Clinicopathological, molecular, and prognostic features of colorectal carcinomas with KRAS c.34G>T (p.G12C) mutation

IF 4.5 2区医学 Q1 ONCOLOGY

Cancer Science Pub Date : 2024-07-22 DOI:10.1111/cas.16262

Satoko Ugai, Qian Yao, Yasutoshi Takashima, Yuxue Zhong, Kosuke Matsuda, Hidetaka Kawamura, Yu Imamura, Kazuo Okadome, Kosuke Mima, Kota Arima, Keisuke Kosumi, Mingyang Song, Jeffrey A. Meyerhardt, Marios Giannakis, Jonathan A. Nowak, Tomotaka Ugai, Shuji Ogino

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Abstract

Evidence indicates that combinations of anti-EGFR antibodies and KRAS p.G12C (c.34G>T) inhibitors can be an effective treatment strategy for advanced colorectal cancer. We hypothesized that KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma might be a distinct tumor subtype. We utilized a prospective cohort incident tumor biobank (including 1347 colorectal carcinomas) and detected KRAS c.34G>T (p.G12C) mutation in 43 cases (3.2%) and other KRAS mutations (in codon 12, 13, 61, or 146) in 467 cases (35%). The CpG island methylator phenotype (CIMP)-low prevalence was similarly higher in KRAS c.34G>T mutants (52%) and other KRAS mutants (49%) than in KRAS-wild-type tumors (31%). KRAS c.34G>T mutants showed higher CIMP-high prevalence (14%) and lower CIMP-negative prevalence (33%) compared with other KRAS mutants (6% and 45%, respectively; p = 0.0036). Similar to other KRAS mutants, KRAS c.34G>T-mutated tumors were associated with cecal location, non-microsatellite instability (MSI)-high status, BRAF wild type, and PIK3CA mutation when compared with KRAS-wild-type tumors. Compared with BRAF-mutated tumors, KRAS c.34G>T mutants showed more frequent LINE-1 hypomethylation, a biomarker for early-onset colorectal carcinoma. KRAS c.34G>T mutants were not associated with other features, including the tumor tissue abundance of Fusobacterium nucleatum (F. animalis), pks⁺ Escherichia coli, Bifidobacterium, or (enterotoxigenic) Bacteroides fragilis. Among 1122 BRAF-wild-type colorectal carcinomas, compared with KRAS-wild-type tumors, multivariable-adjusted colorectal cancer-specific mortality hazard ratios (95% confidence interval) were 1.82 (1.05–3.17) in KRAS c.34G>T (p.G12C)-mutated tumors (p = 0.035) and 1.57 (1.22–2.02) in other KRAS-mutated tumors (p = 0.0004). Our study provides novel evidence for clinical and tumor characteristics of KRAS c.34G>T (p.G12C)-mutated colorectal carcinoma.

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KRAS c.34G>T (p.G12C) 突变结直肠癌的临床病理、分子和预后特征。

有证据表明，抗表皮生长因子受体（EGFR）抗体和 KRAS p.G12C (c.34G>T) 抑制剂的组合是治疗晚期结直肠癌的有效策略。我们假设 KRAS c.34G>T (p.G12C) 突变结直肠癌可能是一种独特的肿瘤亚型。我们利用前瞻性队列事件肿瘤生物库（包括 1347 例结直肠癌），在 43 例（3.2%）病例中检测到 KRAS c.34G>T (p.G12C) 突变，在 467 例（35%）病例中检测到其他 KRAS 突变（位于密码子 12、13、61 或 146）。在 KRAS c.34G>T 突变体（52%）和其他 KRAS 突变体（49%）中，CpG 岛甲基化表型（CIMP）低流行率同样高于 KRAS 野生型肿瘤（31%）。与其他 KRAS 突变体（分别为 6% 和 45%；P = 0.0036）相比，KRAS c.34G>T 突变体显示出更高的 CIMP 高患病率（14%）和更低的 CIMP 阴性患病率（33%）。与其他 KRAS 突变体相似，与 KRAS 野生型肿瘤相比，KRAS c.34G>T 突变肿瘤与盲肠位置、非微卫星不稳定性（MSI）高状态、BRAF 野生型和 PIK3CA 突变有关。与BRAF突变型肿瘤相比，KRAS c.34G>T突变者的LINE-1低甲基化更为常见，而LINE-1低甲基化是早发结直肠癌的生物标志物。KRAS c.34G>T突变体与其他特征无关，包括肿瘤组织中核葡萄球菌（F. animalis）、pks+大肠杆菌、双歧杆菌或（肠毒性）脆弱拟杆菌的丰度。在 1122 例 BRAF 野生型结直肠癌中，与 KRAS 野生型肿瘤相比，经多变量调整后，KRAS c.34G>T (p.G12C) 突变肿瘤的结直肠癌特异性死亡率危险比（95% 置信区间）为 1.82（1.05-3.17）（p = 0.035），其他 KRAS 突变肿瘤的危险比为 1.57（1.22-2.02）（p = 0.0004）。我们的研究为 KRAS c.34G>T (p.G12C) 突变结直肠癌的临床和肿瘤特征提供了新证据。

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来源期刊

Cancer Science 医学-肿瘤学

自引率

3.50%

发文量

406

审稿时长

2 months

期刊介绍： Cancer Science (formerly Japanese Journal of Cancer Research) is a monthly publication of the Japanese Cancer Association. First published in 1907, the Journal continues to publish original articles, editorials, and letters to the editor, describing original research in the fields of basic, translational and clinical cancer research. The Journal also accepts reports and case reports. Cancer Science aims to present highly significant and timely findings that have a significant clinical impact on oncologists or that may alter the disease concept of a tumor. The Journal will not publish case reports that describe a rare tumor or condition without new findings to be added to previous reports; combination of different tumors without new suggestive findings for oncological research; remarkable effect of already known treatments without suggestive data to explain the exceptional result. Review articles may also be published.