Nomograms for Prediction of Molecular Phenotypes in Colorectal Cancer

Zhuojun Yu; Huichuan Yu; Qi Zou; Zenghong Huang; Xiaolin Wang; Guannan Tang; Liangliang Bai; Chuanhai Zhou; Zhuokai Zhuang; Yumo Xie; Heng Wang; Gaopo Xu; Zijian Chen; Xinhui Fu; Meijin Huang; Yanxin Luo

doi:10.2147/OTT.S234495

Nomograms for Prediction of Molecular Phenotypes in Colorectal Cancer

Onco Targets Ther. 2020 Jan 13:13:309-321. doi: 10.2147/OTT.S234495. eCollection 2020.

Authors

Zhuojun Yu^#^{1

2

3}, Huichuan Yu^#¹, Qi Zou^{1

4}, Zenghong Huang^{1

2}, Xiaolin Wang¹, Guannan Tang¹, Liangliang Bai¹, Chuanhai Zhou^{1

2

3}, Zhuokai Zhuang^{1

2}, Yumo Xie^{1

2}, Heng Wang¹, Gaopo Xu¹, Zijian Chen^{1

5}, Xinhui Fu^{1

6}, Meijin Huang^{1

2}, Yanxin Luo²

Affiliations

¹ Guangdong Institute of Gastroenterology, Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Disease, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, People's Republic of China.
² Department of Colorectal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, People's Republic of China.
³ Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510655, People's Republic of China.
⁴ Department of Colorectal and Anal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, People's Republic of China.
⁵ Department of Gastrointestinal Surgery, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong 510655, People's Republic of China.
⁶ Department of Pathology, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, People's Republic of China.

^# Contributed equally.

Abstract

Background: Colorectal cancer (CRC) patients with different molecular phenotypes, including microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and somatic mutations in BRAF and KRAS gene, vary in treatment response and prognosis. However, molecular phenotyping under adequate quality control in a community-based setting may be difficult. We aimed to build the nomograms based on easily accessible clinicopathological characteristics to predict molecular phenotypes.

Methods: Three hundred and six patients with pathologically confirmed stage I-IV CRC were included in the cohort. The assays for MSI, CIMP, and mutations in BRAF and KRAS gene were performed using resected tumor samples. The candidate predictors were identified from clinicopathological variables using multivariate Logistic regression analyses to construct the nomograms that could predict each molecular phenotype.

Results: The incidences of MSI, CIMP, BRAF mutation and KRAS mutation were 25.3% (72/285), 2.5% (7/270), 3.4% (10/293), and 34.8% (96/276) respectively. In the multivariate Logistic analysis, poor differentiation and high neutrophil/lymphocyte ratio (NLR) were independently associated with MSI; poor differentiation, high NLR and high carcinoembryonic antigen/tumor size ratio (CSR) were independently associated with CIMP; poor differentiation, lymphovascular invasion and high CSR were independently associated with BRAF mutation; poor differentiation, proximal tumor, mucinous tumor and high NLR were independently associated with KRAS mutation. Four nomograms for MSI, CIMP, BRAF mutation and KRAS mutation were developed based on these independent predictors, the C-indexes of which were 61.22% (95% CI: 60.28-62.16%), 95.57% (95% CI: 95.20-95.94%), 83.56% (95% CI: 81.54-85.58%), and 69.12% (95% CI: 68.30-69.94%) respectively.

Conclusion: We established four nomograms using easily accessible variables that could well predict the presence of MSI, CIMP, BRAF mutation and KRAS mutation in CRC patients.

Keywords: BRAF; CpG island methylator phenotype; KRAS; colorectal cancer; microsatellite instability; nomogram; prediction of molecular subtypes.

Grants and funding

This work was supported by the National Basic Research Program of China (973 Program) (No. 2015CB554001, JW), the National Natural Science Foundation of China (No. 81972245, YL; No. 81902877, HY), the Natural Science Fund for Distinguished Young Scholars of Guangdong Province (No. 2016A030306002, YL), the Tip-top Scientific and Technical Innovative Youth Talents of Guangdong Special Support Program (No. 2015TQ01R454, YL), the Project 5010 of Clinical Medical Research of Sun Yat-sen University-5010 Cultivation Foundation (No. 2018026, YL), the Natural Science Foundation of Guangdong Province (No. 2016A030310222, HY; No. 2018A0303130303, HY), the Program of Introducing Talents of Discipline to Universities, and National Key Clinical Discipline (2012).