The common Scandinavian human leucocyte antigen ancestral haplotype 62.1 as prognostic factor in patients with advanced malignant melanoma
- 111 Downloads
We have previously demonstrated an association of the human leukocyte antigen (HLA), HLA-A2 allele with ovarian and prostate cancer mortality as well as a segregation of the ancestral HLA haplotype (AHH) 62.1 [(A2) B15 Cw3 DRB1*04] in patients with stage III–IV serous ovarian cancer. The objective of the present study was to determine the role of the HLA phenotype on the prognosis in stage III–IV malignant melanoma patients.
Patients and methods
A cohort of metastatic malignant melanoma patients (n = 91), in stage III (n = 26) or IV (n = 65) were analysed for HLA-A, -B, -Cw and -DRB1 types by PCR/sequence-specific primer method. The frequencies of HLA alleles in the patients were compared to that of healthy Swedish bone marrow donors. The effect of HLA types on prognosis was defined by Kaplan–Meier and Cox analysis.
The presence of the AHH 62.1 in clinical stage IV patients was significantly and independently associated with the worst survival rate recorded from the appearance of metastasis (HR = 2.14; CI = 1.02–4.4; P = 0.04). In contrast, the period from the primary diagnosis to metastasis was the longest in patients with this haplotype (HR = 0.40; CI = 0.17–0.90; P = 0.02).
Melanoma patients in our cohort with 62.1 AHH which is associated with autoimmune diseases have an initial strong anti-tumour control with longer metastasis-free period. These patients have rapid progression after the appearance of metastasis, responding poorly to chemo- or/and immunotherapy. This apparently paradoxical clinical process could be due to the interplay between tumour clones escape and immune surveillance ending up with a rapid disease progression.
KeywordsHLA Ancestral haplotype 62.1 Malignant melanoma Survival Cox analysis
Human leucocyte antigen
Major histocompatibility complex
Ancestral HLA haplotype
Polymerase chain reaction
Healthy Swedish donors
Time from primary diagnosis to first metastasis
Survival time from metastasis
This study was mainly supported by grants from the Cancer Society in Stockholm and the King Gustaf V Jubilee Fund and the Swedish Cancer Society, the Karolinska Institute/Stockholm County ALF grant and the Deutsche Forschungsgemeinschaft (DFG) Se-585-10 (BS). We are also grateful for the financial support provided by the motility grant #040226# from “NordForsk, Holbergs gate 1, NO-0166 Oslo, NORWAY” to the NCEV network project. We thank Dr. Raja Choudhury for the reviewing of the manuscript.
- 1.Anichini A, Mortarini R, Nonaka D, Molla A, Vegetti C, Montaldi E, Wang X, Ferrone S (2006) Association of antigen-processing machinery and HLA antigen phenotype of melanoma cells with survival in American Joint Committee on Cancer stage III and IV melanoma patients. Cancer Res 66:6405–6411PubMedCrossRefGoogle Scholar
- 6.Campillo JA, Martinez-Escribano JA, Muro M, Moya-Quiles R, Marin LA, Montes-Ares O, Guerra N, Sanchez-Pedreno P, Frias JF, Lozano JA, Garcia-Alonso AM, Alvarez-Lopez MR (2006) HLA class I and class II frequencies in patients with cutaneous malignant melanoma from southeastern Spain: the role of HLA-C in disease prognosis. Immunogenetics 57:926–933PubMedCrossRefGoogle Scholar
- 7.Cavalli-Sforza, L, Menozzi, P, Piazza, A (1994) The history and geography of human genes. Princetown University PressGoogle Scholar
- 15.Flores-Villanueva PO, Hendel H, Caillat-Zucman S, Rappaport J, Burgos-Tiburcio A, Bertin-Maghit S, Ruiz-Morales JA, Teran ME, Rodriguez-Tafur J, Zagury JF (2003) Associations of MHC ancestral haplotypes with resistance/susceptibility to AIDS disease development. J Immunol 170:1925–1929PubMedGoogle Scholar
- 17.Gamzatova Z, Villabona L, van der Zanden H, Haasnoot GW, Andersson E, Kiessling R, Seliger B, Kanter L, Dalianis T, Bergfeldt K, Masucci GV (2007) Analysis of HLA class I-II haplotype frequency and segregation in a cohort of patients with advanced stage ovarian cancer. Tissue Antigens 70:205–213PubMedCrossRefGoogle Scholar
- 26.Lee JE, Reveille JD, Platsoucas CD (1996) Association of HLA-DOB1*0301 with malignant melanoma. J Immunother Emphas Tumor Immunol 19:381–385Google Scholar
- 31.Maeurer MJ, Gollin SM, Storkus WJ, Swaney W, Karbach J, Martin D, Castelli C, Salter R, Knuth A, Lotze MT (1996) Tumor escape from immune recognition: loss of HLA-A2 melanoma cell surface expression is associated with a complex rearrangement of the short arm of chromosome 6. Clin Cancer Res 2:641–652PubMedGoogle Scholar
- 37.Rosenberg SA, Packard BS, Aebersold PM, Solomon D, Topalian SL, Toy ST, Simon P, Lotze MT, Yang JC, Seipp CA et al (1988) Use of tumor-infiltrating lymphocytes and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report. N Engl J Med 319:1676–1680PubMedGoogle Scholar
- 43.Sosman JA, Unger JM, Liu PY, Flaherty LE, Park MS, Kempf RA, Thompson JA, Terasaki PI, Sondak VK (2002) Adjuvant immunotherapy of resected, intermediate-thickness, node-negative melanoma with an allogeneic tumor vaccine: impact of HLA class I antigen expression on outcome. J Clin Oncol 20:2067–2075PubMedCrossRefGoogle Scholar