Somatic genetic changes accompanying lung tumor development (original) (raw)

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

Evidence of genetic instability in tumors and normal nearby tissues

Plos One, 2010

Background: Comprehensive analyses have recently been performed on many human cancer tissues, leading to the identification of a number of mutated genes but providing no information on the variety of mutations present in each of them. This information is of interest to understand the possible origin of gene mutations that cause tumors.

Recurrent Genomic Gains in Preinvasive Lesions as a Biomarker of Risk for Lung Cancer

PLoS ONE, 2009

Lung carcinoma development is accompanied by field changes that may have diagnostic significance. We have previously shown the importance of chromosomal aneusomy in lung cancer progression. Here, we tested whether genomic gains in six specific loci, TP63 on 3q28, EGFR on 7p12, MYC on 8q24, 5p15.2, and centromeric regions for chromosomes 3 (CEP3) and 6 (CEP6), may provide further value in the prediction of lung cancer. Bronchial biopsy specimens were obtained by LIFE bronchoscopy from 70 subjects (27 with prevalent lung cancers and 43 individuals without lung cancer). Twenty six biopsies were read as moderate dysplasia, 21 as severe dysplasia and 23 as carcinoma in situ (CIS). Four-micron paraffin sections were submitted to a 4-target FISH assay (LAVysion, Abbott Molecular) and reprobed for TP63 and CEP 3 sequences. Spot counts were obtained in 30-50 nuclei per specimen for each probe. Increased gene copy number in 4 of the 6 probes was associated with increased risk of being diagnosed with lung cancer both in unadjusted analyses (odds ratio = 11, p,0.05) and adjusted for histology grade (odds ratio = 17, p,0.05). The most informative 4 probes were TP63, MYC, CEP3 and CEP6. The combination of these 4 probes offered a sensitivity of 82% for lung cancer and a specificity of 58%. These results indicate that specific cytogenetic alterations present in preinvasive lung lesions are closely associated with the diagnosis of lung cancer and may therefore have value in assessing lung cancer risk.

Genetic Evidence for an Independent Origin of Multiple Preneoplastic and Neoplastic Lung Lesions1

Patients with a primary cancer in the lung or in the upper aerodigestive tract have an increased risk of developing synchronous or metachronous second primary lung tumors. This phenomenon has been related to the chronic exposure of the bronchial tree to carcinogens through a so-called "field cancerization" process. This study was designed to investigate at the somatic level the genetic basis of the field cancerization effect in patients having multiple simultaneous neoplastic and preneoplastic lesions of the lung. The pattern of specific genetic changes occurring with high frequency and in early stages of lung carcinogenesis including p53 mutations, deletions of chromosome 3p, and K-ra.vmutations, was investigated by immunocytochemical, cytogenetic, and molecular approaches in 11 synchronous lesions of five patients with multiple lung cancers. Different genetic lesions were observed in all of the pathological specimens analyzed from each patient The pattern of these changes was different both in topographically distant or adjacent lesions and in tumors with the same histopathological diagnosis supporting their independent origin.

Clonal evolution of lung tumors

Lung Cancer, 1996

Lung tumors, particularly squamous cell carcinomas, are believed to develop through a series of morphological abnormalities, driven by un derlying somatic genetic changes. One way of studying this process is to analyze candidate somatic genetic changes in samples of squamous meta plasia and bronchial dysplasia of varying degrees of severity as well as tumor from the same patient. This assumes a clonal relationship between these lesions. In this article, we provide evidence that adjacent, physically distinct bronchial abnormalities are clonally related. This has been achieved using a plaque assay technique to detect the same p53 mutation, present throughout a tumor specimen, in a small proportion of cells in an adjacent squamous metaplasia. In addition, we have obtained two dyspla sia samples from a tumor-free patient over a 9-month interval. The earlier sample had one p53 mutation, whereas the later sample had two p53 mutations on different alÃ-eles.Thus, the pattern of clonal evolution de tected in the parallel samples mimics the pattern seen in longitudinal samples and supports the analysis of synchronously collected samples for the study of tumor progression.

Genetic evidence for an independent origin of multiple preneoplastic and neoplastic lung lesions

Lung Cancer, 1995

Chromosomal aberrations in premalignant and malignantsquamous epithelium

Cancer Genetics and Cytogenetics, 2003

Biopsies of oropharyngeal cancer were screened for chromosomal imbalances by comparative genomic hybridization (CGH) performed on 22 primary tumors and morphologically nonmalignant surrounding mucosa. The aim was to determine early chromosomal changes of tumor development and to draw conclusions on the mechanisms leading to multiple tumors. The most prominent chromosomal imbalances observed were overrepresentations of genomic material on 3q, 15q, 8q, and 11q and losses on 9p, 3p, and 11q. In morphologically normal mucosa collected at 1 cm from the primary tumor border (M1), amplifications on 15q and 21q were most frequent. Far fewer gains and losses were found in M1 than in the primary tumor (average 2.2 vs. 6.9). Gains dominated over losses, but a tendency toward an increasing proportion of losses in the primary tumor (PT) was observed (ratio of gains to losses: PT, 4.75; M1, 6.3). Almost all the imbalances in M1 were detected in the primary tumor. No chromosomal alterations were identified with CGH in tissue samples dissected at 2 cm from the primary tumor (M2). In all samples, dysplastic morphologic changes decreased with distance from the primary tumor, which correlates with the observed lower level of genetic changes. We suggest that gains of genetic material on 15q and 21q are early events in malignant progression of squamous cell carcinoma, followed by gains on 3q, 8q, and 11q, and losses on 3p and 9p at later stages. Based on our cytogenetic data, we discuss the monoclonal model followed by lateral epithelial spread as an explanation of multiple head and neck squamous cell carcinomas. Ć 2003 Elsevier Inc. All rights reserved.

In situ growth in early lung adenocarcinoma may represent precursor growth or invasive clone outgrowth—a clinically relevant distinction

Modern Pathology, 2019

The switch from in situ to invasive tumor growth represents a crucial stage in the evolution of lung adenocarcinoma. However, the biological understanding of this shift is limited, and 'Noguchi Type C' tumors, being early lung adenocarcinomas with mixed in situ and invasive growth, represent those that are highly valuable in advancing our understanding of this process. All Noguchi Type C adenocarcinomas (n = 110) from the LATTICE-A cohort were reviewed and two patterns of in situ tumor growth were identified: those deemed likely to represent a true shift from precursor in situ to invasive disease ('Noguchi C1') and those in which the lepidic component appeared to represent outgrowth of the invasive tumor along existing airspaces ('Noguchi C2'). Overall Ki67 fraction was greater in C2 tumors and only C1 tumors showed significant increasing Ki67 from in situ to invasive disease. P53 positivity was acquired from in situ to invasive disease in C1 tumors but both components were positive in C2 tumors. Likewise, vimentin expression was increased from in situ to invasive tumor in C1 tumors only. Targeted next generation sequencing of 18 C1 tumors identified four mutations private to the invasive regions, including two in TP53, while 6 C2 tumors showed no private mutations. In the full LATTICe-A cohort, Ki67 fraction classified as either less than or greater than 10% within the in situ component of lung adenocarcinoma was identified as a strong predictor of patient outcome. This supports the proposition that tumors of all stages that have 'high grade' in situ components represent those with aggressive lepidic growth of the invasive clone. Overall these data support that the combined growth of Noguchi C tumors can represent two differing biological states and that 'Noguchi C1' tumors represent the genuine biological shift from in situ to invasive disease.

Fate of Clonal Lineages during Neoplasia and Metastasis Studied with an Incorporated Genetic Marker

Cancer Research, 1992

The fate of clonal lineages in tumor formation and metastasis has been studied by genotypic marking of cells from three separate tumor lines of different malignant potential. Marking was accomplished by random incorporation of the neomycin resistance gene and visualized by Southern blot analysis of integration sites. Primary tumors formed by polvi-lima! cell suspensions of all three cell lines injected s.c. usually remained polyclonal even at late stages of tumor growth and metastatic spread. Lung mÃ©tastases were often clonal, but it was not unusual to find ones of polyclonal origin. Lymph node mÃ©tastases were almost always polyclonal and remained so, as they grew large. Sometimes clones present in the original inoculum were absent in the primary. Other times clones visible in the mÃ©tastases were undetectable in the corresponding primary tumor. Occasionally a single clone became dominant in the primary, and others were eliminated, but this was not a necessary prelude to the onset of invasive or metastatic behavior.

Somatic genetic changes accompanying lung tumor development (original) (raw)

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