NOTCH gene alterations in metastatic colorectal cancer in the Nationwide Cancer Genome Screening Project in Japan (SCRUM-Japan GI-SCREEN)

被引：1

作者：

Kajiwara, Takeshi ^{[1
]}

Nishina, Tomohiro ^{[1
]}

Nakasya, Akio ^{[1
]}

Yamashita, Natsumi ^{[2
]}

Yamashita, Riu ^{[3
]}

Nakamura, Yoshiaki ^{[4
]}

Shiozawa, Manabu ^{[5
]}

Yuki, Satoshi ^{[6
]}

Taniguchi, Hiroya ^{[7
]}

Hara, Hiroki ^{[8
]}

Ohta, Takashi ^{[9
]}

Esaki, Taito ^{[10
]}

Shinozaki, Eiji ^{[11
]}

Takashima, Atsuo ^{[12
]}

Moriwaki, Toshikazu ^{[13
]}

Denda, Tadamichi ^{[14
]}

Ohtsubo, Koushiro ^{[15
]}

Sunakawa, Yu ^{[16
]}

Horita, Yosuke ^{[17
]}

Kawakami, Hisato ^{[18
]}

Kato, Takeshi ^{[19
]}

Satoh, Taroh ^{[20
]}

Ando, Koji ^{[21
]}

Mizutani, Tomonori ^{[22
]}

Yasui, Hisateru ^{[23
]}

Goto, Masahiro ^{[24
]}

Okuyama, Hiroyuki ^{[25
]}

Yamazaki, Kentaro ^{[26
]}

Yoshino, Takayuki ^{[4
]}

Hyodo, Ichinosuke ^{[1
]}

机构：

[1] Natl Hosp Org Shikoku Canc Ctr, Dept Gastrointestinal Med Oncol, 160 Kou,Minamiumemoto Machi, Matsuyama, Ehime 7910280, Japan

[2] Natl Hosp Org Shikoku Canc Ctr, Clin Res Ctr, Matsuyama, Ehime, Japan

[3] Natl Canc Ctr, Exploratory Oncol Res & Clin Trial Ctr, Div Translat Informat, Kashiwa, Chiba, Japan

[4] Natl Canc Ctr Hosp East, Dept Gastroenterol & Gastrointestinal Oncol, Kashiwa, Chiba, Japan

[5] Kanagawa Canc Ctr, Dept Gastrointestinal Surg, Yokohama, Kanagawa, Japan

[6] Hokkaido Univ Hosp, Dept Gastroenterol & Hepatol, Sapporo, Hokkaido, Japan

[7] Aichi Canc Ctr Hosp, Dept Clin Oncol, Nagoya, Aichi, Japan

[8] Saitama Canc Ctr, Dept Gastroenterol, Saitama, Japan

[9] Kansai Rosai Hosp, Dept Clin Oncol, Amagasaki, Hyogo, Japan

[10] Natl Hosp Org Kyushu Canc Ctr, Dept Gastrointestinal & Med Oncol, Fukuoka, Japan

[11] Japanese Fdn Canc Res, Canc Inst Hosp, Dept Gastroenterol Chemotherapy, Tokyo, Japan

[12] Natl Canc Ctr, Dept Gastrointestinal Med Oncol, Tokyo, Japan

[13] Univ Tsukuba, Fac Med, Dept Gastroenterol, Tsukuba, Ibaraki, Japan

[14] Chiba Canc Ctr, Div Gastroenterol, Chiba, Japan

[15] Kanazawa Univ, Canc Res Inst, Div Med Oncol, Kanazawa, Ishikawa, Japan

[16] St Marianna Univ, Sch Med, Dept Clin Oncol, Kawasaki, Kanagawa, Japan

[17] Saitama Med Univ Int Med Ctr, Dept Med Oncol, Hidaka, Japan

[18] Kindai Univ, Dept Med Oncol, Fac Med, Osakasayama, Japan

[19] Natl Hosp Org Osaka Natl Hosp, Dept Surg, Osaka, Japan

[20] Osaka Univ, Grad Sch Med, Dept Frontier Sci Canc & Chemotherapy, Suita, Osaka, Japan

[21] Kyushu Univ, Grad Sch Med Sci, Dept Surg & Sci, Fukuoka, Japan

[22] Kyorin Univ, Dept Gen Med, Dept Med Oncol, Fac Med, Mitaka, Tokyo, Japan

[23] Kobe City Med Ctr Gen Hosp, Dept Med Oncol, Kobe, Hyogo, Japan

[24] Osaka Med & Pharmaceut Univ, Canc Chemotherapy Ctr, Takatsuki, Osaka, Japan

[25] Kagawa Univ Hosp, Dept Clin Oncol, Miki, Kagawa, Japan

[26] Shizuoka Canc Ctr, Div Gastrointestinal Oncol, Nagaizumi, Shizuoka, Japan

来源：

JOURNAL OF CANCER RESEARCH AND CLINICAL ONCOLOGY | 2022年 / 148卷 / 10期

关键词：

NOTCH gene; Colorectal cancer; Next-generation sequencing; Prognosis; NEGATIVE BREAST-CANCER; HUMAN COLON; POOR-PROGNOSIS; MUTATIONS;

D O I：

10.1007/s00432-022-04064-4

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Purpose Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC. Methods Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay. Results The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC. Conclusion NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker.

引用

页码：2841 / 2854

页数：14

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