Identification and validation of plasma biomarkers for diagnosis of breast cancer in South Asian women

Abstract

Breast cancer is the most common malignancy among women globally. Development of a reliable plasma biomarker panel might serve as a non-invasive and cost-effective means for population-based screening of the disease. Transcriptomic profiling of breast tumour, paired normal and apparently normal tissues, followed by validation of the shortlisted genes using TaqMan® Low density arrays and Quantitative real-time PCR was performed in South Asian women. Fifteen candidate protein markers and 3 candidate epigenetic markers were validated first in primary breast tumours and then in plasma samples of cases [N = 202 invasive, 16 DCIS] and controls [N = 203 healthy, 37 benign] using antibody array and methylation specific PCR. Diagnostic efficiency of single and combined markers was assessed. Combination of 6 protein markers (Adipsin, Leptin, Syndecan-1, Basic fibroblast growth factor, Interleukin 17B and Dickopff-3) resulted in 65% sensitivity and 80% specificity in detecting breast cancer. Multivariate diagnostic analysis of methylation status of SOSTDC1, DACT2, WIF1 showed 100% sensitivity and up to 91% specificity in discriminating BC from benign and controls. Hence, combination of SOSTDC1, DACT2 and WIF1 was effective in differentiating breast cancer [non-invasive and invasive] from benign diseases of the breast and healthy individuals and could help as a complementary diagnostic tool for breast cancer.

Role of Sostdc1 in skeletal biology and cancer

“…Consistently, the methylation level is associated with breast cancer prognosis and hence, can be used as a diagnostic marker (Xiao et al, 2018). Moreover, multivariate diagnostic analysis of the methylation status of WIF1, Sostdc1, and DACT2 showed up to 91% specificity and 100% sensitivity in discriminating breast cancer (invasive and non-invasive) from benign tumours and controls and may be a complementary tool for breast cancer diagnosis (Rajkumar et al, 2022). A gastric cancer study found that Sostdc1 expression is modulated by epigenetic mechanisms and its downregulation may be caused by promoter hypermethylation (a potential prognostic factor) and tumour suppression, with the expression of…”

“…Sostdc1 is involved in the progression and development of multiple cancer types, including breast, gastric, renal, bladder, and thyroid cancers (Blish et al, 2008;Gopal et al, 2013;Rawat et al, 2014;Li et al, 2020). Sostdc1 deficiency is associated with larger tumour sizes (Clausen et al, 2011).…”

“…In prostate tumours, the Sostdc1 promoter was hypermethylated in prostate tumours, leading to the suppression of hepcidin secretion due to attenuation of BMP4/7-mediated Smad phosphorylation, resulting in inhibition of cell survival (Lintern et al, 2009). Sostdc1 was also frequently downregulated in primary breast cancers (98.2%), and Sostdc1 promoter hypermethylation at CpG sites inhibited cell proliferation and survival, while E4BP4 reduced Sostdc1 expression and its promoter activity in breast cancer cells (Rawat et al, 2014). Sostdc1 is the only gene associated with survival in patients with metastatic breast cancer (Clausen et al, 2011;Rawat et al, 2014), indicating that Sostdc1 plays multiple roles in metastatic breast cancer.…”

“…Sostdc1 was also frequently downregulated in primary breast cancers (98.2%), and Sostdc1 promoter hypermethylation at CpG sites inhibited cell proliferation and survival, while E4BP4 reduced Sostdc1 expression and its promoter activity in breast cancer cells (Rawat et al, 2014). Sostdc1 is the only gene associated with survival in patients with metastatic breast cancer (Clausen et al, 2011;Rawat et al, 2014), indicating that Sostdc1 plays multiple roles in metastatic breast cancer. In addition, the regulation of breast cancer by Sostdc1 is correlated with its methylation, as the methylation levels of Sostdc1 were evidently lower in control tissues than in cancer tissues.…”

Construction of 2DE-Patterns of Plasma Proteins: Aspect of Potential Tumor Markers

“…Complement factor D (CFD) cleaves factor B when the latter is complexed with factor C3b, activating the C3bbb complex, which then becomes the C3 convertase of the alternate pathway. The levels of CFD (plasma and tissue) were significantly downregulated in patients with ductal carcinoma in-situ (DCIS) and invasive BC when compared to controls [118]. Its precursor polypeptide chain has 253 AA, where AA 1-20 -the signal peptide, AA21-25 -propeptide, AA 26-253complement factor D (Mw: 6.85/24405).…”