Recently, overexpression of BRCA1 mRNA was strongly associated with poor survival in NSCLC patients. Furthermore, BRCA1 deficiency was PREDICTOR OF RESPONSE, BUT ALSO correlated with resistance to poly(ADP-ribose) polymerase (PARP) inhibitors. However, the rationale for this correlation is poorly understood.
We were interested in whether BARD1, a BRCA1 interacting and stabilizing protein and tumor suppressor in its own right, was also overexpressed in NSCLC and a marker of progression. We found that full length (FL) BARD1 was down-regulated in more than 100 samples tested, but deletion-bearing isoforms lacking the BRCA1 interaction domain were overexpressed. We had reported previously that such isoforms are antagonists of the tumor suppressor functions of BARD1 and BRCA1 and that BARD1 isoforms are oncogenic drivers in various cancers including NSCLC.
In a study performed on more than 100 NSCLC cases all expressed BARD1 isoforms, but not FL BARD1, on the protein level. Cancer-associated isoforms of BARD1 are immunogenic and antibodies against could be detected in NSCLC patients. Analysis of more than 200 patients and controls permitted to define a highly sensitive (95%) and specific (93%) test for the detection of lung cancer based on autoimmune antibodies against isoforms of BARD1.
Our studies show that BARD1 isoforms are tumor drivers, thus biomarkers of cancer. Detection of autoimmune antibodies in NSCLC patients presents an early, highly sensitive, least invasive test for individuals at high risk for lung cancer and would permit early detection and better treatment chances.