Evaluation of PTPRT Mutations as Biomarkers for Cancer Metastasis Across Multiple Cancer Types

Cancer metastasis is the main cause of cancer-related death, but the mechanism of metastasis is still unclear, and there is lack of metastasis markers. PTPRT is a protein coding gene which may be involved in both signal transduction and cellular adhesion, it is also known as a tumor suppressor gene that inhibits cell malignant proliferation by inhibiting the STAT3 pathway1-3. Recent studies have reported that PTPRT may be involved in the early metastasis of colorectal cancer, but to our knowledge, no comprehensive study has yet revealed a link between PTPRT and metastasis in other types of cancer4, 5. In this study, we found that mutations in PTPRT were a potential biomarker of cancer metastasis in multiple cancers through a combined analysis using a large data set.


Introduction
Cancer metastasis is the main cause of cancer-related death, but the mechanism of metastasis is still unclear, and there is lack of metastasis markers. PTPRT is a protein coding gene which may be involved in both signal transduction and cellular adhesion, it is also known as a tumor suppressor gene that inhibits cell malignant proliferation by inhibiting the STAT3 pathway [1][2][3]. Recent studies have reported that PTPRT may be involved in the early metastasis of colorectal cancer, but to our knowledge, no comprehensive study has yet revealed a link between PTPRT and metastasis in other types of cancer [4,5]. In this study, we found that mutations in PTPRT were a potential biomarker of cancer metastasis in multiple cancers through a combined analysis using a large data set.

Results
In all 16,182 metastatic cancers and 26,480 early primary cancers, PTPRT non-silent mutations occurred in at least five metastatic cancers in six type of cancers, corresponding to 10,068 of metastatic cancer samples and 13,487 early primary cancer samples, respectively. These 23,555 samples were used for further differential analysis (Table 1). Among the six types of cancer, PTPRT mutations were significantly enriched in metastatic cancer ( Figure 1, A-F, p<0.05, q < 0.05), except that q-value was not significant in melanoma due to the small number of primary cancer tissue samples ( Figure 1E, 14 / 1148 vs 0 / 669, q = 0.156, p= 0.00097). In breast cancer, the combined mutation of PTPRT and PIK3CA in metastatic breast cancer was significantly higher than in primary tissue ( Figure 1A, q = 0.025). In colorectal cancer, as previously reported [4], the combined mutation 3 of APC-PTPRT, APC-PTPRT-TP53 and PTPRT-TP53 were significantly higher in metastatic colorectal cancer than in primary tissue ( Figure 1B, q= 3.4E-05, q= 0.0006 and q=2.6E-06, respectively). In Esophagogastric cancer, the combination of PTPRT and TP53 in metastatic cancer is significantly higher than that in primary tumor tissue ( Figure 1C, q=0.023). In NSCLC, the combined mutation of KEAP1-PTPRT, PTPRD-PTPRT-TP53 and PTPRT-TP53 were significantly higher in metastatic NSCLC than in primary tissue ( Figure 1D, q= 0.02, q= 0.0097 and q=1.68E-07, respectively).
In summary, by analyzing the mutation data of all 42662 cases from GENIE and cBioPortal databases, we found that PTPRT was not only enriched in metastatic cancer tissues of colorectal cancer, but also in other cancer types, such as esophageal cancer, breast cancer, non-small cell lung cancer and melanoma. This finding suggests that PTPRT mutation may be a molecular marker of cancer metastasis in a variety of cancers, and that simultaneous mutations in PTPRT and other driver genes may be responsible for different cancer metastases. Of course, since we do not have the clinical tracking information of these samples, especially GENIE database has not provided the tumor stage and prognosis information, so all primary cancer samples are counted as non-metastasis, which may make our results tend to be conservative. In general, these data suggest that PTPRT may be closely related to metastasis in multiple cancers, so it is necessary to carry out postoperative adjuvant treatment measures, such as chemotherapy, for tumor patients with PTPRT mutations.

Methods
All samples and mutation data were downloaded from the cBioPortal database (https://www.cbioportal.org) and GENIE database (v6.1, http://synapse.org/genie). All nonsynonymous mutations including missense, frameshift, nonsense, nonstop, splice site and translation start site mutations were considered. In order to obtain potential metastasis markers, we screened the samples in cBioPortal as follows: (1) the samples were sequenced by MSK-impact panel; (2) the samples should be clear about whether they are primary tumor tissues or metastasis tissues, and tumor stage. 4 early primary cancers. We search for the molecular markers of metastatic cancer by comparing the mutation difference of a single driver gene (or gene modules) between early cancer and metastatic cancer. The difference analysis uses the two-sided Fisher exact test and Bonferroni's multiple hypothesis test. Driver genes of each cancer type and PTPRT were selected as candidate gene models for comparison [6]. This study was approved by the Ethical Committee of the Union Medical College Hospital Affiliated of Fujian Medical University. Since the data used in this study are all from the public database, the traditional informed consent was waived, and the participants in the original genome research provided informed consent.

Author Contributions
Dr Chao Chen had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Dr C.Chen and XQ.Zhang. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Dr C.Chen and XQ.Zhang.

Competing interests
The authors declare that they have no competing interests.

Availability of data and materials
The datasets generated and analyzed during the current study can be obtained by contacting corresponding author.  Figure 1 Comparison of mutations in different gene modules between early and metastatic cancers.