High-resolution mapping identifies a commonly amplified 11q13.3 region containing multiple genes flanked by segmental duplications.
DNA amplification of the 11q13 region is observed frequently in many carcinomas. Within the amplified region several candidate oncogenes have been mapped, including cyclin D1, TAOS1 and cortactin. Yet, it is unknown which gene(s) is/are responsible for the selective pressure enabling amplicon formation. This is probably due to the use of low-resolution detection methods. Furthermore, the size and structure of the amplified 11q13 region is complex and consists of multiple amplicon cores that differ between different tumor types. We set out to test whether the borders of the 11q13 amplicon are restricted to regions that enable DNA breakage and subsequent amplification. A high-resolution array of the 11q13 region was generated to study the structure of the 11q13 amplicon and analyzed 29 laryngeal and pharyngeal carcinomas and nine cell lines with 11q13 amplification. We found that boundaries of the commonly amplified region were restricted to four segments. Three boundaries coincided with a syntenic breakpoint. Such regions have been suggested to be putatively fragile. Sequence comparisons revealed that the amplicon was flanked by two large low copy repeats known as segmental duplications. These segmental duplications might be responsible for the typical structure and size of the 11q13 amplicon. We hypothesize that the selection for genes through amplification of the 11q13.3 region is determined by the ability to form DNA breaks within specific regions and, consequently, results in large amplicons containing multiple genes.
Gibcus
Johan H
JH
Department of Pathology, University Medical Center Groningen, University of Groningen, 9700 RB Groningen, The Netherlands.
Kok
Klaas
K
Menkema
Lorian
L
Hermsen
Mario A
MA
Mastik
Mirjam
M
Kluin
Philip M
PM
van der Wal
Jacqueline E
JE
Schuuring
Ed
E
D000818:Animals; D002277:Carcinoma / Q000235:genetics; D045744:Cell Line, Tumor; D002874:Chromosome Mapping; D002880:Chromosomes, Human, Pair 11 / Q000648:ultrastructure*; D051356:Cortactin / Q000235:genetics; D019938:Cyclin D1 / Q000235:genetics; D004249:DNA Damage; D020440:Gene Duplication; D006258:Head and Neck Neoplasms / Q000235:genetics; D006801:Humans; D007091:Image Processing, Computer-Assisted; D017404:In Situ Hybridization, Fluorescence; D009363:Neoplasm Proteins / Q000235:genetics; D009693:Nucleic Acid Hybridization
D051356:Cortactin; C465628:LTO1 protein, human; D009363:Neoplasm Proteins; D019938:Cyclin D1