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Cancers (Basel). 2018 Sep 6;10(9). pii: E314. doi: 10.3390/cancers10090314.

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

Hsu HC1,2, Lapke N3, Chen SJ4, Lu YJ5, Jhou RS6, Yeh CY7,8, Tsai WS9,10, Hung HY11,12, Hsieh JC13,14, Yang TS15,16, Thiam TK17, You JF18,19.

Author information

1
Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan. dannyhsuyoyo@gmail.com.
2
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. dannyhsuyoyo@gmail.com.
3
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan. ninalapke@actgenomics.com.
4
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan. sjchen@actgenomics.com.
5
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan. yjlu@actgenomics.com.
6
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan. renshiangjhou@actgenomics.com.
7
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. chnyuh@gmail.com.
8
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan. chnyuh@gmail.com.
9
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. wensyt@gmail.com.
10
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan. wensyt@gmail.com.
11
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. hsin3345@gmail.com.
12
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan. hsin3345@gmail.com.
13
Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan. wisdom5000@gmail.com.
14
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. wisdom5000@gmail.com.
15
Division of Hematology/Oncology, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan. a481124@cgmh.org.tw.
16
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. a481124@cgmh.org.tw.
17
ACT Genomics, Neihu Dist., Taipei City 114, Taiwan. jtchen@actgenomics.com.
18
College of Medicine, Chang Gung University, Taoyuan City 33302, Taiwan. jenodyssey@gmail.com.
19
Division of Colon and Rectal Surgery, Chang Gung Memorial Hospital at Linkou, Taoyuan City 333, Taiwan. jenodyssey@gmail.com.

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:

PTPRT/PTPRD mutation and deletion; VEGF; bevacizumab resistance; metastatic colorectal cancer; next-generation sequencing

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