Table 3.
Germline Immune Genetic Associations with Targeted Therapy and Chemotherapy Outcomes
| Ref | Cancer | Treatment | Outcome | # subjects | Immune Genes | Immune gene function* | Main germline immune genetic associations found | Statistical significance of association |
|---|---|---|---|---|---|---|---|---|
|
| ||||||||
| (41) | Breast | Preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C) | Response to treatment | 73 | FCGR3a | Antigen-antibody (Immunoglobulin receptor on macrophages, neutrophils) | FCGR3a V allele carriers had a significant improvement in pathological complete response rate with trastuzumab and lapatinib in HER2+ BC patients. | OR=9.4 (2.3–39.6), p=0.003 |
| (37) | CML | Tyrosine kinase inhibitors (imatinib, dasatinib, nilotinib, or bosutinib) | Complete molecular response (which was equivalent to undetectable BCR–ABL transcript expression) | 76 | KIR and HLA genes | Antigen processing and presentation | Weak interacting KIR3DL1*005 and HLA-B pairs were associated with improved molecular response to TKIs. | HR=14.22 (3.69–55.44), p<0.001 |
| (48) | Multiple myeloma | Lenalidomide and bortezomib | PFS, OS | 255 | TIRAP | Antimicrobial – Pathogen recognition and activation of innate immunity | TIRAP rs8177374 was associated with a decreased PFS and OS. | PFS: HR=1.74 (1.15–2.62), p=0.008; OS: HR=3.06 (1.74–5.4), p<0.001 |
| (47) | Follicular lymphoma; DLBCL | Rituximab | Event free survival | 107 FL; 82 DLBCL |
Several complement pathway genes | Complement pathway | CFH rs376404 and CFHR5 rs 6694672 variants were the most strongly associated with event free survival in follicular lymphoma patients receiving rituximab. |
CFH: HR=9.49 (2.59–505.6), p=0.0007 CFHR5: HR=6.00 (1.59–22.67), p=0.0083 |
| (51) | Neuroblastoma | Anti-GD2 mAb 3F8 | PFS, OS | 245 | KIR3DL1, HLA-B | Antigen processing and presentation | Noninteracting combinations had the most favorable PFS and OS outcomes. | HR (PFS)=0.43 (0.28–0.66), p<0.001; HR (OS)= 0.41 (0.25–0.65), p<0.001 |
| (38) | Colorectal | 5-fluorouracil, leucovorin, and irinotecan | CR (complete response) | 224 | KIR3DL1, HLA-Bw-I80 | Antigen processing and presentation | Presence of KIR3DL1/HLA-Bw4-I80 was associated with improved CR. | 1 Bw4-I80 allele: HR=2.7, p<0.001; 2 Bw4-I80 alleles: HR=1.8, p<0.006 |
| (55) | Colorectal | Primary surgery and then ADJ-CT based on fluoropyrimidine (FL) (i.e., 5-fluorouracil/folinic acid or capecitabine), or FL plus oxaliplatin (FL+OXA) | DFS, OS | 253 | HLA-G | Antigen processing and presentation | Presence of HLA-G +3035 C>T and +2960 14-bp INDEL were associated with improved DFS. Presence of HLA-G +3187 A>G was associated with worse DFS and OS. |
+2960: HR=0.60 (0.38–0.93), p-0.023; +3035: HR=0.51 (0.26–0.99), p=0.045; +3187: DFS, HR=2.46 (1.19–5.05), p-0.015; OS, HR=2.71 (1.16–6.63), p=0.022 |
| (52) | Lung NSCLC | First line Chemotherapy +/− radiotherapy | OS | 502 discovery; 355 internal validation |
11930 SNPs related to immune system | Antigen processing and presentation | HLA-DOB rs2071554 patients had decrease in median survival time. Variant was predicted to alter function. KLRK1 rs2900420 was protective and prolonged overall survival. |
HLA-DOB: HR=1.46 (1.02–2.09). KLRK1: HR=0.77 (0.61–0.99) |
| (68) | DLBCL | R-CHOP or R-CHOP-like treatment | OS, CR | 129 | C1qA | Complement pathway | C1qA 276 AA was associated with improved CR and OS. |
CR: p=0.0001
OR: p=0.023 |
| (69) | CLL | R-FC, R-CVP, chlorambucil, alemtuzumab | Response to treatment | 144 | CXCL12 | Cytokine -Chemokine | CXCL12 rs1801157 A allele was associated with poorer response to treatment (independent of the treatment type). | p<0.001 |
| (53) | Childhood ALL | Induction therapy (doxorubicin, vincristine, etc.) | Infections | 69 | GWAS - 34,000 SNPs in 2350 genes related to pharmacogenetics, immunogenetics, apoptosis, organ-specific toxicities, cell cycle control, and DNA repair and mitosis | Antigen processing and presentation | In pathway analyses, variants in Class I MHC-mediated antigen processing and presentation genes were predictive of infectious events. | AUC=0.83 |
*
Immune gene function: The immune system role of the protein encoded by the gene identified as being associated with cancer treatment outcome is indicated. The category designation was made as per Immport.org/shared/genelists and/or Genecards.org. Note that Cytokines can have various functions in mediating the immune system (such as inflammation, response to infection, etc.) through cell signaling; please refer to Genecards.org for a more comprehensive discussion of the gene functions.