Whole-Exome Sequencing Identifies a Novel Germline Variant in PTK7 Gene in Familial Colorectal Cancer.

Beiping Miao,Magdalena Kuświk,Sara Giangiobbe,Diamanto Skopelitou,Matthias Schlesner,Obul Reddy Bandapalli,Katarzyna Paszkowska-Szczur,Kari Hemminki,Jan Lubinski,Asta Försti,Dagmara Dymerska,Aayushi Srivastava,Nagarajan Paramasivam,Abhishek Kumar,Wojciech Kluźniak

doi:10.3390/ijms23031295

Abstract

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide. Only 5% of all CRC cases are due to germline mutations in known predisposition genes, and the remaining genetic burden still has to be discovered. In this study, we performed whole-exome sequencing on six members of a Polish family diagnosed with CRC and identified a novel germline variant in the protein tyrosine kinase 7 (inactive) gene (PTK7, ENST00000230419, V354M). Targeted screening of the variant in 1705 familial CRC cases and 1674 healthy elderly individuals identified the variant in an additional familial CRC case. Introduction of this variant in HT-29 cells resulted in increased cell proliferation, migration, and invasion; it also caused down-regulation of CREB, p21 and p53 mRNA and protein levels, and increased AKT phosphorylation. These changes indicated inhibition of apoptosis pathways and activation of AKT signaling. Our study confirmed the oncogenic function of PTK7 and supported its role in genetic predisposition of familial CRC.

Highlights

IntroductionColorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide, accounting for 10.2% of all cancer cases in 2018
Introduction conditions of the Creative CommonsColorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide, accounting for 10.2% of all cancer cases in 2018
The current state of research indicates very few germline variants for the PTK7 gene that have been associated with the development of any disease

Summary

Introduction

Colorectal cancer (CRC) is the third most frequently diagnosed malignancy worldwide, accounting for 10.2% of all cancer cases in 2018. Since an important approach to cancer prevention targets the improvement of screening and early diagnosis methods, understanding the heterogeneous etiological background of CRC, including environmental and inherited genetic factors, is of great relevance. 35% of CRC susceptibility is considered to be explained by heritability and around 15% of CRC patients have a family history of CRC, less than 5% of all cases are due to highly penetrant germline variants in established predisposition genes, such as APC, mismatch repair genes (MLH1, MSH2, MSH6, PMS2), EPCAM, SMAD4/BMPR1A, and MUTYH, resulting in well-characterized clinical features of known Mendelian CRC syndromes [3–5]. The remaining genetic burden of familial CRC has still not been sufficiently explored and may reveal novel highly penetrant germline variants

Methods

Results

Conclusion