Recurrent hemizygous deletions in cancers may optimize proliferative potential.
Tumors exhibit numerous recurrent hemizygous focal deletions that contain no known tumor suppressors and are poorly understood. To investigate whether these regions contribute to tumorigenesis, we searched genetically for genes with cancer-relevant properties within these hemizygous deletions. We identified STOP and GO genes, which negatively and positively regulate proliferation, respectively. STOP genes include many known tumor suppressors, whereas GO genes are enriched for essential genes. Analysis of their chromosomal distribution revealed that recurring deletions preferentially overrepresent STOP genes and underrepresent GO genes. We propose a hypothesis called the cancer gene island model, whereby gene islands encompassing high densities of STOP genes and low densities of GO genes are hemizygously deleted to maximize proliferative fitness through cumulative haploinsufficiencies. Because hundreds to thousands of genes are hemizygously deleted per tumor, this mechanism may help to drive tumorigenesis across many cancer types.
Department of Genetics, Harvard University Medical School, and Division of Genetics, Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA 02115, USA.
Nicole L
NL
Solimini
Qikai
Q
Xu
Craig H
CH
Mermel
Anthony C
AC
Liang
Michael R
MR
Schlabach
Ji
J
Luo
Anna E
AE
Burrows
Anthony N
AN
Anselmo
Andrea L
AL
Bredemeyer
Mamie Z
MZ
Li
Rameen
R
Beroukhim
Matthew
M
Meyerson
Stephen J
SJ
Elledge
D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002874:Chromosome Mapping; D020043:Genes, Essential; D052138:Genes, Neoplasm; D005808:Genes, Recessive; D016147:Genes, Tumor Suppressor; D057895:Haploinsufficiency; D057898:Hemizygote; D006801:Humans; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology*; D009857:Oncogenes; D017384:Sequence Deletion