IGKC and FcγR genotypes and humoral immunity to HER2 in breast cancer

Immunoglobulin κ constant (IGKC) gene has recently been identified as a strong prognostic marker in several human solid tumors, including breast cancer. Although the mechanisms underlying the IGKC signature are not yet known, identification of tumor-infiltrating plasma cells as the source of IGKC expression strongly suggests a role for humoral immunity in breast cancer progression. The primary aim of the present investigation was to determine whether the genetic variants of IGKC, KM (κ marker) allotypes, are risk factors for breast cancer, and whether they influence the magnitude of humoral immunity to epidermal growth factor receptor 2 (HER2), which is overexpressed in 25-30% of breast cancer patients and is associated with poor prognosis. Using a matched case-control design, we genotyped a large (1719 subjects) study population from Japan and Brazil for KM alleles. Both cases and controls in this study population had been previously characterized for GM (γ marker) and Fcγ receptor (FcγR) alleles, and the cases had also been characterized for anti-HER2 antibodies. Conditional logistic regression analysis of the data showed that KM1 allele additively contributed to the risk of breast cancer in the Japanese subjects from Nagano: Compared to KM3 homozygotes, KM1 homozygotes were almost twice as likely to develop breast cancer (OR = 1.77, CI 1.06-2.95). Additionally, KM genotypes-individually and in particular epistatic combinations with FcγRIIa genotypes-contributed to the magnitude of anti-HER2 antibody responsiveness in the Japanese patients. This is the first report implicating KM alleles in the immunobiology of breast cancer.