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

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

doi:10.18632/oncotarget.20510

Abstract

ObjectivesAnti-epidermal growth factor receptor (EGFR) therapy has been found to be more effective against left-sided colorectal cancer (LCRC) than right-sided 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 methodsA 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”.ResultsFifty-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).ConclusionsRCRC 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.

Highlights

The colon is an embryological derivative of the midgut and hindgut separately, and the right-sided colon, the leftsided colon, and the rectum each have different anatomical and physiological features
We hypothesized that rightsided colorectal cancer (RCRC) is more likely to harbor genetic alterations associated with resistance to anti-epidermal growth factor receptor (EGFR) therapy and tested this using comprehensive genomic sequencing
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 left-sided colorectal cancer (LCRC) (P = 0.009)

Summary

Introduction

The colon is an embryological derivative of the midgut and hindgut separately, and the right-sided colon, the leftsided colon, and the rectum each have different anatomical and physiological features. Left-sided colorectal cancer (LCRC) is more common in men, and associated with familial adenomatous polyposis syndrome, Wnt and EGFR signaling, chromosomal instability, ERBB1 and ERBB2 amplifications, and APC, p53, and NRAS mutations [10, 11]. Based on these molecular differences, sidedness of CRC is thought to be associated with efficacy of chemotherapy and targeted therapy. Several retrospective, unplanned analyses examined primary tumor sidedness and revealed that antiEGFR therapy clearly benefitted patients with LCRC, whereas patients with RCRC derived limited benefit [1517] While these analyses were limited by low numbers of RCRC patients, the related imbalance between groups, and no randomization; primary tumor sidedness of CRC has emerged as new predictive marker for efficacy of anti-EGFR therapy

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