SORBS1 expression as a biomarker for obesity and breast cancer prognosis: Insights from genomic analysis and survival outcomes.
Authors: Bhat Ajaz Ahmad , Ahmed Ikhlak , Usmani Shahabuddin , Sadida Hana. Q. , Masoodi Tariq , Kumar Rakesh , Singh Mayank , Mir Manzoor Ahmad , Mirza Sameer , Uddin Shahab , Macha Muzafar Ahmad , Al-Shabeeb Akil Ammira S 
Published: June 2024

e13050

Background: Obesity is a known risk factor for breast cancer development and poorer survival. Correlation between the expression of the adaptor protein SORBS1 (Sorbin and SH3 domain-containing protein 1) and body mass index (BMI). Methods: Bioinformatics analysis. Results: We analyzed published datasets and plotted SORBS1 expression against patient BMI. Our findings show a negative correlation between SORBS1 expression and BMI in both datasets (R = -0.42, p = 0.00087, and R = -0.45 p = 0.00083, respectively). We also observed a negative correlation between SORBS1 expression and Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) (R = -0.43, p = 0.00016). Additionally, we examined BMI-associated variants of the SORBS1 gene in the Qatar Biobank cohort of 15k individuals. We identified a total of 26 variants that were associated with an elevated risk for BMI in this population at a nominal significance. The top risk variant associated with the BMI is a missense variant (rs35480352; beta=0.058, p-value = 3.3e-03) with a frequency of 9.1% for the risk allele in our population. These results suggest that SORBS1 expression decreases with obesity and diabetes. This is significant because obesity is a known risk factor for breast cancer development and poorer survival. We also examined the SORBS1 gene expression in breast adenocarcinoma using UCSC TOIL RNA-seq recompute and TCGA-BRCA genomic and methylation data. Out of the 963 patients analyzed, only 12 (1.2%) showed any SORBS1 gene alteration, such as mutation (0.7%), amplification (0.2%), or deep deletion (0.3%), indicating a low occurrence of genomic alterations. Furthermore, our findings revealed no significant difference in SORBS1 methylation levels between the tumor and matched normal samples, indicating that the SORBS1 gene is not hypermethylated in breast carcinoma. Interestingly, our comparison of SORBS1 expression values between tumor and normal samples indicated significant under-expression in BRCA (log2FC = -2.7, p = 1.07E-127). SORBS1 expression was found to vary across various clinical stages (p = 0.0082, Kruskal-Wallis rank test), exhibiting a decline in advanced cancer stages. Moreover, we detected a significant difference in SORBS1 expression among different molecular subtypes (p < 2E-16, Kruskal-Wallis rank test), with a lower expression level in more aggressive subtypes like HER2. Patients were classified into two groups according to their SORBS1 expression levels, using the median expression as a threshold: high and low. Conclusions: Our findings showed that the SORBS1 low group had substantially lower overall survival (log-rank p = 0.0024) and progression-free survival rates (log-rank p = 0.028). Silencing of SORBS1 in MCF-7 and MDA-MB-231 cells increased cell proliferation, migration, and invasion, underscoring its importance in breast cancer prognosis and as a target for intervention.