A new study published in Scientific Reports sheds light on the genetic factors contributing to severe toxicities observed in Amazonian indigenous populations undergoing treatment for Acute Lymphoblastic Leukemia (ALL). The research identifies novel genetic variants within genes associated with glucocorticoid pathways that could influence treatment response and toxicity.
The study, which is the first to investigate genes related to glucocorticoid treatment in ALL within indigenous populations, aims to elucidate the causes behind the elevated rates of treatment toxicity observed in this group. Researchers compared the gene profiles of indigenous individuals with and without ALL, as well as with larger continental populations.
Key Genetic Variants Identified
The research team identified 13 variants exclusively reported in the study population, distributed across genes including CTNNB1, ADH1C, FGFR4, HMMR, and BMP7. Notably, the variant chr5:163473551 in HMMR was predicted to have a high impact on protein activity.
Previous research has demonstrated the impact of steroid treatment on HMMR expression. A study by Fajardo and colleagues showed that steroid use led to a 40% reduction in macrophage accumulation in the lungs of injured animals, suggesting that steroids decrease HMMR expression in vivo. The presence of genetic variants in the HMMR gene could potentially affect variation in steroid response and inflammation regulation.
Cortese et al. showed that the glucocorticoid response element of the human ADH1 gene could be induced by dexamethasone in mice. Dong et al. demonstrated that dexamethasone treatment caused a dose-dependent increase in total ADH1 mRNA levels in cells, indicating enhanced transcription. The ADH1C gene exhibits peak activity in the liver, a critical organ for drug metabolism.
Impact on Treatment Outcomes
Comparing variant frequencies in the indigenous population with other world populations revealed that variants rs2032582 (ABCB1), rs1966265 and rs351855 (FGFR4), rs1051775 (GSTA1), rs2294918 and rs738409 (PNPLA3), and rs1979277 (SHMT1) have been previously evaluated for their impact on therapeutic outcomes.
The rs2032582 (ABCB1) variant is associated with decreased overall survival in multiple myeloma patients treated with dexamethasone. The rs1966265 (FGFR4) variant was linked to drug response in cyclophosphamide-epirubicin-docetaxel-based therapy in breast cancer patients. The rs351855 (FGFR4) variant may serve as a prognostic marker for patients with hepatocellular carcinoma treated with lenvatinib and has also been associated with febrile neutropenia occurrence in breast cancer patients undergoing chemotherapy.
The high-impact variant rs1051775 (GSTA1) has been linked to mortality related to cyclophosphamide treatment in individuals undergoing hematopoietic stem cell transplantation. The rs738409 (PNPLA3) variant was found to be associated with altered liver function in pediatric ALL patients undergoing therapy.
Implications for Precision Medicine
The study underscores the importance of considering ethnic-genetic characteristics during the therapeutic process for indigenous populations. The oversight of these factors has resulted in elevated incidences of treatment-related toxicities. Further studies on the genetic profile of indigenous populations are needed to enhance clinical strategies and enable personalized treatments.
By understanding the genetic peculiarities of these communities, clinical strategies can be enhanced, enabling personalized treatments tailored in a more effective and adapted manner. Such targeted approaches not only aim to minimize toxicity risks but also represent a pivotal step toward substantially increasing survival rates in these communities, fostering a more inclusive and responsive approach to their unique healthcare needs.
The researchers emphasize the need for further functional and association studies to deepen the understanding of how genetic variants impact glucocorticoid response in ALL therapy. Investigating populations characterized by a high incidence of severe and fatal toxicities, such as indigenous populations, is crucial for directing efforts towards the prevention and management of these adverse events. This underscores the importance of implementing precision medicine strategies tailored to the unique genetic characteristics of these groups.
