Abstract
The caspase 8 variants CASP8 -652 6N InsDel and Asp302His have previously been identified to promote survival of T-lymphocytes and to indicate reduced breast cancer susceptibility. Besides some preliminary findings, prognostic relevance of these polymorphisms in patients with existing breast cancer has not been investigated. Considering an immunomodulatory role of these polymorphisms, we genotyped 785 early breast cancer patients and correlated caspase 8 variants with disease-free survival (DFS) and the presence of tumor infiltrating lymphocytes (TILs). Early breast cancer specimens were collected as part of the multicenter prospective PiA study. Genotyping was performed by pyrosequencing, TILs status was assessed using hematoxylin & eosin staining. The CASP8 -652Del variant was significantly associated with improved DFS in an allele-dose dependent manner (p = 0.027). Homozygosity for the -652Del variant was an independent predictor for improved DFS (HR = 0.36; 95% CI = 0.174–0.726; p = 0.005). In patients with the 302HisHis genotype, there was no event of recurrence during observation time. Combined analysis of diplotypes revealed an influence of both polymorphisms on DFS (p = 0.029). Interestingly, patients with the 302HisHis variant among the unstratified patient cohort (and among the luminal-like subtype, by trend) had tumors with lower lymphocyte infiltration (p = 0.025). We propose a prognostically favorable role of the -652Del and the 302His variant in primary breast cancer and suggest for the first time an association between polymorphisms in apoptosis-related genes and the immunophenotype in breast cancer. Our findings encourage further investigation of caspase 8 polymorphisms as biomarkers for prognostic and immunotherapeutic considerations.
Highlights
Programmed cell death, known as apoptosis, is an important process in multicellular organisms and is dysregulated during malignant progression
We assume that functional polymorphisms, which are associated with cancer susceptibility, are likely to influence prognosis of an existing cancer
Our findings add a new layer of complexity to immunological interaction in breast cancer and indicate that the immunophenotype of a given tumor could pre-defined by genetic variability in apoptosis regulating genes
Summary
Programmed cell death, known as apoptosis, is an important process in multicellular organisms and is dysregulated during malignant progression. Based on the assumption that this polymorphism has an immunomodulatory role, it was further reported that the CASP8 -652Del variant significantly decreases breast cancer susceptibility in healthy individuals. This was explained by the fact that -652Del reduces the apoptotic threshold of lymphocytes, which are responsible for “tumor surveillance”, i.e. the detection and elimination of pre-malignant lesions[6]. The objective of the current study was to analyze 785 clinically documented breast cancer patients for the CASP8 -652 6N Ins/Del and CASP8 Asp302His polymorphism and to correlate resulting genotypes with disease-free survival (DFS) and the presence of TILs
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