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Article

PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients

by
Hung-Chih Hsu
1,2,
Nina Lapke
3,
Shu-Jen Chen
3,
Yen-Jung Lu
3,
Ren-Shiang Jhou
3,
Chien-Yuh Yeh
2,3,
Wen-Sy Tsai
2,4,
Hsin-Yuan Hung
2,4,
Jason Chia-Hsun Hsieh
1,2,
Tsai-Sheng Yang
1,2,
Tan Kien Thiam
3,*,† and
Jeng-Fu You
2,4,*,†
1
Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan
2
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan
3
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan
4
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan
*
Authors to whom correspondence should be addressed.
†
These authors have contributed equally to this work as senior authors.
Cancers 2018, 10(9), 314; https://doi.org/10.3390/cancers10090314
Submission received: 12 July 2018 / Revised: 25 August 2018 / Accepted: 3 September 2018 / Published: 6 September 2018
(This article belongs to the Special Issue Drug Resistance in Cancers)
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Abstract

Background: Bevacizumab-based regimens are used as standard treatments for colorectal cancer. Unfortunately, there are no established predictive markers for bevacizumab response. Methods: Tumor samples from 36 metastatic colorectal cancer patients treated with bevacizumab plus chemotherapy were analyzed by next-generation sequencing of all coding exons of more than 400 genes. Single gene and signaling pathway analyses were performed to correlate genomic data with response. Results: Among the genes most frequently mutated in our cohort, only mutations in PTPRT, a phosphatase involved in JAK/STAT signaling, were associated with response status, with deleterious mutations being enriched in non-responders. Pathway analysis revealed that deleterious mutations in genes of the JAK/STAT pathway, namely in PTPRT and the related gene PTPRD, correlated with resistance. Mutations in RTK/PI3K/RAS, Wnt and TGFβ pathways did not associate with response. Lack of response was observed in all patients with deleterious mutations or copy number loss of PTPRT/PTPRD (n = 10), compared to only 30.8% (n = 8) of patients without such alterations (relative risk, 3.25; 95% CI, 1.83–5.79, p = 0.0003). Similarly, PTPRT/PTPRD deleterious alterations were associated with shorter progression-free survival, an association that was retained in multivariate analysis (HR, 3.33; 95% CI, 1.47–7.54; p = 0.0038). Conclusion: Deleterious alterations in PTPRT/PTPRD are potential biomarkers for bevacizumab resistance.
Keywords: metastatic colorectal cancer; bevacizumab resistance; next-generation sequencing; VEGF; PTPRT/PTPRD mutation and deletion metastatic colorectal cancer; bevacizumab resistance; next-generation sequencing; VEGF; PTPRT/PTPRD mutation and deletion

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MDPI and ACS Style

Hsu, H.-C.; Lapke, N.; Chen, S.-J.; Lu, Y.-J.; Jhou, R.-S.; Yeh, C.-Y.; Tsai, W.-S.; Hung, H.-Y.; Hsieh, J.C.-H.; Yang, T.-S.; et al. PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients. Cancers 2018, 10, 314. https://doi.org/10.3390/cancers10090314

AMA Style

Hsu H-C, Lapke N, Chen S-J, Lu Y-J, Jhou R-S, Yeh C-Y, Tsai W-S, Hung H-Y, Hsieh JC-H, Yang T-S, et al. PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients. Cancers. 2018; 10(9):314. https://doi.org/10.3390/cancers10090314

Chicago/Turabian Style

Hsu, Hung-Chih, Nina Lapke, Shu-Jen Chen, Yen-Jung Lu, Ren-Shiang Jhou, Chien-Yuh Yeh, Wen-Sy Tsai, Hsin-Yuan Hung, Jason Chia-Hsun Hsieh, Tsai-Sheng Yang, and et al. 2018. "PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients" Cancers 10, no. 9: 314. https://doi.org/10.3390/cancers10090314

APA Style

Hsu, H.-C., Lapke, N., Chen, S.-J., Lu, Y.-J., Jhou, R.-S., Yeh, C.-Y., Tsai, W.-S., Hung, H.-Y., Hsieh, J. C.-H., Yang, T.-S., Thiam, T. K., & You, J.-F. (2018). PTPRT and PTPRD Deleterious Mutations and Deletion Predict Bevacizumab Resistance in Metastatic Colorectal Cancer Patients. Cancers, 10(9), 314. https://doi.org/10.3390/cancers10090314

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