Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer

Yoshifumi Shimada, Hitoshi Kameyama, Masayuki Nagahashi, Hiroshi Ichikawa, Yusuke Muneoka, Ryoma Yagi, Yosuke Tajima, Takuma Okamura, Masato Nakano, Jun Sakata, Takashi Kobayashi, Hitoshi Nogami, Satoshi Maruyama, Yasumasa Takii, Tetsu Hayashida, Hiromasa Takaishi, Yuukou Kitagawa, Eiji Oki, Tsuyoshi Konishi, Fumio IshidaShin ei Kudo, Jennifer E. Ring, Alexei Protopopov, Stephen Lyle, Yiwei Ling, Shujiro Okuda, Takashi Ishikawa, Kohei Akazawa, Kazuaki Takabe, Toshifumi Wakai

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than rightsided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

Original languageEnglish
Pages (from-to)93567-93579
Number of pages13
JournalOncotarget
Volume8
Issue number55
DOIs
Publication statusPublished - 2017 Nov 1

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Colorectal Neoplasms
Epidermal Growth Factor Receptor
Therapeutics
Disease-Free Survival
Neoplasms
Phosphatidylinositol 3-Kinases
Genes

Keywords

  • Anti-EGFR therapy
  • Colorectal cancer
  • Comprehensive genomic sequencing
  • Next-generation sequencing
  • Right-sided

ASJC Scopus subject areas

  • Oncology

Cite this

Shimada, Y., Kameyama, H., Nagahashi, M., Ichikawa, H., Muneoka, Y., Yagi, R., ... Wakai, T. (2017). Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer. Oncotarget, 8(55), 93567-93579. https://doi.org/10.18632/oncotarget.20510

Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer. / Shimada, Yoshifumi; Kameyama, Hitoshi; Nagahashi, Masayuki; Ichikawa, Hiroshi; Muneoka, Yusuke; Yagi, Ryoma; Tajima, Yosuke; Okamura, Takuma; Nakano, Masato; Sakata, Jun; Kobayashi, Takashi; Nogami, Hitoshi; Maruyama, Satoshi; Takii, Yasumasa; Hayashida, Tetsu; Takaishi, Hiromasa; Kitagawa, Yuukou; Oki, Eiji; Konishi, Tsuyoshi; Ishida, Fumio; Kudo, Shin ei; Ring, Jennifer E.; Protopopov, Alexei; Lyle, Stephen; Ling, Yiwei; Okuda, Shujiro; Ishikawa, Takashi; Akazawa, Kohei; Takabe, Kazuaki; Wakai, Toshifumi.

In: Oncotarget, Vol. 8, No. 55, 01.11.2017, p. 93567-93579.

Research output: Contribution to journalArticle

Shimada, Y, Kameyama, H, Nagahashi, M, Ichikawa, H, Muneoka, Y, Yagi, R, Tajima, Y, Okamura, T, Nakano, M, Sakata, J, Kobayashi, T, Nogami, H, Maruyama, S, Takii, Y, Hayashida, T, Takaishi, H, Kitagawa, Y, Oki, E, Konishi, T, Ishida, F, Kudo, SE, Ring, JE, Protopopov, A, Lyle, S, Ling, Y, Okuda, S, Ishikawa, T, Akazawa, K, Takabe, K & Wakai, T 2017, 'Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer', Oncotarget, vol. 8, no. 55, pp. 93567-93579. https://doi.org/10.18632/oncotarget.20510
Shimada, Yoshifumi ; Kameyama, Hitoshi ; Nagahashi, Masayuki ; Ichikawa, Hiroshi ; Muneoka, Yusuke ; Yagi, Ryoma ; Tajima, Yosuke ; Okamura, Takuma ; Nakano, Masato ; Sakata, Jun ; Kobayashi, Takashi ; Nogami, Hitoshi ; Maruyama, Satoshi ; Takii, Yasumasa ; Hayashida, Tetsu ; Takaishi, Hiromasa ; Kitagawa, Yuukou ; Oki, Eiji ; Konishi, Tsuyoshi ; Ishida, Fumio ; Kudo, Shin ei ; Ring, Jennifer E. ; Protopopov, Alexei ; Lyle, Stephen ; Ling, Yiwei ; Okuda, Shujiro ; Ishikawa, Takashi ; Akazawa, Kohei ; Takabe, Kazuaki ; Wakai, Toshifumi. / Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer. In: Oncotarget. 2017 ; Vol. 8, No. 55. pp. 93567-93579.
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abstract = "Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than rightsided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as {"}all wild-type{"}, while remaining patients were defined as {"}mutant-type{"}. Results: Fifty-six patients (28{\%}) and 145 patients (72{\%}) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11{\%}) with RCRC were {"}all wild-type{"} compared with 41 of 145 patients (28{\%}) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and {"}mutant-type{"} RCRC showed significantly worse PFS compared with {"}all wild-type{"} LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.",
keywords = "Anti-EGFR therapy, Colorectal cancer, Comprehensive genomic sequencing, Next-generation sequencing, Right-sided",
author = "Yoshifumi Shimada and Hitoshi Kameyama and Masayuki Nagahashi and Hiroshi Ichikawa and Yusuke Muneoka and Ryoma Yagi and Yosuke Tajima and Takuma Okamura and Masato Nakano and Jun Sakata and Takashi Kobayashi and Hitoshi Nogami and Satoshi Maruyama and Yasumasa Takii and Tetsu Hayashida and Hiromasa Takaishi and Yuukou Kitagawa and Eiji Oki and Tsuyoshi Konishi and Fumio Ishida and Kudo, {Shin ei} and Ring, {Jennifer E.} and Alexei Protopopov and Stephen Lyle and Yiwei Ling and Shujiro Okuda and Takashi Ishikawa and Kohei Akazawa and Kazuaki Takabe and Toshifumi Wakai",
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T1 - Comprehensive genomic sequencing detects important genetic differences between right-sided and left-sided colorectal cancer

AU - Shimada, Yoshifumi

AU - Kameyama, Hitoshi

AU - Nagahashi, Masayuki

AU - Ichikawa, Hiroshi

AU - Muneoka, Yusuke

AU - Yagi, Ryoma

AU - Tajima, Yosuke

AU - Okamura, Takuma

AU - Nakano, Masato

AU - Sakata, Jun

AU - Kobayashi, Takashi

AU - Nogami, Hitoshi

AU - Maruyama, Satoshi

AU - Takii, Yasumasa

AU - Hayashida, Tetsu

AU - Takaishi, Hiromasa

AU - Kitagawa, Yuukou

AU - Oki, Eiji

AU - Konishi, Tsuyoshi

AU - Ishida, Fumio

AU - Kudo, Shin ei

AU - Ring, Jennifer E.

AU - Protopopov, Alexei

AU - Lyle, Stephen

AU - Ling, Yiwei

AU - Okuda, Shujiro

AU - Ishikawa, Takashi

AU - Akazawa, Kohei

AU - Takabe, Kazuaki

AU - Wakai, Toshifumi

PY - 2017/11/1

Y1 - 2017/11/1

N2 - Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than rightsided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

AB - Objectives: Anti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than rightsided colorectal cancer (RCRC). We hypothesized that RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy and tested this using comprehensive genomic sequencing. Materials and methods: A total of 201 patients with either primary RCRC or LCRC were analyzed. We investigated tumors for genetic alterations using a 415-gene panel, which included alterations associated with resistance to anti-EGFR therapy: TK receptors (ERBB2, MET, EGFR, FGFR1, and PDGFRA), RAS pathway (KRAS, NRAS, HRAS, BRAF, and MAPK2K1), and PI3K pathway (PTEN and PIK3CA). Patients whose tumors had no alterations in these 12 genes, theoretically considered to respond to anti-EGFR therapy, were defined as "all wild-type", while remaining patients were defined as "mutant-type". Results: Fifty-six patients (28%) and 145 patients (72%) had RCRC and LCRC, respectively. Regarding genetic alterations associated with anti-EGFR therapy, only 6 of 56 patients (11%) with RCRC were "all wild-type" compared with 41 of 145 patients (28%) with LCRC (P = 0.009). Among the 49 patients who received anti-EGFR therapy, RCRC showed significantly worse progression-free survival (PFS) than LCRC (P = 0.022), and "mutant-type" RCRC showed significantly worse PFS compared with "all wild-type" LCRC (P = 0.004). Conclusions: RCRC is more likely to harbor genetic alterations associated with resistance to anti-EGFR therapy compared with LCRC. Furthermore, our data shows primary tumor sidedness is a surrogate for the non-random distribution of genetic alterations in CRC.

KW - Anti-EGFR therapy

KW - Colorectal cancer

KW - Comprehensive genomic sequencing

KW - Next-generation sequencing

KW - Right-sided

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