patterns from probed Southern blots (n = 36); radioimmunoassay for motilin, bombesin, gastrin, vasoactive intestinal peptide, and cholecystokinin (n = 18); and cytogenetic analysis (n = 39). All lung cancers were hyperploid. Adenocarcinomas andepidermoid carcinomas were generaUy hexaploid to nearly septaploid; comparisons by stage and histologic features suggested potential prognostic correlations. There was general hypomethylation of deoxyribonucleic acid (p < 0.(01). Deoxyribonucleic acid digests from restriction endonuclease Hpa II, when probed with deoxyribonucleic acid homologous to KPN, showed banding patterns that separated histologicaUy indistinguishable primary adenocarcinomas and metastatic adenocarcinomas from one another. Cancers studied with radioimmunoassay were aU negative for polypeptide hormones. Five cancers grew adequately in vitro to permit study of 190 detailed karyotypes (20 to 50 per tumor). Chromosome modal numbers ranged from 49 to 109. There were from 4 to 20 clearly abnormal marker chromosomes per tumor; abnormality derived from chromosome 1 was prevalent. Ten of 19 tumors xenotransplanted to nude mice were carried through two to five transplant generations without a change in histologic patterns.

Distinct patterns of genetic alterations in adenocarcinoma and squamous cell carcinoma of the lung

European Journal of Cancer, 2004

Squamous cell carcinoma (SqC) and adenocarcinoma (AdC) are the two most common subtypes of non-small cell lung cancer (NSCLC). Cumulative information suggests that the SqC and AdC subtypes progress through different carcinogenic pathways, but the genetic aberrations promoting such differences remain unclear. Here we have assessed the overall genomic imbalances and structural abnormalities in SqC and AdC . By parallel analyses with comparative genomic hybridisation (CGH) on tumorous lung tissues and spectral karyotyping (SKY) on short-term cultured primary tumours, genome-wide characterisation was carried out on 69 NSCLC (35 SqC, 34 AdC). Molecular cytogenetic characterisation indicated common and distinct genetic changes in SqC and AdC. Common events of +1q21-q24, +5p15-p14, and +8q22-q24.1, and À17p13-p12 were found in both groups, although hierarchical clustering simulation on CGH findings depicted +2p13-p11.2, +3q25-q29, +9q13-q34, +12p, +12q12-q15 and +17q21, and À8p in preferential association with SqC pathogenesis (P< 0.05). Corresponding SKY analysis suggested that these changes occur in simple and complex rearrangements, and further indicated the clonal presence of translocation partners leading to chromosomal over-representations. These recurring rearrangements involved chromosome pairs of t(1;13), t(1;15), t(7;8), t(8;15), t(8;9), t(2;17) and t(15;20). Of particular interest was the finding that the t(8;12) translocation partner was exclusive to AdC. The combined application of SKY and CGH has thus uncovered the genome-wide chromosomal aberrations in NSCLC. Specific chromosomal imbalances and translocation partners found in SqC and AdC have highlighted regions for further molecular investigation into gene(s) that may hold importance in the carcinogenesis of NSCLC. #

Somatic genetic changes accompanying lung tumor development

Genes, Chromosomes and Cancer, 2005

Carcinomas are believed to develop by incremental steps of increasingly abnormal morphology driven by accumulating somatic genetic changes. This process is often difficult to study, as the early stages are undetectable. We used fluorescence bronchoscopy, which enhances detection of preinvasive bronchial lesions, and have obtained sequential biopsies of carcinoma in situ (CIS) from a patient with no detectable tumor and from a squamous cell carcinoma that developed 19 months after presentation at the site of one of the previous CIS lesions. Biopsies of preinvasive CIS, which follow-up showed had different pathologic outcomes, and tumor were microdissected to obtain enriched cell populations and DNA prepared from them. Molecular characteristics of these biopsies were compared by loss of heterozygosity analysis, TP53 mutation analysis, and comparative genomic hybridization. Although all lesions examined had the same TP53 mutation and almost identical allelotypes, differences were observed. Loss in 5q21 and amplification of 3q25-26 were associated with the lesion that progressed and the subsequent carcinoma. Allele loss at 4p16 was detected in the tumor but not in any of the CIS lesions, suggesting it was a late event associated with tumor invasion. Amplification at 4q12 was specifically observed in the tumor and in the CIS at the site of eventual tumor formation. Although these findings may be unique to this one patient, the successful demonstration of sequential genetic changes raises the possibility that this approach, unencumbered by interpatient variability between lesions, will greatly facilitate the identification of molecular events driving the invasive process V V C 2005 Wiley-Liss, Inc.

Multiple Clonal Abnormalities in the Bronchial Epithelium of Patients With Lung Cancer

Background: Several molecular changes, including loss of heterozygosity (i.e., deletion of one copy of allelic DNA sequences) and alterations in microsatellite DNA, have been detected early in the pathogenesis of lung cancer, even in histologically normal epithelium. In the bronchial epithelium of patients with lung cancer, we have determined the frequency, size, and patterns of molecularly abnormal clonal patches. Methods: We studied formalin-fixed, paraffin-embedded samples from 16 surgically resected lung carcinomas (five squamous cell carcinomas, four small-cell carcinomas, six adenocarcinomas, and one large-cell carcinoma). From each carcinoma, we microdissected foci (each containing about 200 cells) of tumor tissue and equivalent samples of histologically normal and abnormal epithelium. Furthermore, multiple discontinuous foci of bronchial epithelium were analyzed from methanol-fixed samples from three additional patients with lung cancer (two with squamous cell carcinoma and one with adenocarcinoma). We used two-step polymerase chain reactionbased assays involving 12 microsatellite markers at seven chromosomal regions frequently deleted in lung cancer. Results: Two hundred eighteen foci of nonmalignant bronchial epithelium (195 of histologically normal or slightly abnormal epithelium and 23 of dysplastic epithelium) were studied from the 19 surgically resected lobectomy specimens. Thirteen (68%) of the 19 specimens had at least one focus of bronchial epithelium with molecular changes. At least one molecular abnormality was detected in 32% of the 195 histologically normal or slightly abnormal foci and in 52% of the 23 dysplastic foci. Extrapolating from our twodimensional analyses, we estimate that

Immunohistochemical markers of cancerogenesis in the lung

Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society, 2007

Lung cancer is the leading cause of cancer deaths for people of both sexes worldwide. Early diagnosis of precancer lesions may be of crucial significance to lowering lung cancer mortality. The World Health Organization has defined three preneoplastic lesions of the bronchial epithelium: squamous dysplasia and carcinoma in situ, atypical adenomatous hyperplasia and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia. These lesions are believed to progress to squamous cell carcinoma, adenocarcinoma and carcinoid tumors, respectively. Apart from WHO classification, two other lesions such as bronchiolization and bronchiolar columnar cell dysplasia (BCCD) can be observed and thought to be preneoplastic lesions leading to adenocarcinoma. In this review we summarize the data of morphological and cell cycle related proteins changes in both central and peripheral compartments of lung. Many molecular changes, which accompany the multistep process of the development of invasive types ...

Bronchioloalveolar differentiation in lung adenocarcinomas

Bosnian journal of basic medical sciences / Udruženje basičnih mediciniskih znanosti = Association of Basic Medical Sciences, 2011

The goals of the study were to determine what percentage of neoplasms with a bronchioloalveolar (BAC) component were considered pure BAC by current World Health Organization (WHO) criteria. Next, we wanted to determine the number of mucinous BACs using histochemical staining with Alcian Blue PAS. Finally, we aimed to elucidate by immunohistochemistry the thyroid transcription factor-1 (TTF-1) frequency and cytokeratin 7 (CK7) expression, particularly in regard to the mucinous and non-mucinous subtypes of BAC tumors. We made a retrospective review of Hematoxylin and Eosin stained slides and classification of histologic grade, tumor subtype, and percentage of pure BAC pattern, with further characterization by histochemical staining for Alcian Blue PAS and Immunohistochemical staining for thyroid TTF-1 and CK7. Only 10 of 30 tumors examined could be classified as BAC by current strict WHO criteria. Nine cases were classified into non-mucinous and only one case was recognized as mucinou...

Genomic imbalances in human lung adenocarcinomas and squamous cell carcinomas

Genes, Chromosomes and Cancer, 2001

Comparative genomic hybridization analysis was performed on 67 non-small-cell lung cancers (NSCLCs), including 32 squamous cell carcinomas (SCCs) and 35 adenocarcinomas (ACs), to identify differences in the patterns of genomic imbalance between these two histologic subtypes. Among the entire tumor set, the chromosome arms most often overrepresented were 1q, 3q, 5p, and 8q, each detected in 50 -55% of cases. The most frequently underrepresented arms were 9q, 3p, 8p, and 17p. The number of imbalances was similar in SCCs and ACs (median number/case: 12 and 11, respectively). Moreover, many imbalances, such as gains of 1q, 5p, and 8q, occurred at a high frequency in both histologic subgroups. Several statistically significant differences, however, were found. The most prominent difference was gain of 3q24-qter, seen in 81% of SCCs compared with 31% of ACs (P Ͻ 0.0001), with amplification at 3q25-26 being detected in eight of 32 (25%) SCCs but in only two of 35 (6%) ACs. Gain of 20p13 and loss of 4q also were seen at a significantly higher rate in SCCs than in ACs, whereas overrepresentation of 6p was more common in ACs. Gains of 7q and 8q each were associated with higher-stage tumors and either positive nodal involvement or higher tumor grade. These data suggest that genes located in several chromosomal regions, particularly 3q25-26, may be associated with phenotypic properties that differentiate lung SCCs from ACs. Furthermore, certain imbalances, prominent among them gains of 7q and 8q, may be indicative of tumor aggressiveness in NSCLCs.

Patterns of chromosomal imbalances in adenocarcinoma and squamous cell carcinoma of the lung

Cancer research, 1997

Comparative genomic hybridization was used to screen 25 adenocarci nomas and 25 squamous cell carcinomas of the lung for chromosomal imbalances. DNA copy number decreases common to both entities were observed on chromosomes ip, 3p, 4q, 5q, 6q, Sp, 9p, 13q, lSq, and 21q. Similarly, DNA gains were observed for chromosomes 5p, Sq, 11q13, l6p, 17q, and 19q. Adenocarcinomas showed more frequently DNA overrep resentations of chromosome lq and DNA losses on chromosomes 3q, 9q, lop, and 19, whereas squamous cell carcinomas were characterized by increased overrepresentations of chromosome 3q and l2p as well as deletions of2q. For the first time, we used a histogram representation and statistical analysis to evaluate the differences between both tumor groups. In particular, the overrepresentation of the chromosomal band 1q23 and the deletion at 9q22 were significantly associated with adenoid differen tiation, whereas the DNA loss of chromosomal band 2q36-37 and the overrepresentations at 3q21-22 and 3q24-qter were statistically signifi cant markers for the squamous cell type. The study strengthens the notion that different tumor subgroups of the respiratory tract are characterized by distinct patterns of chromosomal alterations.