Design of Marker Panels for Prediction of Neoadjuvant Chemotherapy Response of Triple-Negative Breast Tumors Based on the Results of Genome-Wide DNA Methylation Screening

• Published in: Russian journal of genetics 2022-07, Vol.58 (7), p.835-843
• Main Authors: Kalinkin, A. I., Sigin, V. O., Ignatova, E. O., Frolova, M. A., Kuznetsova, E. B., Vinogradov, I. Y., Vinogradov, M. I., Vinogradov, I. I., Nemtsova, M. V., Zaletaev, D. V., Tanas, A. S., Strelnikov, V. V.
• Format: Article
• Language: English
• Subjects: Animal Genetics and Genomics; Biomedical and Life Sciences; Biomedicine; Human Genetics; Microbial Genetics and Genomics
• ISSN: 1022-7954; 1608-3369
• DOI: 10.1134/S1022795422070080

The rate of complete pathomorphological response to neoadjuvant chemotherapy (NACT) in triple-negative breast cancer is low and ranges from 30 to 40%. At the same time, to date, there are practically no predictive markers of the effectiveness of NACT for this subtype of tumors. We suggest an approach to the identification of prognostic epigenetic markers of the sensitivity of triple-negative breast tumors to NACT, which can be diagnosed using methylation sensitive PCR. We have selected markers from the XmaI-RRBS genome-wide bisulfite DNA sequencing dataset performed for tumor biopsies obtained from 34 patients before the initiation of NACT and for six samples of normal breast tissue. The patients were divided into groups of responders (complete pathological response) or nonresponders (presence of residual tumor). CpG dinucleotides were identified, the differential methylation of which distinguishes samples of triple-negative tumors with different sensitivity to NACT, and a panel of methylation markers was developed, including regions of CpG islands of the RUSC1 / RUSC1-AS1 , MXRA5 , and ANKRD46 genes, the design of which meets the requirements for the test systems based on methylation sensitive PCR. The estimated diagnostic accuracy of a panel of these three methylation markers is 0.79 (cvAUC = 0.80, 95% CI: 0.79–0.82).