Retrospective Study
Copyright ©The Author(s) 2020. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Mar 21, 2020; 26(11): 1197-1207
Published online Mar 21, 2020. doi: 10.3748/wjg.v26.i11.1197
Landscape of BRIP1 molecular lesions in gastrointestinal cancers from published genomic studies
Ioannis A Voutsadakis
Ioannis A Voutsadakis, Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, ON P6B 0A8, Canada
Ioannis A Voutsadakis, Section of Internal Medicine, Division of Clinical Sciences, Northern Ontario School of Medicine, Sudbury, ON P0M 2Z0, Canada
Author contributions: Voutsadakis IA designed research, performed research, analyzed data and wrote the paper.
Institutional review board statement: This study was a retrospective analysis of previously published data, available in the public domain, no IRB approval is required.
Informed consent statement: Given that this is a retrospective analysis of previously published, anonymized data, no patient informed consent was required or obtained.
Conflict-of-interest statement: I have no financial relationships to disclose.
Data sharing statement: No additional data are available.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
Corresponding author: Ioannis A Voutsadakis, MD, PhD, Assistant Professor, Doctor, Algoma District Cancer Program, Sault Area Hospital, 750 Great Northern Road, Sault Ste Marie, ON P6B 0A8, Canada.
Received: December 6, 2019
Peer-review started: December 6, 2019
First decision: February 16, 2020
Revised: February 21, 2020
Accepted: March 5, 2020
Article in press: March 5, 2020
Published online: March 21, 2020
Research background

Gastrointestinal (GI) cancers are, as a group, very common and their pathogenesis has been progressively elucidated over the last 30 years. However, the role of genetic lesions in homologous recombination (HR) DNA repair remains less well characterized in these cancers.

Research motivation

BRIP1 is a helicase with a role in HR as well as other key functions in DNA metabolism. Its specific role in GI cancers has rarely been reported. Further elucidation of molecular lesions in this gene may pave the way for targeted therapeutic interventions.

Research objectives

To analyze molecular defects of helicase BRIP1 (FANCJ) in GIcancers pathogenesis.

Research methods

GIcancer studies from The Cancer Genome Atlas (TCGA) were analyzed using the cBioportal platform and other precision medicine databases. TCGA studies were interrogated for BRIP1 mutations and copy number alterations. Associations with other key lesions in GIcancers as well as with the total tumor mutation burden in these cancers were analyzed. Additional analyses that could not be performed directly in the cBioportal platform were performed in Excel (Microsoft Corp., Redmond, WA) after transfer of the relevant data. Appropriate statistical tests (the Fisher’s exact test and the t test respectively) were used for analysis of categorical and continuous data.

Research results

Molecular lesions in BRIP1 are observed in 3.6% of GI cancers and consisted almost exclusively of mutations and amplifications. Two fifths of all BRIP1 mutations are considered possibly pathogenic. Most BRIP1 mutated GI cancers have concomitant mutations in MMR genes or one of the replication polymerases, polymerase ε and δ1 genes. No associations were discovered between amplifications of BRIP1 and any mutated genes. BRIP1 amplification commonly co-occurs with ERBB2 amplification, a comparatively common amplification in gastroesophageal cancers.

Research conclusions

BRIP1 gene lesions are not major pathogenic players in GI cancers. Association with microsatellite unstable cancers and ERBB2 amplifications in gastroesophageal cancers is worth noting.

Research perspectives

Molecular defects in helicase BRIP1, albeit rare, may provide opportunities for novel therapies in GI cancers. Their association with the mutator phenotype is intriguing in the current era of immunotherapy of cancer. BRIP1 defects may contribute to an expansion of instability in hypermutated cancers. Thus, BRIP1 mutations could be an additional potential predictive marker of response to immunotherapies. A role of combination therapies, including immunotherapies with targeted therapies active in cancers with HR defects such as PARP inhibitors, in BRIP defective GI cancers is worth exploring.