Daphne W. Bell

Advances in the analysis of chromosome alterations in human lung carcinomas

A review of chromosomal analyses of human lung carcinomas is presented. Karyotypic studies have revealed multiple cytogenetic changes in most small cell lung carcinomas (SCLCs) and non-small cell lung carcinomas (NSCLCs). In SCLCs, losses from 3p, 5q, 13q, and 17p predominate; double minutes associated with amplification of members of the MYC oncogene family may be common late in disease. In NSCLCs, deletions of 3p, 9p, and 17p, +7, i(5)(p10), and i(8)(q10) often are reported. The recurrent deletions encompass sites of tumor suppressor genes commonly inactivated in lung carcinomas, such as CDKN2 (9p21), RB1 (13q14), and TP53 (17p13). Despite technical advances in cell culture, the rate of successful karyotypic analysis of lung carcinomas has remained low. Alternative molecular cytogenetic methods to assess chromosome changes in lung cancer, particularly comparative genomic hybridization (CGH) analysis, are discussed. Initial CGH studies confirm the existence of many of the karyotypic imbalances identified earlier in lung cancer and have revealed several recurrent abnormalities, such as 10q- in SCLC, that had not been recognized previously. The further application of such molecular cytogenetic approaches should enable investigators to define more precisely the spectrum and clinical implications of chromosome alterations in lung cancer.

Detection of DNA gains and losses in primary endometrial carcinomas by comparative genomic hybridization

Comparative genomic hybridization (CGH) was used in a retrospective analysis of chromosomal imbalances in frozen primary tumor specimens from 14 endometrial carcinoma patients. Chromosome changes were detected in nine cases (64%), and tumor stage and grade tended to parallel the degree of genomic imbalances. Gain of the entire long arm of chromosome I was observed in six cases (43%), three of which displayed only this chromosome change. Other common sites of copy number increases included 8q21 → qter (4 cases), 10p15 (4 cases), 10q11 → q24 (3 cases), and 13q21 → qter (3 cases, each with stage III disease). Two of the tumors with gains of chromosome 10 involved the whole chromosome, and this was the sole abnormality in one case. DNA amplification at 5p14 → p15 was identified in one specimen, a stage III tumor having numerous imbalances. DNA microsatellite analysis revealed multiple replication errors (RER), indicative of the RER+ phenotype, in four of 13 (31%) cases evaluated. The RER+ phenotype was observed in four of six stage Ia tumors but in none of seven stage Ib or stage III tumors. Multiple genomic imbalances detected by CGH were not observed in RER+ tumors but were detected in five of nine tumors without the RER+ phenotype. These investigations demonstrate the feasibility of CGH for the retrospective assessment of chromosomal changes in endometrial carcinoma specimens. Moreover, these data suggest that the etiologies in tumors with and without the RER+ phenotype may differ. Genes Chromosom. Cancer 18:115–125, 1997.

Chromosomal localization of a gene, GFI1, encoding a novel zinc finger protein reveals a new syntenic region between man and rodents

The Gfi1 gene encodes a zinc finger protein which binds DNA and is involved in transcriptional regulation. Gfi1 was assigned to the central portion of mouse Chr 5 by interspecific backcross mapping and to human chromosome band 1p22 and rat chromosome band 14p22 by fluorescence in situ hybridization (FISH). Comparative mapping data presented here describes a new syntenic region between man and rodents.

Combined chromosome microdissection and comparative genomic hybridization detect multiple sites of amplified DNA in a human lung carcinoma cell line

Chromosome microdissection‐fluorescence in situ hybridization and comparative genomic hybridization (CGH) were performed in parallel to identify the native location of amplified DNA in a human non‐small cell lung cancer (NSCLC) cell line exhibiting a homogeneously staining region (hsr) and double minutes (dmin). The native locations of microdissected DNA from the hsr and dmin were 7p12‐13 and 8q24, respectively. Southern analysis revealed coamplification of EGFR (7p12) and MYC (8q24). CGH detected amplification of DNA not only from 7p12‐13 and 8q24, but also from 9p24 and 10q22. Genes Chromosomes Cancer 20:208–212, 1997.

Human annexin 31 genetic mapping and origin

The cDNA encoding novel human annexin 31 was utilized for chromosomal mapping, structural comparison, and phylogenetic analysis to clarify its genetic relationship to other annexins. The ANX31 gene locus was mapped by fluorescence in situ hybridization to human chromosome 1q21, remote from ten other paralogous human annexins on different chromosomes but near the epidermal differentiation gene complex, the S100A gene cluster and a breast-cancer translocation region. Protein homology testing and characterization of incompletely processed expressed sequence tags identified annexin 2 as the closest extant homologue. Maximum likelihood analysis confirmed its most recent common ancestor with vertebrate annexin 2 and validated its classification, in order of discovery, as annexin 31. This subfamily was formed approx. 500-600millionyears ago, subsequent to the gene duplication that produced annexin 1. It has diverged relatively rapidly and extensively, and specifically in the well-conserved, functionally critical type II calcium-binding sites.

A microdissection library of the rat renal carcinoma gene region

Predisposition to hereditary renal carcinoma in the Eker rat involves a mutation of a putative tumor suppressor gene within chromosome band 10q12. We describe the identification of three unique polymorphic sequences in the vicinity of this locus following the microdissection, construction and characterization of a region-specific DNA library for rat chromosome band 10q12.

A genetic, physical, and comparative map of rat chromosome 10

A map of rat Chromosome (Chr) 10 was generated from 21 markers, mostly of conserved structural genes, by linkage analysis and fluorescence in situ hybridization. The study emphasizes the proximal third of the chromosome which, until now, has been relatively devoid of markers. Based on comparative analysis, our data suggest that genes on rat Chr 10 are conserved on mouse Chr 11, 16, 17 and human Chr 16, 5, and 17.

Chromosomes in Lung Cancer

Lung carcinomas are now the leading cause of neoplastic deaths among both men and women in the United States (1). With the increasing incidence of lung cancer, it is apparent that new diagnostic and staging techniques are needed. Because of the inadequacies of current therapeutic protocols, < 10% of all patients will achieve long-term survival and potential cures (2,3). Most therapeutic modalities currently available are specific to the histopathological type, i.e., small cell lung carcinoma (SCLC) versus nonsmall cell lung carcinoma (NSCLC). Our understanding of the biology of lung cancer indicates shared features among several histological variants (4). Identification of cytogenetic markers could allow for a better comprehension of this relationship that should, in turn, expand our knowledge of the overall disease process and offer the possibility of new treatment options. However, despite the high incidence of lung cancer, the cytogenetic data available are rather limited in this neoplasm compared to that for the hematological malignancies (5).