HLA traits linked to development of head and neck squamous cell carcinoma affect the progression-free survival of patients

Wichmann, Gunnar; Herchenhahn, Cindy; Boehm, Andreas; Mozet, Christian; Hofer, Mathias; Fischer, M; Kolb, Marlen; Dietz, Andreas

doi:10.1016/j.oraloncology.2017.04.017

Cited by 13 publications

(27 citation statements)

References 25 publications

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“…Avoiding overlap with the 12 DeLOS-II patients in TC, the iVC consists of N = 32 independent samples. Presence of the eight HLA traits constituting Pi of PFS in the TC was assessed as described ( 19 ).…”

Section: Methodsmentioning

confidence: 99%

“…The recently published HR of HLA traits detected in the TC that consistently remained significant Pi for PFS after bootstrapping with 1,000 iterations ( 19 ) were used to build the HLA-score. This data set from the TC ( 19 ) fulfils all prerequisites to classify the patients based on a score combining up to eight independent predictors ( n = 90 > 64 = 8 2 ). The HR for each of the eight HLA traits was transformed into its natural logarithm, ln HR (Table 2 ).…”

Section: Methodsmentioning

confidence: 99%

“…The risk for development of HNSCC is increased by genetic variants in genes encoding enzymes involved in DNA repair or metabolism of alcohol ( 9 – 11 , 13 ); Fanconi anemia patients have a 700-fold increased risk for HNSCC and high rate of relapses ( 17 , 18 ). Moreover, research implicated that polymorphisms in cytokine genes and members of the immunoglobulin supergene family including human leukocyte antigens (HLAs) are involved in either improved or impaired ability to control somatic mutations by adequate immune responses and maintenance of immune surveillance: we recently demonstrated in a German cohort of white Caucasian genetic descent that polymorphisms in HLA, in particular HLA-B antigens and homozygosity in HLA-Cw and DRB4, are associated with increased risk for HNSCC ( 19 ). Moreover, the highly frequent disruption of functionally coupled HLA antigens (haplotypes) and presence of uncommon haplotypes in a significant proportion of patients are linked not only to development of HNSCC but even more to reduced progression-free survival (PFS) independent of lifestyle-associated risk factors ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

“…The fewer carriers of such haplotypes have improved PFS, whereas those that are over-represented did not. Hence, genetic heterogeneity seems to account for altered risk of developing HNSCC but also PFS ( 19 ). The hazard ratios (HR) for PFS of B*13, B*35, B*51, HLA-DQB1*06, homozygous Cw and DRB4, and the haplotypes A*01/B*08 and B*08/C*07 were stably significant independent predictors ( Pi ) in multivariate analyses ( 19 ).…”

Section: Introductionmentioning

confidence: 99%

“…As the aggregation of independent risk factors in a score offers a way to abstract from individual risk factors by summarizing only their (potential) impact as Pi ( 20 ), we had the hypothesis that HR for PFS may be useful to construct an HLA-score. Therefore, we newly defined an HLA-score based on published HR from our recent findings in a test cohort (TC) ( 19 ). Here, we aim to verify a potential impact of the scored HLA traits on PFS of HNSCC and to particularly elucidate, if this HLA-score reliably predicts outcome differences in the context of clinical trials.…”

Section: Introductionmentioning

confidence: 99%

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Development of a Human Leukocyte Antigen Score to Predict Progression-Free Survival in Head and Neck Squamous Cell Carcinoma Patients

et al. 2018

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BackgroundIn personalized medicine and treatment stratification of head and neck squamous cell carcinoma (HNSCC), the heterogeneous genetic background of patients is not considered. Human leukocyte antigen (HLA) alleles and HLA haplotypes (HLA traits) are linked to development of HNSCC and affect progression-free survival (PFS) of HNSCC patients but most head and neck oncologists are not familiar with HLA typing. Hence, we developed an HLA-score abstracting from complexity of HLA-typing results to facilitate potential use of HLA-associated hazard ratios (HR) for prognostic stratification.MethodsThe HR for PFS of 8 HLA traits shown to be independent predictors (Pi) of PFS in a test cohort (TC) of 90 HNSCC patients were used to build the HLA-score based on the natural logarithm (ln) of the Pi-associated HR. Crude ln-transformed HR of the eight Pi, alleles B*13 (2), B*35 (1), B*51 (2), DQB1*06 (1), homozygous Cw (1), homozygous DRB4 (2), and haplotypes A*01/B*08 (−6) and B*08/C*07 (4), were summed up to yield the individual patient’s HLA-score. Receiver operating characteristic (ROC) and Kaplan–Meier curves were used to proof the suitability of the HLA-score as prognostic marker for PFS. An independent validation cohort (iVC) of 32 patients treated in the larynx-organ preservation trial DeLOS-II was utilized for validation.ResultsThe individual HLA-scores (range −2 to 6) in TC classified HNSCC patients regarding PFS. ROC analysis (area under the curve = 0.750, 95% CI 0.665–0.836; P = 0.0000034) demonstrated an optimum cutoff for the HLA-score at 0.5 (97.9% sensitivity, 34.7% specificity), and 70/90 patients in TC with HLA-score > 0 had significant reduced PFS (P = 0.001). Applying the same classifier (HLA-score > 0) confirmed these findings in the iVC revealing reduced PFS of 25/32 patients (P = 0.040).ConclusionHLA traits constitute critical Pi. Considering the HLA-score may potentially facilitate the use of genetic information from HLA typing for prognostic stratification, e.g., within clinical trials.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%