Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: A phenotype/genotype correlation

Abstract

The transition of normal epithelium to invasive carcinoma occurs sequentially. In colorectal and cervical carcinogenesis, this transition is reflected by histomorphologically defined grades of increasing dysplasia that untreated may progress to invasive disease. In an attempt to understand the role of chromosomal aberrations during tumorigenesis we have applied comparative genomic hybridization using DNA extracted from defined stages of colorectal and cervical tumors, from low‐ and high‐grade astrocytic tumors and from diploid and aneuploid breast carcinomas. Genetic instability, as measured by the number of chromosomal copy alterations per case, increases significantly at the transition from precursor lesions to invasive carcinomas and continues to increase with tumor stage. Aggressive tumors have a higher number of copy alterations per case. High‐level copy number changes (amplifications) become more prevalent in advanced‐stage disease. Subtractive karyograms of chromosomal gains and losses were used to map tumor stage‐specific chromosomal aberrations and clearly showed that nonrandom chromosomal aberrations occur during disease progression. In colorectal and cervical tumors, chromosomal copy number changes were correlated with nuclear DNA content, proliferative activity, expression levels of the tumor suppressor gene TP53, and the cyclin‐dependent kinase inhibitor p21/WAF1, as well as the presence of viral genomes. Here we summarize and review the results of this comprehensive phenotype/genotype correlation and discuss the relevance of stage‐specific chromosomal aberrations with respect to diagnostic applications. Genes Chromosomes Cancer 25:195–204, 1999. Published 1999 Wiley‐Liss, Inc.

p53 Alteration and Chromosomal Instability in Prostatic High-Grade Intraepithelial Neoplasia and Concurrent Carcinoma: Analysis by Immunohistochemistry, Interphase In Situ Hybridization, and Sequencing of Laser-Captured Microdissected Specimens

“…IFISH has higher sensitivity than other methods used for this purpose, such as CGH, which detects copy number changes if they are present in more than 50% of the cell population (21). IFISH can identify CI in small subpopulations of interphase cells (68), allowing the detection of infrequent, possibly random changes before they lead to clonal expansion (20).…”

PIK3CA as an oncogene in cervical cancer

“…One critical downstream target of this signaling pathway is the activation of protein-Ser/ Thr kinase (AKT)-1, which subsequently e ects multiple cellular processes, including increased cellular proliferation or decreased apoptosis, and contributes to tumorigenesis (Klippel et al, 1998;Kennedy et al, 1997;Tlsty, 1999). Because ampli®cation in 3q is also the most consistent chromosomal aberration found in cervical cancer, and is implicated in the progression of dysplastic uterine cervical cells into invasive cancer (for review, Rooney et al, 1999;Ried et al, 1999), the present study sought to determine the contribution of PIK3CA in cervical tumorigenesis.…”

Assessments of clonal composition of colorectal adenomas by FISH analysis of chromosomes 1, 7, 13 and 20

“…[21][22][23][24] CGH studies on both colorectal adenomas and carcinomas have also confirmed the gain of chromosome 7 material as a frequent change. 11,12,25,26 Ried et al 12 demonstrated gain of chromosome 7 material in 4 of 12 in what they described as high-grade adenomas. The neoplasia-specificity of ϩ7 has been questioned, however, both in the context of colorectal carcinogenesis and in general.…”

“…5-7,16 -18 Similar results have been obtained by CGH analyses of colorectal adenomas and carcinomas. 11,25,26 In adenomas, Ried et al 12 described gain of chromosome 13 material in 1 of 26 adenomas and gain of chromosome 20 material in 3 of 26 adenomas. All cases with these changes were described as high-grade adenomas.…”