Opposing effects of BRCA1 mRNA expression on patient survival in breast and colorectal cancer and variations among African American, Asian, and younger patients

Abstract

Breast cancer (BC) and colorectal cancer (CRC) are common and show poor survival in advanced stages. Using The Cancer Genome Atlas (TCGA) computational tool cBioPortal, we evaluated overall patient survival in BRCA1 mRNA-low versus -high cohorts (<−1.29 versus >1.05 SD from mean BRCA1 expression, respectively). Analysis included 1082 BC patients with mRNA data (PanCancer Atlas), 382 CRCs (Firehose Legacy) and 592 CRCs (PanCancer Atlas). As previously reported, BRCA1 mRNA-low tumor expression positively correlated with BC patient survival but was negatively associated in CRC. We observed a correlation between BRCA1 mRNA-high and age <45 years at CRC diagnosis using a Fisher’s exact test [Firehose Legacy database ( p -value = 0.0091); CRC PanCancer Atlas ( p -value = 0.0778)]. We correlated BRCA1 mRNA-low expression and basal BC ( p -value = 0.0016) and BRCA1 mRNA-low tumors and frequency of African American patients ( p -value = 0.0448) with BC. Other trends included higher frequency of advanced lymph node stage and mucinous adenocarcinoma among BRCA1 mRNA-low CRC and higher frequency of males in BRCA1 mRNA-high BC and CRC. African Americans more frequently had BRCA1 mRNA-low BC and BRCA1 mRNA-high CRC and the opposite was observed among Asians. Using a gene co-expression tool (cBioPortal), we observed TOP2A and ATAD5 levels correlate (Spearman’s correlation>0.6) with BRCA1 in BC and CRC, whereas LMNB2 correlates with BRCA1 in CRC, suggesting tissue-specific BRCA1 interactions. Our results indicate potential for BRCA1 mRNA expression levels as a prognostic biomarker in BC and CRC, suggest tissue-specificity in BRCA1 molecular interactions, and point to BRCA1 mRNA-high levels as a characteristic of CRC tumors in younger versus older individuals.

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

“…Conversely, low BRCA1 or BRCA2 mRNA/protein expression levels have been substantially associated with poor prognosis in CRC [ 115 , 116 , 117 , 118 ]. A recent study that retrieved information from The Cancer Genome Atlas (TCGA) and other databases containing CRC patients has revealed an association between BRCA1 mRNA-low tumor expression and worse clinicopathological features, including a higher proportion of advanced lymph node stages (N1/N2), a higher frequency of mucinous adenocarcinomas in conjunction with poor 5-year overall survival compared to the BRCA1 mRNA-high expression group [ 116 ].…”

“…Conversely, low BRCA1 or BRCA2 mRNA/protein expression levels have been substantially associated with poor prognosis in CRC [ 115 , 116 , 117 , 118 ]. A recent study that retrieved information from The Cancer Genome Atlas (TCGA) and other databases containing CRC patients has revealed an association between BRCA1 mRNA-low tumor expression and worse clinicopathological features, including a higher proportion of advanced lymph node stages (N1/N2), a higher frequency of mucinous adenocarcinomas in conjunction with poor 5-year overall survival compared to the BRCA1 mRNA-high expression group [ 116 ]. Similarly, one previous investigation has demonstrated that the down-regulation of BRCA1 mRNA and protein expression in 120 CRC patients who underwent surgery without preoperative chemotherapy or radiotherapy correlated with advanced lymph node metastasis, TNM stage, shorter 5-year recurrence-free, and overall survival [ 117 ].…”

Redefining and expanding the sphere of influence of BRCA in breast and colorectal cancers and beyond

“…In this issue, Leaf, Carlsen, and El-Deiry tackle the question of how expression of BRCA at the transcriptional level affects prognosis in breast and colorectal cancers, and furthermore what additional factors play a role [ 1 ]. While evaluation of BRCA1 has been so closely associated with breast cancer (the initials stemming from the words BReast CAncer point to that directly!…”

BRCA Role Changes with Association: Tissue-specific impact on the prognosis

“…The recently published study in Oncotarget [ 3 ] contributes to the idea of the tissue-specific impact of BRCA1 expression level on the prognosis of the patient. For this objective, they chose breast cancer (BC) and colorectal cancer (CRC) since there is prior work reporting the conflicting prognostic significance of BRCA1 in these cancers.…”

“…These tissue type-specific associations are explained by the correlation of BRCA1 mRNA expression with different genes in these cancers. In conclusion, the authors show that BRCA1 level correlates with TOP2A and ATAD5 both in BC and CRC and uniquely with LMNB2 in CRC [ 3 ].…”