BRCA mutations and gastrointestinal cancers: When to expect the unexpected?

Abstract

BRCA1/2 pathogenic variants are widely known as major risk factors mainly for breast and ovarian cancer, while their role in gastrointestinal (GI) malignancies such as colorectal cancer (CRC), gastric cancer and oesophageal cancer (OeC) is still not well established. The main objective of this review is to summarise the available evidence on this matter. The studies included in the review were selected from PubMed/GoogleScholar/ScienceDirect databases to identify published articles where BRCA1/2 pathogenic variants were assessed either as a risk factor or a prognostic/predictive factor in these malignancies. Our review suggests that BRCA1/2 might have a role as a risk factor for colorectal, gastric and OeC, albeit with differences among these diseases: In particular BRCA1 seems to be much more frequently mutated in CRC whereas BRCA2 appears to be much more closely associated with gastric and OeC. Early-onset cancer seems to be also associated with BRCA1/2 mutations and a few studies suggest a positive prognostic role of these mutations. The assessment of a potentially predictive role of these mutations is hampered by the fact that most patients with these diseases have been treated with platinum compounds, where it is expected that a higher probability of response should be seen. A few clinical trials focused on poly (ADP-ribose) polymerase inhibitors use in GI cancers are currently ongoing.

Distinct molecular phenotype and the potential prognostic value of immune prognostic index and tumor infiltrating lymphocytes in hepatoid adenocarcinoma of stomach

“…Additionally, the positive status of EBV and MSI-h was extremely low [7] to meet the requirements for practical applications in the HAS cohort. A meaningfully retrospective study also suggested BRCA2 alteration as a potential biomarker associated with response to ICIs [25] , however due to the interference of medication and the lack of prospective data [26] , the specific roles and the screening value of BRCA1/2 in immunotherapy for GC patients remains uncharacterized. These current findings indicated that the screening of biomarkers to predict the treatment response and selecting suitable candidates for ICIs have become a priority in the HAS cohort.…”

The Construction and Analysis of ceRNA Network in H pylori infection atrophic gastritis

“…The 597 DEGs in the lncRNA-miRNA-mRNA regulatory network were screened by "degree, MNC, MCC" top20 in cytoHubba software, and then intersected to obtain 11 key hub targets, namely BRCA1, RAD54L, MKI67, ESPL1, KIF23, MCM6, CDK2, RFC4, RACGAP1, PRC1, UBE2C.BRCA mutations are de ned as pathogenic variants in either the BRCA1 or BRCA2 gene: These two tumour suppressor genes are involved in different crucial pathways including DNA repair, cell proliferation control and apoptosis. In particular, BRCA1 and BRCA2 genes are mainly involved in the homologous recombination (HR) process, responsible for maintenance of genome integrity through an error-free repair pathway for DNA doublestrand breaks in response to DNA damage [37] . Loss-of-function mutations in BRCA1/2 may lead to accumulation of DNA double-strand breaks and result in genomic instability and tumour development.BRCA1/2mutation carriers are known to have a higher risk of developing breast and ovarian cancer [38] .Over the last decade, awareness of the BRCA1 and BRCA2 genes in the oncological community has led to more aggressive patient screening and the subsequent discovery of other BRCA-related alignancies.…”

“…Loss-of-function mutations in BRCA1/2 may lead to accumulation of DNA double-strand breaks and result in genomic instability and tumour development.BRCA1/2mutation carriers are known to have a higher risk of developing breast and ovarian cancer [38] .Over the last decade, awareness of the BRCA1 and BRCA2 genes in the oncological community has led to more aggressive patient screening and the subsequent discovery of other BRCA-related alignancies. Cancer of the prostate, pancreas, gallbladder, bile duct and stomach, along with malignant melanoma, have all been described at increased incidences in BRCA mutation carriers.BRCA mutations are the most common germline genetic alterations known to occur in pancreatic cancer (PC), inherited in an autosomal dominant pattern with incomplete penetrance [39] .Recently,Hännimen et al [40] and Quaas et al [41] highlighted a possible role of BRCA1 and BRCA2 mutations in small bowel cancer pathogenesis.DU et al's [42] study highlights BRCA1 as an independent rognosticator of early-stage colon cancer.Mauri et al [43] suggested that BRCA1/2 mutations might determine an increase in colorectal cancer(CRC) diagnoses, particularly in young patients.More and more reseachs indicate a positive correlation of germline BRCA1/2 mutations and an increased GI cancer risk [37] .BRCA1/2 variant assessment will soon become one of the most promising elds of research in these kinds of diseases.KEGG enrichment analysis showed that BRCA1 was enriched in PI3K/Akt signaling pathway. Combined with ceRNA network, we deduced that the expression of lncRNA PCGEM1-miRNA hsa-miR-340-5p-mRNA BRCA1 may regulated by PI3K/Akt signaling pathway induced atrophic gastritis.…”

Fanconi Anemia Pathway in Colorectal Cancer: A Novel Opportunity for Diagnosis, Prognosis and Therapy

“…Their fruitful study did not show any statistically significant increase in CRC development among BRCA1/2 mutation carriers, regardless of the age or ethnicity of patients. Overall, despite all genuine attempts, the significance of BRCA mutation in CRC incidence remains controversial and, still, there are no specific guidelines or recommendations for gastric and bowel screening procedures for carriers of BRCA1/2 mutations [ 93 ].…”