A Bioinformatics Assessment Indicating Better Outcomes With Breast Cancer Resident, Immunoglobulin CDR3-MMP2 Binding

Abstract

Background/aim: The recombination of V, D, and J immunoglobulin (IG) gene segments leads to many variations in the amino acids (AAs) encoded at that site, the complementarity determining region-3 (CDR3). Thus, cancer patients may have varying degrees of CDR3 AA binding specificity for cancer proteases, for example, matrix metalloproteinase 2 (MMP2). MMP2 in breast cancer has been found to contribute to metastasis and is used as a marker for tumor staging. Thus, this report evaluated the tumor resident, patient specific IG CDR3 binding affinities to cancer proteases to test the hypothesis that greater binding affinities would be associated with a better outcome.

Materials and methods: Using two independent bioinformatics tools, we evaluated the IG CDR3-MMP2 binding affinities throughout the cancer genome atlas breast cancer (TCGA-BRCA) dataset.

Results: Results indicated that the better the CDR3-MMP2 binding, the better the survival probability. An analogous evaluation for four other proteases, including calpain-1 and thermolysin, displayed no such associations with survival probabilities.

Conclusion: This study is consistent with the possibility that patient IG-cancer protease interactions could impact outcomes and raises the question of whether therapeutic antibody targeting of MMP2 would reduce breast cancer mediated tissue destruction and breast cancer mortality rates.

Keywords: Chemical complementarity bioinformatics; MMP2; breast cancer; immunoglobulin CDR3s.

Figure 1. Survival distinctions represented by breast cancer (BRCA) immunoglobulin (IG) CDR3 AA sequence protease sensitivities. Kaplan-Meier (KM) analyses of the overall survival (OS) for case ID’s representing the top 25^th percentile of CDR3 protease sensitivity (black) versus the bottom 25^th percentile of sensitivity (gray), according to the SitePrediction algorithm (See Methods section). (A) BRCA primary tumor IG CDR3s and MMP2; logrank p=0.0392. (B) LUAD primary tumor IG CDR3s and MMP2; logrank p=0.4766. (C) BRCA blood derivative IG CDR3’s, matrix metalloproteinase 2 (MMP2). Logrank p=0.581. (D) BRCA primary tumor IG CDR3’s, thermolysin (MME). Logrank p=0.4857.

Figure 2. Survival distinction represented by chemical complementarity of breast cancer (BRCA) primary tumor immunoglobulin (IG) CDR3 AA sequences and matrix metalloproteinase 2 (MMP2) AA sequence segments. (A) Kaplan-Meier (KM) analysis for BRCA primary tumor IG CDR3 AA sequences and MMP2 Segment 1 based on the Combo complementarity score (CS) calculations (See Methods section). Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.0189. (B) KM analysis for BRCA primary tumor IG CDR3 AA sequences and MMP2 Segment 4 based on the Combo CS calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.0286. (C) KM analysis for BRCA primary tumor IG CDR3 AA sequences and MMP2 Segment 5 based on the Combo CS calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.0465.

Figure 3. Survival distinction represented by Combo complementarity scores (CSs) for LUAD primary tumor immunoglobulin (IG) CDR3 AA sequences and matrix metalloproteinase 2 (MMP2). (A) Kaplan-Meier (KM) analysis for LUAD primary tumor IG CDR3 AA sequences and MMP2 Segment 1 based on Combo CS calculations. Upper 50^th percentile, black; bottom 50^th percentile, gray; logrank comparison p=0.951. (B) KM analysis for LUAD primary tumor IG CDR3 AA sequences and MMP2 Segment 4 based on the Combo CS calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.8288. (C) KM analysis for LUAD primary tumor CDR3 AA sequences and MMP2 Segment 5 based on the Combo CS calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.620.

Figure 4. Survival distinctions represented by breast cancer (BRCA) primary tumor immunoglobulin (IG) CDR3-CTSB protease sensitivities and complementarity scoring. (A) Kaplan-Meier (KM) analysis for BRCA cases representing the upper and lower 25th percentiles, based on the cathepsin B (CTSB) protease sensitivity of the primary tumor IG CDR3’s, in turn based on the SitePrediction algorithm. Upper 25th percentile sensitivity scores, black; bottom 25th percentile sensitivity scores, gray logrank comparison p=0.0850 (Table I). (B) KM analysis for BRCA cases based on the primary tumor, IG CDR3-CTSB Segment 2 Electrostatic complementarity score (CS) calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.0098. (C) KM analysis for BRCA cases based on the primary tumor, IG CDR3-CTSB Segment 5 Hydro CS calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.0175. (D) KM analysis for BRCA cases based on primary tumor, IG CDR3-CTSB Segment 4 Combo CS calculations. Upper 50^th percentile CSs, black; bottom 50^th percentile CSs, gray; logrank comparison p=0.0098.