Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors

Rhonda F. Souza, Jing Yin, Kara N. Smolinski, Tong Tong Zou, Suna Wang, Ying Qiang Shi, Mun Gan Rhyu, John Cottrell, John M. Abraham, Kelli Biden, Lisa Simms, Barbara Leggett, G. Steven Bova, Tom Frank, Steven M. Powell, Haruhiko Sugimura, Joanne Young, Noam Harpaz, Kenji Shimizu, Nagahide MatsubaraStephen J. Meltzer

Research output: Contribution to journalArticle

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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, function 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.

Original languageEnglish (US)
Pages (from-to)2350-2353
Number of pages4
JournalCancer Research
Volume57
Issue number12
StatePublished - Jun 15 1997

Fingerprint

cdc Genes
Mutation
Colorectal Neoplasms
Neoplasms
Trinucleotide Repeats
Genes
Ulcerative Colitis
Serine
Stomach
E2F Transcription Factors
Catenins
Retinoblastoma Protein
Neoplasm Genes
Cadherins
Endometrial Neoplasms
Oncogenes
DNA Repair
Prostate
Cell Cycle
Carcinogenesis

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Souza, R. F., Yin, J., Smolinski, K. N., Zou, T. T., Wang, S., Shi, Y. Q., ... Meltzer, S. J. (1997). Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer Research, 57(12), 2350-2353.

Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. / Souza, Rhonda F.; Yin, Jing; Smolinski, Kara N.; Zou, Tong Tong; Wang, Suna; Shi, Ying Qiang; Rhyu, Mun Gan; Cottrell, John; Abraham, John M.; Biden, Kelli; Simms, Lisa; Leggett, Barbara; Bova, G. Steven; Frank, Tom; Powell, Steven M.; Sugimura, Haruhiko; Young, Joanne; Harpaz, Noam; Shimizu, Kenji; Matsubara, Nagahide; Meltzer, Stephen J.

In: Cancer Research, Vol. 57, No. 12, 15.06.1997, p. 2350-2353.

Research output: Contribution to journalArticle

Souza, RF, Yin, J, Smolinski, KN, Zou, TT, Wang, S, Shi, YQ, Rhyu, MG, Cottrell, J, Abraham, JM, Biden, K, Simms, L, Leggett, B, Bova, GS, Frank, T, Powell, SM, Sugimura, H, Young, J, Harpaz, N, Shimizu, K, Matsubara, N & Meltzer, SJ 1997, 'Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors', Cancer Research, vol. 57, no. 12, pp. 2350-2353.
Souza RF, Yin J, Smolinski KN, Zou TT, Wang S, Shi YQ et al. Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. Cancer Research. 1997 Jun 15;57(12):2350-2353.
Souza, Rhonda F. ; Yin, Jing ; Smolinski, Kara N. ; Zou, Tong Tong ; Wang, Suna ; Shi, Ying Qiang ; Rhyu, Mun Gan ; Cottrell, John ; Abraham, John M. ; Biden, Kelli ; Simms, Lisa ; Leggett, Barbara ; Bova, G. Steven ; Frank, Tom ; Powell, Steven M. ; Sugimura, Haruhiko ; Young, Joanne ; Harpaz, Noam ; Shimizu, Kenji ; Matsubara, Nagahide ; Meltzer, Stephen J. / Frequent mutation of the E2F-4 cell cycle gene in primary human gastrointestinal tumors. In: Cancer Research. 1997 ; Vol. 57, No. 12. pp. 2350-2353.
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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, function 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.",
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AU - Souza, Rhonda F.

AU - Yin, Jing

AU - Smolinski, Kara N.

AU - Zou, Tong Tong

AU - Wang, Suna

AU - Shi, Ying Qiang

AU - Rhyu, Mun Gan

AU - Cottrell, John

AU - Abraham, John M.

AU - Biden, Kelli

AU - Simms, Lisa

AU - Leggett, Barbara

AU - Bova, G. Steven

AU - Frank, Tom

AU - Powell, Steven M.

AU - Sugimura, Haruhiko

AU - Young, Joanne

AU - Harpaz, Noam

AU - Shimizu, Kenji

AU - Matsubara, Nagahide

AU - Meltzer, Stephen J.

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N2 - 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, function 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.

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