The role of HLA-A'02 and biomarkers in solid malignant tumours

Sammanfattning: HLA-A'02 genotype generates significantly worse outcome in patients with metastatic serous ovarian cancer and malignant melanoma. HLA-A'02 is common in the Swedish population (about 60 %), but has decreasing frequency in European countries further south. Mortality in the aforementioned tumours correlates with both the latitude and the corresponding HLA-A ' 02 frequency. This thesis is based on the original findings that a combination of HLA-A'02 genotype, ovarian cancer of serous histology and advanced surgical stage has an extremely dismal prognosis. This combination of factors was named “worst prognosis group”. The aim of the thesis was to elucidate the frequency and distribution of different HLA genotypes in patients with ovarian carcinoma and cutaneous malignant melanoma. We then investigated the correlation between HLA-A'02 genotype and prognosis in these tumour diseases as well as expression of immunological biomarkers for classical and non-classical MHC class I, β2-mikroglobulin and infiltrating immune cells. Ovarian cancer symptoms are discrete and about 75% of patients are detected late, when the tumour has already spread. Cutaneous malignant melanoma on the other hand, is often discovered early since it is visible on the skin and the disease progression more easily recorded. The studies confirmed previous finding that HLA-A'02 is associated with a significantly shortened survival in patients with metastatic tumours of serous ovarian carcinoma or malignant melanoma. There is a high over-representation of HLA-A'02 in patients with advanced ovarian carcinoma. Especially a segregation of the ancestral haplotype 62.1 (HLAA'02, -B'15, -Cw'3, -DRB1'04) was identified. This haplotype was also present in the group of patients with malignant melanoma. The ancestral haplotype 62.1 seems to give an initial enhanced protection against cancer cells and the time to recurrence is significantly extended. After metastases, however, the disease progression is significantly shorter compared to patients with other haplotypes. The results indicate that the AHH 62.1 might be involved in immune selection, possibly through a specific immunological mechanism called "eliminationequilibrium-escape" mechanism. Down- regulation of MHC or up-regulation of HLA-G or aberrant expression of HLA–E has been described as tumour escape mechanisms and linked to poor prognosis in other studies. These findings were confirmed in our cohorts, but only in patients with HLA-A'02 genotype and not in the others. In multivariate analysis HLA-A'02 was the second most important prognostic factor, only surgical stage had a higher hazard ratio. Our results demonstrate that a multifactorial approach, considering tumour characteristics and biomarkers as well as the patient's genetics, can outline subgroups of patients. This may provide improved opportunities to tailor targeted therapies.