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

https://doi.org/10.1016/j.ejca.2004.01.012Get rights and content

Abstract

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 −17p13-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 −8p 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.

Introduction

Lung cancer is responsible for the highest cancer-related morbidity and mortality worldwide [1]. Non-small cell lung cancer (NSCLC) comprises approximately 80% of all lung cancers, among which adenocarcinoma (AdC) and squamous cell carcinoma (SqC) are now the two most common histological subtypes. Cigarette smoking continues to be an important aetiological factor, with a clear implication of involvement in over 95% of male cases [2]. A correlation between the incidence of lung cancer in females and smoking habit has also been observed in recent years [3].

Due to the high incidence and mortality rates, much effort has been drawn towards investigating the cause and course of NSCLC. Although classical cytogenetic studies by banding analysis can provide an overall view of structural and numerical abnormalities, the frequent presence of karyotypic complexity has precluded more accurate interpretation. Conversely, molecular characterisation by comparative genomic hybridisation (CGH) and allelotyping has shown common over-representations of 1q, 3q, 5p, 8q and 20, and loss of heterozygosity (LOH) on 3p, 8p, 13q and 17p in NSCLC 4, 5, 6. Despite the reportedly frequent genomic imbalances, the pattern of karyotypic alterations associated with AdC and SqC remains uncertain.

We have now conducted a comprehensive molecular cytogenetic characterisation of AdC and SqC tumours. By utilising CGH findings as a frame, individual information was examined in relation to chromosomal rearrangements described from spectral karyotyping (SKY). Cytogenetic information on NSCLC has mainly been derived from cell lines 7, 8, and we believe our study is the first to describe such information in primary tumours. Our combined CGH and SKY analysis shows distinct patterns of genetic aberration in the two specific NSCLC subtypes, which might in turn influence the different pathogenetic pathways adopted by these tumours.

Section snippets

Patients

Tumorous lung tissues were collected from 69 patients who underwent curative surgery for lung cancer at the Prince of Wales Hospital, Hong Kong. Tumours were classified according to the World Health Organisation histological typing of lung tumours, and staged according to the TNM classification of malignant tumours. 34 cases were diagnosed as AdC (age 43–79 years; stage T1–4N0–2M0–1) and 35 cases as SqC (age 47–83 years; stage T1–4N0–2M0). All patients had a smoking history. A smoker was

Results and discussion

CGH analysis of 69 NSCLC specimens produced informative findings in 61 (88%). In the series of SqC and AdC examined, genomic gains prevailed over losses (P<0.0005): a ratio of 10.1±5.6 copy gains ±(mean+S.D.) to 4.9±4.1 losses ±occurred in SqC, and a ratio of 6.2±5.1 copy gains ±to 2.2±1.8 losses in AdC. The aberrant tumour metaphases derived from SqC and AdC displayed a karyotype ranging from hyperdiploid to hypotetraploid. There was no significant difference in ploidy status between SqC and

Acknowledgements

This work was supported by a grant from the Research Grants Council of Hong Kong (Ref. No.: CUHK 4112/00M), and by The Kadoorie Charitable Foundations (under the auspices of the Hong Kong Cancer Genetics Research Group).

References (39)

  • A Jemal et al.

    Cancer Statistics, 2002

    CA Cancer J. Clin.

    (2002)
  • E.L Wynder et al.

    Lung cancer etiologychallenges of the future

    Carcinog. Compr. Surv.

    (1985)
  • I Petersen et al.

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

    Cancer Res.

    (1997)
  • J Pei et al.

    Genomic imbalances in human lung adenocarcinomas and squamous cell carcinomas

    Genes, Chromosomes & Cancer

    (2001)
  • A.K.O.-P Kallioniemi et al.

    Comparavtive genomic hybridization for molecular cytogenetic analysis of solid tumors

    Science

    (1992)
  • S du Manoir et al.

    Quantitative analysis of comparative genomic hybridization

    Cytometry

    (1995)
  • S du Manoir et al.

    Hardware and software requirements for quantitative analysis of comparative genomic hybridization

    Cytometry

    (1995)
  • M.B Eisen et al.

    Cluster analysis and display of genome-wide expression patterns

    PNAS

    (1998)
  • E.D.M.S Schrock et al.

    Multicolor spectral karyotyping of human chromosomes [Reports]

    Science

    (1996)
  • Cited by (58)

    • Prognostic value of chromosomal imbalances in squamous cell carcinoma and adenocarcinoma of the lung

      2011, Annals of Thoracic Surgery
      Citation Excerpt :

      Although genetic imbalances have already been described, we focused primarily on the sequential cytogenetic events that may be relevant for the discrimination of these tumor types and the influence on survival of this devastating entity. As reported by others [6, 8, 18] we observed high frequencies of chromosomal gains at 1q, 5p, and 8q in both SCC and AC. These chromosomal arms harbor genes such as the ARG oncogene at 1q, SKP2 and GDNF gene at 5p, and the c-myc oncogene at 8q, which can determine the biological behavior of tumor cells [19, 20].

    View all citing articles on Scopus
    View full text