Validation of single nucleotide polymorphisms potentially related to R-CHOP resistance in diffuse large B-cell lymphoma patients

Gabriele Perrone; Luigi Rigacci; Giandomenico Roviello; Ida Landini; Alberto Fabbri; Lorenzo Iovino; Benedetta Puccini; Emanuele Cencini; Enrico Orciuolo; Monica Bocchia; Alberto Bosi; Enrico Mini; Stefania Nobili

doi:10.20517/cdr.2024.10

Validation of single nucleotide polymorphisms potentially related to R-CHOP resistance in diffuse large B-cell lymphoma patients

Cancer Drug Resist. 2024 May 24:7:21. doi: 10.20517/cdr.2024.10. eCollection 2024.

Authors

Gabriele Perrone¹, Luigi Rigacci², Giandomenico Roviello¹, Ida Landini¹, Alberto Fabbri³, Lorenzo Iovino^{4

5}, Benedetta Puccini⁶, Emanuele Cencini³, Enrico Orciuolo⁴, Monica Bocchia³, Alberto Bosi⁷, Enrico Mini^{1

8}, Stefania Nobili^{9

8}

Affiliations

¹ Department of Health Sciences, University of Florence, Florence 50139, Italy.
² Research Unit of Hematology, Department of Medicine and Surgery, Campus Biomedico University, Rome 00128, Italy.
³ Unit of Hematology, Azienda Ospedaliera Universitaria Senese, University of Siena, Siena 53100, Italy.
⁴ Unit of Hematology, Santa Chiara University Hospital, University of Pisa, Pisa 56126, Italy.
⁵ Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA 98109-4433, USA.
⁶ Unit of Hematology, Careggi University-Hospital, Florence 50134, Italy.
⁷ Department of Experimental and Clinical Medicine, University of Florence, Florence 50134, Italy.
⁸ Authors contributed equally.
⁹ Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence 50139, Italy.

Abstract

Aim: Diffuse large B-cell lymphoma (DLBCL) is the most common B-cell non-Hodgkin lymphoma (NHL). Despite the availability of clinical and molecular algorithms applied for the prediction of prognosis, in up to 30%-40% of patients, intrinsic or acquired drug resistance occurs. Constitutional genetics may help to predict R-CHOP resistance. This study aimed to validate previously identified single nucleotide polymorphisms (SNPs) in the literature as potential predictors of R-CHOP resistance in DLBCL patients, SNPs. Methods: Twenty SNPs, involved in R-CHOP pharmacokinetics/pharmacodynamics or other pathobiological processes, were investigated in 185 stage I-IV DLBCL patients included in a multi-institution pharmacogenetic study to validate their previously identified correlations with resistance to R-CHOP. Results: Correlations between rs2010963 (VEGFA gene) and sex (P = 0.046), and rs1625895 (TP53 gene) and stage (P = 0.003) were shown. After multivariate analyses, a concordant effect (i.e., increased risk of disease progression and death) was observed for rs1883112 (NCF4 gene) and rs1800871 (IL10 gene). When patients were grouped according to the revised International Prognostic Index (R-IPI), both these SNPs further discriminated progression-free survival (PFS) and overall survival (OS) of the R-IPI-1-2 subgroup. Overall, patients harboring the rare allele showed shorter PFS and OS compared with wild-type patients. Conclusions: Two out of the 20 study SNPs were validated. Thus, these results support the role of previously identified rs1883112 and rs1800871 in predicting DLBCL resistance to R-CHOP and highlight their ability to further discriminate the prognosis of R-IPI-1-2 patients. These data point to the need to also focus on host genetics for a more comprehensive assessment of DLBCL patient outcomes in future prospective trials.

Keywords: Diffuse large B-cell lymphoma (DLBCL); R-CHOP regimen; biomarkers; host genetics; single nucleotide polymorphism (SNP); tumor drug resistance.