TY - JOUR
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, Yuko
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
N1 - Publisher Copyright:
© Shimada et al.
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.
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U2 - 10.18632/oncotarget.20510
DO - 10.18632/oncotarget.20510
M3 - Article
AN - SCOPUS:85032967314
SN - 1949-2553
VL - 8
SP - 93567
EP - 93579
JO - Oncotarget
JF - Oncotarget
IS - 55
ER -