Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2017 Nov 18;8(62):105957-105970.
doi: 10.18632/oncotarget.22515. eCollection 2017 Dec 1.

HLA-G+3027 polymorphism is associated with tumor relapse in pediatric Hodgkin's lymphoma

Valli De Re #  1 , Laura Caggiari #  1 , Lara Mussolin  2 , Emanuele Stefano d'Amore  3 , Barbara Famengo  3 , Mariangela De Zorzi  1 , Lia Martina  1 , Caterina Elia  4 , Marta Pillon  5 , Nicola Santoro  6 , Paola Muggeo  6 , Salvatore Buffardi  7 , Maurizio Bianchi  8 , Alessandra Sala  9 , Piero Farruggia  10 , Luciana Vinti  11 , Edgardo D Carosella  12 , Roberta Burnelli  13 , Maurizio Mascarin  4
Affiliations

HLA-G+3027 polymorphism is associated with tumor relapse in pediatric Hodgkin's lymphoma

Valli De Re et al. Oncotarget. .

Abstract

In this study, we tested whether polymorphisms in human leukocyte antigen G (HLA-G) were associated with event-free survival (EFS) in pediatric Hodgkin's lymphoma (HL). We evaluated the association of HLA-G 3'-UTR polymorphisms with EFS in 113 pediatric HL patients treated using the AIEOP LH-2004 protocol. Patients with the +3027-C/A genotype (rs17179101, UTR-7 haplotype) showed lower EFS than those with the +3027-C/C genotype (HR= 3.23, 95%CI: 0.99-10.54, P=0.012). Female patients and systemic B symptomatic patients with the HLA-G +3027 polymorphism showed lower EFS. Multivariate analysis showed that the +3027-A polymorphism (HR 3.17, 95%CI 1.16-8.66, P=0.025) was an independent prognostic factor. Immunohistochemical analysis showed that HL cells from patients with the +3027-C/A genotype did not express HLA-G. Moreover, HLA-G +3027 polymorphism improved EFS prediction when added to the algorithm for therapeutic group classification of pediatric HL patients. Our findings suggest HLA-G +3027 polymorphism is a prognostic marker in pediatric HL patients undergoing treatment according to LH-2004 protocol.

Keywords: +3027 C/A genotype; 3’UTR polymorphism; HLA-G; event-free survival; pediatric hodgkin lymphoma.

PubMed Disclaimer

Conflict of interest statement

CONFLICTS OF INTEREST The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1. Kaplan-Meier survival analysis of +3027C/A HLA-G polymorphisms
Kaplan Meier survival curves show 72.3% and 34% EFS for patients with the +3027 C/C and C/A variant, respectively (C/A vs. C/C, HR=3.23, 95% CI 0.99-10.54; P=0.012). The solitary patient with A/A genotype was excluded from the analysis.
Figure 2
Figure 2. Cox regression analysis of event-free survival based on gender and systemic symptoms
Cox regression analysis shows patients carrying +3027 HLA-G polymorphism show lower EFS in (A) female and (B) systemic B symptomatic patients.
Figure 3
Figure 3. Kaplan Meier survival analysis comparing algorithms based on the HLA-G genotype and AIEOP LH-2004 risk score classification
(A) Kaplan Meiersurvival curves based on HLA-G +3027 algorithm is shown. Patients were divided into 2 groups based on their HLA-G +3027 genotype (C/C and C/A) and further divided into 3 groups based the AIEOP LH-2004 therapeutic risk score (GR). Since the GR1 and GR2 groups with the +3027 C/A variant included less than 2 patients, GR1, GR2 and GR3 groups with the +3027 C/A variant were merged to form a unique GR123-C/A group. (B) Kaplan Meier survival curves based on the AIEOP LH-2004 risk score for therapeutic response (GR) in pediatric HL patients. Note: Criteria for the AIEOP LH2004 therapeutic group (GR) classification are in the methods section.
Figure 4
Figure 4. Comparison of the risk values based on AIEOP LH-2004 group therapy protocol and HLA-G +3027 algorithm
Kaplan-Meier survival analysis show hazard ratios (HR) for GR1, GR2 and GR3 groups based on AIEOP LH-2004 therapy and the HLA-G genetic groups, GR1,2,3-C/C and GR123-C/A based on our analysis. Note: GR1 and GR 1-C/C as reference categories; 95% CI confidence intervals are shown for event-free survival (EFS).
Figure 5
Figure 5. Overall survival in pediatric HL patients based on therapeutic grouping
Cox regression analysis showing OS in pediatric HL patients (n=113) based on therapeutic grouping (GR). As shown, GR1-C/C and GR2- C/C patients show higher EFS than GR3-C/C and GR123-C/A patients.
Figure 6
Figure 6. Immunohistochemical analysis of HLA-G protein expression in Reed-Sternberg cells in pediatric HL patients
Representative image shows immunohistochemical staining for HLA-G in a HL patient carrying the wild type C/C +3027 genotype. Formalin/PFA-fixed paraffin-embedded sections were stained with primary anti-HLA-G antibody (4H84). Lymphoma cells show strong membrane staining for HLAG. Note: Only 5 out of 25 patients analyzed were positive for HLA-G in our analysis.
See this image and copyright information in PMC

References

    1. AIRTUM Working Group. CCM. AIEOP Working Group [Article in English, Italian]. Italian cancer figures, report 2012: cancer in children and adolescents. Epidemiol Prev. 2013;37:1–225. - PubMed
    1. Janz M, Mathas S. The pathogenesis of classical Hodgkin's lymphoma: what can we learn from analyses of genomic alterations in Hodgkin and Reed-Sternberg cells? Haematologica. 2008;93:1292–5. https://doi.org/10.3324/haematol.13614 - DOI - PubMed
    1. Boiocchi M, De Re V, Dolcetti R, Carbone A, Scarpa A, Menestrina F. Association of Epstein-Barr virus genome with mixed cellularity and cellular phase nodular sclerosis Hodgkin's disease subtypes. Ann Oncol. 1992;3:307–10. - PubMed
    1. Farruggia P, Puccio G, Sala A, Todesco A, Buffardi S, Garaventa A, Bottigliero G, Bianchi M, Zecca M, Locatelli F, Pession A, Pillon M, Favre C, et al. The prognostic value of biological markers in paediatric Hodgkin lymphoma. Eur J Cancer. 2016;52:33–40. https://doi.org/10.1016/j.ejca.2015.09.003 - DOI - PubMed
    1. Castellino SM, Geiger AM, Mertens AC, Leisenring WM, Tooze JA, Goodman P, Stovall M, Robison LL, Hudson MM. Morbidity and mortality in long-term survivors of Hodgkin lymphoma: a report from the Childhood Cancer Survivor Study. Blood. 2011;117:1806–16. https://doi.org/10.1182/blood-2010-04-278796 - DOI - PMC - PubMed