High-resolution 19p13.2-13.3 allelotyping of breast carcinomas demonstrates frequent loss of heterozygosity
Journal
Genes Chromosomes and Cancer
Journal Volume
41
Journal Issue
3
Pages
250-256
Date Issued
2004
Author(s)
Abstract
In breast cancer, a high frequency of genomic deletion is found in chromosomal region 19p13. Of particular interest is that the LKB1 gene (also known as STK11) has been mapped to this region. LKB1 is responsible for Peutz-Jeghers syndrome (PJS), a genetic disease characterized by mucocutaneous pigmentation and gastrointestinal hematoma with an increased risk of developing cancer, including breast cancer. To further clarify the role of chromosomal region 19p13.2-13.3 in the pathogenesis of breast cancer and to identify more precisely candidate tumor-suppressor genes (TSGs) for positional cloning studies, we performed detailed high-resolution allelotyping analysis to detect allelic loss or loss of heterozygosity (LOH) in this region on microdissected samples from 140 primary breast tumors using 24 microsatellite markers. The highest frequencies of LOH were seen with D19S883 (30%) and D19S216 (29%), both at 19p13.3, D19S922 (28%), at 19p13.3-19p13.2, and D19S865 (39%), at 19p13.2; in addition, identification was made of at least four common deletion regions, including the LKB1 locus, that are centered on these four markers. In all the cases, we found discontinuous allele loss at several 19p13.2-13.3 sites in the same tumor (with the markers with the highest frequency of LOH adjacent to markers retaining heterozygosity), suggesting the presence of multiple TSGs. Interestingly, in tumors, the extent of allelic loss at these markers (measured as the fractional allele loss) increased significantly as the tumors progressed to poorer grades (P < 0.05). We conclude that 19p13.2-13.3 allele loss is a common event in the pathogenesis of breast carcinoma that often involves discontinuous LOH of multiple, localized TSGs (including LKB1), the concurrent inactivation of which may contribute to breast cancer progression. ? 2004 Wiley-Liss, Inc.
SDGs
Other Subjects
allele; article; breast carcinoma; chromosome 19p; familial cancer; female; gene; gene deletion; gene locus; gene mapping; genetic analysis; genetic risk; heterozygosity loss; human; human tissue; laser capture microdissection; LKB1 gene; molecular cloning; multigene family; Peutz Jeghers syndrome; priority journal; tumor localization; tumor suppressor gene; Adult; Aged; Aged, 80 and over; Alleles; Breast Neoplasms; Chromosomes, Human, Pair 19; Disease Progression; Family Health; Female; Gene Deletion; Genes, Tumor Suppressor; Hematoma; Humans; Lasers; Loss of Heterozygosity; Microsatellite Repeats; Middle Aged; Polymerase Chain Reaction
Type
journal article