Published online Mar 21, 2020. doi: 10.3748/wjg.v26.i11.1197
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
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.
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.
To analyze molecular defects of helicase BRIP1 (FANCJ) in GIcancers pathogenesis.
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.
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.
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.
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.