Plasma Mucin-1 (CA15-3) Levels in Autosomal Dominant Tubulointerstitial Kidney Disease due to MUC1 Mutations

Abstract

Introduction: Patients with ADTKD-MUC1 have one allele producing normal mucin-1 (MUC1) and one allele producing mutant MUC1, which remains intracellular. We hypothesized that ADTKD-MUC1 patients, who have only 1 secretory-competent wild-type MUC1 allele, should exhibit decreased plasma mucin-1 (MUC1) levels. To test this hypothesis, we repurposed the serum CA15-3 assay used to measure MUC1 in breast cancer to measure plasma MUC1 levels in ADTKD-MUC1.

Methods: This cross-sectional study analyzed CA15-3 levels in a reference population of 6,850 individuals, in 85 individuals with ADTKD-MUC1, and in a control population including 135 individuals with ADTKD-UMOD and 114 healthy individuals.

Results: Plasma CA15-3 levels (mean ± standard deviation) were 8.6 ± 4.3 U/mL in individuals with ADTKD-MUC1 and 14.6 ± 5.6 U/mL in controls (p < 0.001). While there was a significant difference in mean CA15-3 levels, there was substantial overlap between the 2 groups. Plasma CA15-3 levels were <5 U/mL in 22% of ADTKD-MUC1 patients, in 0/249 controls, and in 1% of the reference population. Plasma CA15-3 levels were >20 U/mL in 1/85 ADTKD-MUC1 patients, in 18% of control individuals, and in 25% of the reference population. Segregation of plasma CA15-3 levels by the rs4072037 genotype did not significantly improve differentiation between affected and unaffected individuals. CA15-3 levels were minimally affected by gender and estimated glomerular filtration rate.

Discussion/conclusions: Plasma CA15-3 levels in ADTKD-MUC1 patients are approximately 40% lower than levels in healthy individuals, though there is significant overlap between groups. Further investigations need to be performed to see if plasma CA15-3 levels would be useful in diagnosis, prognosis, or assessing response to new therapies in this disorder.

Keywords: ADTKD-MUC1; Autosomal dominant tubulointerstitial kidney disease; CA15-3; Mucin-1; rs4072037.

Fig. 1

Distribution of serum CA15-3 levels in reference and study populations. a Distributions of CA15-3 levels were estimated using kernel density methods for 3 populations (ADTKD-MUC1, a control population consisting of patients with ADTKD-UMOD and of unaffected family members from both ADTKD-MUC1 and ADTKD-UMOD families, and a reference population). The mean CA15-3 levels were comparable in reference and control populations (15.7 ± 6.65 U/mL vs. 14.6 ± 5.6 U/mL). The mean serum CA15-3 level in the ADTKD-MUC1 group was significantly lower than in the control population (p < 0.001). The ADTKD-MUC1 distribution curve has 2 peaks. The lower CA15-3 level peak is from patients with the rs4072037 T/T and C/T genotype, and the higher CA15-3 level peak represents the C/C genotype. b Distributions of CA15-3 levels were estimated using kernel density methods for ADTKD-MUC1 (solid line) and control individuals (dotted line) in the training dataset (n = 267). CA15-3 levels (data points) are shown for each group at the x-axis. Using these density estimates, we calculated the CA15-3 levels that provided maximum separation in the lower and upper tails, corresponding to estimated 5 (U/mL) and 20 (U/mL), respectively. These thresholds are shown in gray and were used as classification rules for ADTKD-MUC1 assignment: <5 = positive, >20 = negative, and values between 5 and 20 were assigned as indeterminate. These thresholds were applied and summarized in the training and independent validation datasets (shown in online suppl. Table 2).

Fig. 2

Plasma CA15-3 levels in ADTKD families. The CA15-3 thresholds identified as predictive of ADTKD-MUC1 (<5 U/mL) and not ADTKD-MUC1 (>20 U/mL) are shaded. a Families included were identified as having 3 or more individuals present in the study population (n = 43). Each column represents an ADTKD family (n = 43); genetically unaffected individuals (n = 96) with white circles, ADTKD-MUC1 (n = 57) with black circles, and ADTKD-UMOD (n = 78) with gray circles. b Families included are negative for mutations in UMOD and MUC1 (n = 53); asymptomatic family members are represented by white circles, and clinically affected family members are represented by dark gray circles. ADTKD, autosomal dominant tubulointerstitial kidney disease.