Table 2.
Clinical studies discussed in this Review
| DNA source | Clinical trial format | Number of patients (n) | Phenotypes tested | Top SNPs and P values | Replication? | Refs |
|---|---|---|---|---|---|---|
| Blood after ALL remission | Three standard methotrexate plus 6-mercaptopurine (both of which are antimetabolites) paediatric ALL treatment regimens were followed; GWAS | Discovery n = 434; initial study replication n = 206; additional study replication n = 115 | Methotrexate clearance | rs11045879 in SLCO1B1 (P = 1.7 × 10−10) | rs11045879 in SLCO1B1 (P = 0.018 initial study; P = 0.030 additional study) | 15,60 |
| Blood | Drug A versus drug B; patients with breast cancer treated with one of two aromatase inhibitors (anastrozole versus exemestane); GWAS | Cases n = 293; controls matched to treatment arm and other covariates n = 585 | Musculoskeletal toxicity | rs11849538 near 3′ end of TCL1A (P = 6.7 × 10−7) | No replication in patients, but the risk allele creates an oestrogen response element, and extensive in vitro functional evidence implicates the locus | 13,61 |
| Blood | Drug A versus drug A + B; patients with pancreatic cancer treated with gemcitabine (an antimetabolite) alone or in combination with bevacizumab (a VEGF inhibitor); GWAS | n = 351 (combined treatment arms because no difference in overall survival was observed) | Overall survival | rs7771466 in IL17F (P = 2.6 × 10−8) | None | 14 |
| CML samples | Not a clinical trial: compared patient CML samples that were sensitive or resistant to imatinib (a tyrosine kinase inhibitor) using paired-end whole-genome sequencing to identify structural variants | Initial sequencing study: sensitive n = 2 and resistant n = 3; CML replication cohort n = 203; NSCLC replication cohort n = 141 | Resitance to TKIs; progression- free survival in NSCLC patients treated with TKIs | A deletion in BIM was common to the resistant samples and not present in the sensitive samples; found to be a germline polymorphism after screening 2,597 healthy individuals (12.3% carrier frequency in East Asians) | BIM deletion associates with TKI resistance in CML patients (P = 0.02) and shorter progression-free survival in NSCLC patients (P = 0.03); extensive in vitro functional evidence implicates the locus | 62 |
| Blood after ALL remission | Follow-up to the study described in REF. 15; deep resequencing of SLCO1B1 | n = 699 | Methotrexate clearance | Nonsynonymous SNPs, including common and rare variants, that were predicted to be functionally damaging were more likely to be found in patients with lower methotrexate clearance | None | 76 |
| Blood | Drug A versus drug B; patients with breast cancer treated with either cyclophosphamide and doxorubicin or paclitaxel; GWAS of the paclitaxel treatment arm only | European discovery n = 855; European replication n = 154; African–American replication n = 117 | Paclitaxel- induced sensory peripheral neuropathy | rs10771973 in FGD4 (P = 2.6 × 10−6) | rs10771973 in FGD4 (P = 0.013 European replication; P = 6.7 × 10−3 African–American replication) | 22 |
ALL, acute lymphoid leukaemia; BIM, also known as BCL2L11; CML, chronic myeloid leukaemia; FGD4, FYVE, RhoGEF and PH domain containing 4; GWAS, genome-wide association study; IL17F, interleukin 17F; NSCLC, non-small-cell lung cancer; SLCO1B1, solute carrier organic anion transporter family, member 1B1; TCL1A, T cell leukaemia/lymphoma 1A; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.