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Frequent Mutation of the E2F-4 Cell Cycle Gene in Primary Human Gastrointestinal Tumors¹

Departments of Medicine (Gl Division) [R. F. S., J. Y., K. N. S., T-T. Z., S. W., Y-Q. S., J. M. A., S. J. M.], Pathology [J. C., S. J. M.], and Greenebaum Cancer Center [J. M. A., S. J. M.], University of Maryland School of Medicine and Baltimore Veterans Affairs Medical Center, Baltimore, maryland 21201-1595; Department of Microbiology, Catholic University Medical College, 137-701 Seoul, South Korea [M-G. R.]; Glaxo Conjoint Gastroenterology Laboratory, Royal Brisbane Hospital, Q4029 Herston, Australia [K. B., L. S., B. L., J. Y.]; Brady Urological Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland 21287 [G. S. B.]; Department of Pathology, University of Michigan School of Medicine, Michigan 48109 [T. F.]; Department of Medicine/Gl Division, University of Virginia, Charlottesville, Virginia 22908 [S. M. P.]; First Department of Pathology, Hamamatsu University School of Medicine, 431-31 Hamamatsu, Japan [H. S.]; Department of Pathology, Mt. Sinai University School of Medicine, New York, New York 10029 [N. H.]; and First Department of Surgery and Molecular Genetics, Okayama University Medical School, 700 Okayama, Japan [K. S., N. M.]

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.

¹ Supported by USPHS Grants DK47717, CA67497, and ES07120, American Cancer Society Grant EDT-74525, National Aeronautics and Space Administration Grant 9307-0502, and the Office of Medical Research, Department of Veterans Affairs, R. F. S. is the recipient of National Research Service Award CA68765.

² To whom requests for reprints should be addressed, at University of Maryland, Med/GI, 22 South Greene Street, Room N3W62, Baltimore, MD 21201, Phone: (410) 706-3375; Fax: (410) 328-6559.

Received 1/17/97. Accepted 5/ 5/97.

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