Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer

Keishi Sugimachi, Atsushi Niida, Ken Yamamoto, Teppei Shimamura, Seiya Imoto, Hisae Iinuma, Yoshiaki Shinden, Hidetoshi Eguchi, Tomoya Sudo, Masahiko Watanabe, Junichi Tanaka, Shinei Kudo, Kazuo Hase, Masato Kusunoki, Kazutaka Yamada, Yasuhiro Shimada, Kenichi Sugihara, Yoshihiko Maehara, Satoru Miyano, Masaki Mori & 1 others Koshi Mimori

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Abstract

Background: The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs).

Methods: The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH).

Results: The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy (UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases.

Conclusions: The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor.

Original languageEnglish
Pages (from-to)515-521
Number of pages7
JournalAnnals of Surgical Oncology
Volume21
Issue number4
DOIs
Publication statusPublished - Jan 1 2014

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Allelic Imbalance
Single Nucleotide Polymorphism
Colorectal Neoplasms
Alleles
Uniparental Disomy
Loss of Heterozygosity
Neoplasms
Genotype
Cell Line
Transcription Factors
Binding Sites
Databases
Phenotype

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

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Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer. / Sugimachi, Keishi; Niida, Atsushi; Yamamoto, Ken; Shimamura, Teppei; Imoto, Seiya; Iinuma, Hisae; Shinden, Yoshiaki; Eguchi, Hidetoshi; Sudo, Tomoya; Watanabe, Masahiko; Tanaka, Junichi; Kudo, Shinei; Hase, Kazuo; Kusunoki, Masato; Yamada, Kazutaka; Shimada, Yasuhiro; Sugihara, Kenichi; Maehara, Yoshihiko; Miyano, Satoru; Mori, Masaki; Mimori, Koshi.

In: Annals of Surgical Oncology, Vol. 21, No. 4, 01.01.2014, p. 515-521.

Research output: Contribution to journalArticle

Sugimachi, K, Niida, A, Yamamoto, K, Shimamura, T, Imoto, S, Iinuma, H, Shinden, Y, Eguchi, H, Sudo, T, Watanabe, M, Tanaka, J, Kudo, S, Hase, K, Kusunoki, M, Yamada, K, Shimada, Y, Sugihara, K, Maehara, Y, Miyano, S, Mori, M & Mimori, K 2014, 'Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer', Annals of Surgical Oncology, vol. 21, no. 4, pp. 515-521. https://doi.org/10.1245/s10434-013-3468-6
Sugimachi, Keishi ; Niida, Atsushi ; Yamamoto, Ken ; Shimamura, Teppei ; Imoto, Seiya ; Iinuma, Hisae ; Shinden, Yoshiaki ; Eguchi, Hidetoshi ; Sudo, Tomoya ; Watanabe, Masahiko ; Tanaka, Junichi ; Kudo, Shinei ; Hase, Kazuo ; Kusunoki, Masato ; Yamada, Kazutaka ; Shimada, Yasuhiro ; Sugihara, Kenichi ; Maehara, Yoshihiko ; Miyano, Satoru ; Mori, Masaki ; Mimori, Koshi. / Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer. In: Annals of Surgical Oncology. 2014 ; Vol. 21, No. 4. pp. 515-521.
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title = "Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer",
abstract = "Background: The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs).Methods: The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH).Results: The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy (UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases.Conclusions: The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor.",
author = "Keishi Sugimachi and Atsushi Niida and Ken Yamamoto and Teppei Shimamura and Seiya Imoto and Hisae Iinuma and Yoshiaki Shinden and Hidetoshi Eguchi and Tomoya Sudo and Masahiko Watanabe and Junichi Tanaka and Shinei Kudo and Kazuo Hase and Masato Kusunoki and Kazutaka Yamada and Yasuhiro Shimada and Kenichi Sugihara and Yoshihiko Maehara and Satoru Miyano and Masaki Mori and Koshi Mimori",
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T1 - Allelic Imbalance at an 8q24 Oncogenic SNP is Involved in Activating MYC in Human Colorectal Cancer

AU - Sugimachi, Keishi

AU - Niida, Atsushi

AU - Yamamoto, Ken

AU - Shimamura, Teppei

AU - Imoto, Seiya

AU - Iinuma, Hisae

AU - Shinden, Yoshiaki

AU - Eguchi, Hidetoshi

AU - Sudo, Tomoya

AU - Watanabe, Masahiko

AU - Tanaka, Junichi

AU - Kudo, Shinei

AU - Hase, Kazuo

AU - Kusunoki, Masato

AU - Yamada, Kazutaka

AU - Shimada, Yasuhiro

AU - Sugihara, Kenichi

AU - Maehara, Yoshihiko

AU - Miyano, Satoru

AU - Mori, Masaki

AU - Mimori, Koshi

PY - 2014/1/1

Y1 - 2014/1/1

N2 - Background: The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs).Methods: The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH).Results: The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy (UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases.Conclusions: The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor.

AB - Background: The rs6983267 at 8q24.21 has been established as a significant cancer-related single nucleotide polymorphism (SNP). The risk allele showed similarity to the binding site of transcription factor TCF4/LEF1 that activates transcription of MYC. However, little is known about the role of this SNP in increasing MYC activity in colorectal cancers (CRCs).Methods: The genotypes of rs6983267 in peripheral blood and primary cancers, MYC activity and copy number (CN) alteration were examined in 107 CRCs. Next, we plotted the number of cancers cell lines exhibiting specific G/T genotypes in 746 cancer cell lines of the Sanger Institute database. Then we validated the relationship between the 8q24 SNP status and clinicopathologic parameters in 68 CRCs with loss of heterozygosity (LOH).Results: The MYC module activity was activated by either transcription in the risk allele (G) or by amplification in the non-risk allele (T). Then, we confirmed that the CN amplification dominantly occurred in the non-risk allele, whereas CN neutral LOH, which indicated uniparental disomy (UPD) was more frequently observed for the risk allele. Finally, we confirmed that risk allele dominant cases, either by amplification or by UPD, indicated a more malignant clinical phenotype than non-risk allele dominant cases.Conclusions: The development of CRC requires MYC activation through retention of the risk allele, or amplification of the non-risk allele at the oncogenic SNP in the site of primary tumor.

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DO - 10.1245/s10434-013-3468-6

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EP - 521

JO - Annals of Surgical Oncology

JF - Annals of Surgical Oncology

SN - 1068-9265

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