title: Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors.
abstract: The E2F group of transcription factors transactivates genes that promote progression through the G1-S transition of the cell cycle. Members of the retinoblastoma (Rb) family of proteins bind to E2Fs and inhibit this function. E2F-4, one example of the E2F group, functions as an oncogene when transfected into nontransformed cells in vitro. On the other hand, mice that are homozygously lacking a normal E2F-1 gene develop cancers, consistent with a tumor-suppressive role for this gene. The exact function of E2Fs has thus been unclear; moreover, direct involvement of this gene in primary human tumorigenesis has not been shown. We, therefore, investigated mutation within the E2F-4 coding region in 16 primary gastric adenocarcinomas, 12 ulcerative colitis-associated neoplasms, 46 sporadic colorectal carcinomas, 9 endometrial cancers, and 3 prostatic carcinomas. We limited our investigation to the serine repeat within E2F-4, reasoning that this tract might be altered in genetically unstable tumors (replication error-positive, or RER+). All tumors were RER+, with the exception of a control group of 15 RER- sporadic colorectal carcinomas. PCR with incorporation of [32P]dCTP was performed using primers flanking the serine trinucleotide (AGC) repeat. Twenty-two of 59 gastrointestinal tumors (37%) contained E2F-4 mutations; these comprised 5 of 16 gastric tumors (31%), 4 of 12 ulcerative colitis-associated neoplasms (33%, including 1 dysplastic lesion), and 13 of 31 sporadic colorectal cancers (42%). No mutation was present in any of the endometrial, prostate, or RER- colorectal tumors. Of note, homozygous mutations occurred in three cases, and two of seven informative patients showed loss of one E2F-4 allele in their tumors. Furthermore, the RER+ sporadic colorectal tumors were evaluated at trinucleotide repeats within the genes for N-cadherin and B-catenin; no tumors demonstrated mutation of these genes. These data suggest that E2F-4 is a target of defective DNA repair in these tumors.
authors.affiliation: Department of Medicine, University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, 21201-1595, USA.
authors.forename: R F
authors.initials: RF
authors.lastname: Souza
authors.forename: J
authors.initials: J
authors.lastname: Yin
authors.forename: K N
authors.initials: KN
authors.lastname: Smolinski
authors.forename: T T
authors.initials: TT
authors.lastname: Zou
authors.forename: S
authors.initials: S
authors.lastname: Wang
authors.forename: Y Q
authors.initials: YQ
authors.lastname: Shi
authors.forename: M G
authors.initials: MG
authors.lastname: Rhyu
authors.forename: J
authors.initials: J
authors.lastname: Cottrell
authors.forename: J M
authors.initials: JM
authors.lastname: Abraham
authors.forename: K
authors.initials: K
authors.lastname: Biden
authors.forename: L
authors.initials: L
authors.lastname: Simms
authors.forename: B
authors.initials: B
authors.lastname: Leggett
authors.forename: G S
authors.initials: GS
authors.lastname: Bova
authors.forename: T
authors.initials: T
authors.lastname: Frank
authors.forename: S M
authors.initials: SM
authors.lastname: Powell
authors.forename: H
authors.initials: H
authors.lastname: Sugimura
authors.forename: J
authors.initials: J
authors.lastname: Young
authors.forename: N
authors.initials: N
authors.lastname: Harpaz
authors.forename: K
authors.initials: K
authors.lastname: Shimizu
authors.forename: N
authors.initials: N
authors.lastname: Matsubara
authors.forename: S J
authors.initials: SJ
authors.lastname: Meltzer
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics*; D000483:Alleles; D015820:Cadherins / Q000235:genetics; D002872:Chromosome Deletion; D003598:Cytoskeletal Proteins / Q000235:genetics; D004273:DNA, Neoplasm / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D050704:E2F4 Transcription Factor; D016889:Endometrial Neoplasms / Q000235:genetics; D005260:Female; D005770:Gastrointestinal Neoplasms / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000235:genetics; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics*; D051176:beta Catenin
chemical_list: C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; D050704:E2F4 Transcription Factor; D015534:Trans-Activators; D014157:Transcription Factors; D051176:beta Catenin