Title:Pharmacogenomic Alterations in High-Risk Triple-Negative Breast Cancer and Its Adverse Drug Reactions: A Cross-Sectional and Observational Study
Volume: 23
Author(s): Priyanka Namdev, Vignesh Krishnasamy, Andrew Vanllawma, Lalengkimi Ralte, Lalawmpuii Pachuau, Zothankima Bawitlung, Lalfakzuala Khenglawt, Lalsangmawia Khawlhring, Ashok K. Varma and Nachimuthu Senthil Kumar*
Affiliation:
- Department of Biotechnology, Mizoram University, Aizawl, Mizoram, 796004, India
Keywords:
Pharmacogenes, Triple-negative breast cancer (TNBC), adverse drug reactions (ADRs), chemotherapy, high risk population.
Abstract:
Introduction: Triple-negative breast cancer (TNBC) is a highly aggressive
subtype of breast cancer, with a significant prevalence in India, potentially due to distinct
etiological factors. Genetic mutations are closely associated with an increased risk of
TNBC. While chemotherapy remains the primary treatment, it is associated with a high
risk of adverse drug reactions (ADRs). This study aims to investigate genetic mutations
and their association with TNBC in the Mizo geo-ethnic population, which has a high incidence
of TNBC.
Methods: A cross-sectional study including 27 participants, comprising TNBC patients
and healthy controls, was conducted, and ADR events were monitored in patients. Wholeexome
sequencing was performed using blood genomic DNA. The sequence data were
evaluated, and the pathogenicity of variants was predicted using in-silico tools. Associations
and correlations of the variants with ADRs were analyzed using statistical methods.
Results: Genetic variants were observed in BRCA1, BRCA2, ABCB1, ALKBH3,
CYP4F2, DPYD, MTHFR, and SLC22A10. Pathogenic variants in pharmacogenes, including
DPYD (rs1801265), CYP2C9 (T620C), SLC22A16 (rs201574154), SLCO1B1
(rs201722521), RYR1 (rs777680485), AHR (C1282A), and NUDT15 (rs116855232),
were identified in association with ADRs. Patients carrying variants in UGT1A1
(rs4148323) and CYP2B6 (rs8192709) experienced ADRs following chemotherapy
treatment regimens.
Discussion: In addition to known BRCA1 mutations, novel gene associations were identified,
including CYP4F2, DPYD, and ABCB1. Some variants were associated with side
effects such as hair loss, fatigue, and cardiac complications. G6PD variants may also contribute
to drug resistance.
Conclusion: This study identified certain gene variants linked to a higher risk of TNBC
and ADRs during chemotherapy. Alongside established BRCA1 mutations, associations
were observed in CYP4F2, DPYD, and ABCB1. Some variants were linked to side effects
including hair loss, fatigue, and heart-related issues. As a pilot study with a small
sample size, it was underpowered to detect small or medium effects, and its primary purpose
is to estimate variability and effect sizes to inform the design of a larger study.
