Association of HLA-G 3'UTR Polymorphisms with Response to First-Line FOLFIRI Treatment in Metastatic Colorectal Cancer

Lucia Scarabel; Jerry Polesel; Elena De Mattia; Angela Buonadonna; Mario Rosario D'Andrea; Erika Cecchin; Giuseppe Toffoli

doi:10.3390/pharmaceutics14122737

Association of HLA-G 3'UTR Polymorphisms with Response to First-Line FOLFIRI Treatment in Metastatic Colorectal Cancer

Pharmaceutics. 2022 Dec 7;14(12):2737. doi: 10.3390/pharmaceutics14122737.

Authors

Lucia Scarabel¹, Jerry Polesel², Elena De Mattia¹, Angela Buonadonna³, Mario Rosario D'Andrea⁴, Erika Cecchin¹, Giuseppe Toffoli¹

Affiliations

¹ Experimental and Clinical Pharmacology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini n. 2, 33081 Aviano, Italy.
² Unit of Cancer Epidemiology, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini n. 2, 33081 Aviano, Italy.
³ Medical Oncology Unit, Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Via Franco Gallini n. 2, 33081 Aviano, Italy.
⁴ Ospedale S. Paolo, 00053 Civitavecchia, Italy.

Abstract

Microenvironmental factors such as non-classical human leukocyte antigen-G (HLA-G) have been associated with cancer invasiveness and metastatic progression. HLA-G expression has been associated with specific single-nucleotide polymorphisms (SNP) in HLA-G 3'untranslated region (UTR) in several diseases. The primary aim was to investigate the predictive role of HLA-G polymorphisms on treatment efficacy in metastatic colorectal cancer (mCRC) patients homogeneously treated with first-line FOLFIRI (irinotecan, 5-fluorouracil, and leucovorin) and their association with soluble HLA-G (sHLA-G) plasma concentration. HLA-G 3'UTR was sequenced in 248 patients. A set of eight polymorphisms and related haplotypes were analyzed for their association with best tumor response, overall survival (OS), and progression-free survival (PFS). sHLA-G was measured by immunoassay in 35 available plasma samples and correlated with HLA-G 3'UTR polymorphisms/haplotypes. Our results showed that carriers of rs371194629 (+2960)-Ins allele were at risk for lack of complete response (hazard ratio (HR):0.29, p_BH = 0.0336), while carriers of rs1710 (+3010)-G allele (rs1063320 (+3142)-C allele in linkage-disequilibrium), and rs9380142 (+3187)-G allele had a higher chance of complete response according to additive models (HR:4.58, p_BH = 0.0245; HR:3.18, p_BH = 0.0336, respectively). The combination of rs371194629-Del, rs1710-G, and rs9380142-G alleles forms the UTR1 haplotype. Patients who were carriers of UTR1/UTR-1 diplotype had a greater chance of complete response to therapy (HR:10.59, p_BH = 0.0294). The same three beneficial alleles showed a trend toward higher pre-treatment sHLA-G plasma levels, supporting a functional role for polymorphisms in protein secretion. In conclusion, genetic variants of HLA-G are associated with treatment efficacy in mCRC patients treated with first-line FOLFIRI. This finding shed light on the combined effect of this immune system factor and chemotherapy in cancer patients.

Keywords: HLA-G; colorectal cancer; immune system; immunobiomarker; immunocheckpoint; personalized medicine.

Grants and funding

This work was supported by the Italian Ministry of Health (Ricerca Corrente) and 5 × 1000 “Ricerca Sanitaria”.