Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

Abstract

, Milos Brodak aBackground and Aims. Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC). Materials and Methods. We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCGresponsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). Results. Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312 ** ) and MUS81a (P=0.0191 * ) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. Conclusion.The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.

Targeting the Immune system and Epigenetic Landscape of Urological Tumors

“…A summary of most recent studies addressing combination strategies between epigenetics and immune environment in BlCa is presented in Table 1 [54][55][56][57][58][59][60][61][62][63][64]. Some studies have focused on obtaining methylation-based biomarkers with predictive value, namely concerning response to BCG-therapy [55][56][57]. As previously mentioned, BCG is a commonly used therapy for NMIBC, with the main aim to impede (or at least delay) recurrence of the disease after excision (occurring eventually in >50% of patients), which might also mean shifting to invasive disease, with metastatic potential [56].…”

“…As previously mentioned, BCG is a commonly used therapy for NMIBC, with the main aim to impede (or at least delay) recurrence of the disease after excision (occurring eventually in >50% of patients), which might also mean shifting to invasive disease, with metastatic potential [56]. Two studies pursued a screening of several gene promoters known to be frequently involved in tumor biology, and found that hypermethylation of genes such as CDKN2B (involved in cell cycle regulation), MUS81a and MSH6 (involved in DNA repair) and THBS1 (involved in cell adhesion), associated with better response to BCG-therapy, and both studies acknowledge that the exact mechanisms for explaining these findings deserve investigation in the future [55,57]. Nevertheless, they are an example of how to bring together epigenetic phenomena and biomarkers that may predict response to immune therapies.…”

Bladder cancer, a unique model to understand cancer immunity and develop immunotherapy approaches

“…DNA damage repair gene alterations and TML were not correlated with BCG immunotherapy response . No cancer transcriptome study has been reported and the correlation of DNA methylation of myopodin (SYNPO2) , PAX6, MSH6, RB1, THBS1, PYCARD, TP73, ESR1, GATA5, PMF‐1, CDKN2B and MUS81a ( MUS81 ) with cancer recurrence, progression and/or survival under BCG treatment were detected through candidate gene analysis . Further NGS studies of tumour immunogenicity are required.…”

Toll‑like receptor agonist rMBP‑NAP enhances antitumor cytokines production and CTL activity of peripheral blood mononuclear cells from patients with lung cancer

“…Toll-like receptor (TLR) alone or combined with other antitumor drugs have been used in cancer therapy due to the capability of TLR agonists to enhance the immune response of patients with cancer by improving the function of innate and adaptive immune cells (1,2). Currently, the US Food and Drug Administration (FDA) have licensed three TLRs agonists, including Bacille Calmette-Guérin (BCG), Monophosphoryl lipid A and Imiquimod, for use as prophylactics and/or therapeutic agents in cancer treatment (3)(4)(5). Although abundant natural and synthetic TLR agonists have been discovered and developed, a number of clinical research studies have reported that various TLR agonists that exhibited promising results in in vivo studies were not efficacious in humans (6,7).…”