Three tumor-suppressor regions on chromosome 11p identified by high- resolution deletion mapping in human non-small-cell lung cancer

Abstract

Non-small-cell lung cancer is the leading cause of cancer death for men and women in the ind ald nations. Identification of regions for genes involved in its pathogenesis has been difficult. Data presented here show three distinct regions identified on chromosome 11p. Two regions on 11pl3 distal to the Wilms tumor gene WT1 and on 11pl1.5 between the markers HBB and DIIS860 are described. The third region on the telomere of 11plS.5 has been previously described and is further delineated in this communication. By high-resolution mapping the size of each of these regions was estimated to be 2-3 megabases. The frequency of somatic loss of genetic information in these regions (57%, 71%, and 45%, respectively) was comparable to that seen in heritable tumors such as Wilms tumor (55%) and retinoblastoma (70%) and suggests their involvement in pathogenesis of non-small-cell lung cancer. Gene dosage analyses revealed duplication of the remaining allele in the majority of cases in the 11pl3 and the proximal 11p15.5 region but rarely in the distal 11pl5.5 region. In tumors with loss of heterozygosity in all three regions any combination of duplctin or simple deletion was observed, suggesting that loss ofheterozygosity occurs independently and perhaps at different points in time. These results provide a basis for studies directed at cloning potential tumor-suppressor genes in these regions and for assessing their biological and clinical sgnifcance In non-small-cell lung cancer.Non-small-cell lung cancer (NSCLC) comprises all primary malignant lung tumors except small-cell tumors and accounts for 80%o of all lung cancers. Many reasons should place NSCLC in the front line ofcancer research. Some ofthese are as follows: (i) the annual incidence of lung cancer is --3 x 106 worldwide and continues to rise; (ii) the number of young individuals without exposure to tobacco, in particular women, is rising; (iii) 87% of patients with NSCLC will die of the disease, and approximately 115,000 people annually succumb to NSCLC in the United States; (iv) the 5-year survival rate of 13% has not changed appreciably in the last 20 years; (v) screening of high-risk individuals with frequent chest radiographs and sputum cytological examinations was proven unsuccessful; and (vi) fresh specimens and wellcharacterized immortalized cell lines are now available (1). The molecular genetic data presented here will provide a focus for investigations to isolate genetic elements involved in NSCLC development and progression.The identification of regions for genes involved in the pathogenesis of NSCLC has been difficult because a possible familial rsk is obscured by environmental risk factors (2, 3) and because cytogenetic analyses have shown complex aberrations (4, 5). Molecular genetic studies have implicated chromosomes 3 (6, 7), 5 (8), 8 (9), 9 (10, 11), 11 (12, 13), and 17 (12) as possibly carrying disease-related regions. The present study was performed to specifically address whether chromosome 11 harbors NSCLC regions.Mechanisms by which re...