Table 1.

Role of genetic susceptibility in the development of treatment-related adverse events

StudyGWAS vs. candidate geneStudy designReplication studySample sizeResults
Anthracycline-related cardiomyopathy
Wojnowski et al (24)Candidate gene (82 genes with conceivable relevance to anthracycline-related cardiomyopathy)Prospective cohort studyNo; instead, follow-up with mice studies1,697 patients (54 with chronic anthracycline-related cardiomyopathy)Anthracycline-related cardiomyopathy was associated with a variant of the NAD(P)H oxidase subunit NCF4 (rs1883112: OR = 2.5; 95% CI, 1.3–5.0). Mice deficient in NAD(P)H oxidase activity were resistant to chronic doxorubicin exposure, unlike the wild-type mice.
Blanco et al (23)Candidate gene (CBR3, NQO1)Nested case–control studyNo; instead, follow-up with functional studies30 cases with CHF; 115 matched cancer survivors with no CHFA trend toward an association between the CBR V244M polymorphism and risk of CHF (OR = 8.16, P = 0.056 for G/G vs. A/A; OR = 5.44, P = 0.09 for GA vs. AA). Recombinant CBR3 V244 (G allele) synthesized 2.6-fold more cardiotoxic doxorubicinol per unit of time than CBR3 M244 (A allele; CBR V244, P = 0.01)
Osteonecrosis
Kawedia et al (52)GWASProspective cohort studyNo364 patients (69 with symptomatic osteonecrosis)Polymorphisms of ACP1 (e.g., rs12714403: OR = 5.6; 95% CI, 2.7–11.3) were associated with symptomatic osteonecrosis; ACP1 regulates lipid levels and osteoblast differentiation.
Relling et al (32)Candidate gene (16 polymorphisms in genes likely to play a role in pharmacogenetics/pharmacokinetics of antileukemic therapy)Prospective cohort studyNo64 (25 patients with osteonecrosis)Vitamin D receptor Fokl start site CC genotype (OR = 4.5, P = 0.045) and thymidylate synthase low activity 2/2 enhancer repeat genotype (OR = 7.4, P = 0.049)
French et al (47)Candidate gene (TYMS, MTHFR, ABCB1, BLGAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, PTHR–12 polymorphisms–chosen on the basis of putative mechanisms underlying osteonecrosis risk)Prospective cohort studyNo361 patients (51 with osteonecrosis)PAI-1 polymorphism (rs6092) was associated with risk of osteonecrosis (OR = 2.89, P = 0.002). PAI-1 polymorphisms and PAI-1 serum levels have been associated with thrombosis.
Obesity
Ross et al (84)Candidate gene (polymorphism in LEPR gene, Gln223Arg)Retrospective cohort studyNo600 patients (278 with BMI ≥ 25 kg/m2)Female patients with BMI > 25 kg/m2 weremore likely Srg homozygous than those with BMI less than 25 kg/m2 (24% vs. 12%, P = 0.007). This difference was not observed in males. Among females treated with >20 Gy cranial irradiation, Arg/Arg individuals had 6 times higher odds of having BMI > 25 kg/m2 (95% CI, 2.1–22) than those with Gln allele (P = 0.04 for interaction). Thus, LEPR polymorphism may influence obesity in female survivors of childhood ALL, particularly those exposed to cranial irradiation.
Ototoxicity
Ross et al (70)Candidate gene (220 drug metabolism genes; 1,949 polymorphisms)Case–controlYesDiscovery set: 33 cases, 20 controls; replication set: 73 cases, 36 controls; controls treated with cisplatinum but with no ototoxicityGenetic variants in TPMT (rs12201199: OR = 17.0; 95% CI, 2.3–125.9) and COMT (rs9332377: OR = 5.5; 95% CI, 1.9–15.9) were associated with cisplatinum-induced hearing loss in children
Oldenburg et al (67)Candidate gene [known functional polymorphisms in GSTT1 and GSTM1 and codon 105 A/G (Ile/Val) in GSTP1]Prospective cohort studyNo173 patients; 89 with hearing impairmentRisk of inferior audiometric result was higher in testicular cancer survivors with 105Ile/105Ile-GSTP1 or 105Val/105Ile-GSTP1 compared with 105Val-GSTP1 (OR = 4.21; 95% CI, 1.99–8.88). GSTM1-positivity increased risk of hearing loss. Two combined genotypes were associated with hearing ability. Presence of pattern 1 (GSTT1-positive, GSTM1-positive, and 105Ile/105Ile GSTP1) was associated with hearing impairment (OR = 2.76; 95% CI, 1.35–5.64). Presence of pattern 2 (GSTT1-positive, GSTM1-positive, and 105Val/105Val-GSTP1) resulted in better hearing ability (OR = 5.35; 95% CI, 2.25–12.76)
Riedemann et al (69)Candidate gene (polymorphisms in megalin gene (rs2075252 and rs4668123)]; megalin is a member of the low-density lipoprotein receptor family, and is highly expressed in the marginal cells of the stria vascularis of the inner ear–resulting in high accumulation of platinum-DNA adductsCase–controlNo25 cases; 25 controls (cancer patients exposed to cisplatin with no hearing loss)An association was found between the A allele of rs2075252 and hearing impairment (OR = 3.45; 95% CI, 1.11–11.2), indicating that SNPs at the megalin gene may impact the individual susceptibility against cisplatin-induced toxicity.
Therapy-related leukemia
Knight et al (174)GWASCase–control (healthy controls)YesDiscovery set: 80 cases, 150 controls; replication set: 70 cases, 95 controlsAmong patients with acquired abnormalities of chromosomes 5 or 7; 3 SNPs [rs1394384 (OR = 0.29; 95% CI, 0.15–0.56), rs1381392 (OR = 2.08; 95% CI, 1.29–3.35), and rs1199098 (OR = 0.46; 95% CI, 0.27–0.79)] were associated with t-MDS/AML; rs1394384 is intronic to ACCN1, a gene encoding an amiloride-sensitive cation channel that is a member of the degenerin/epithelial sodium channel; rs1199098 is in LD with IPMK, which encodes a multikinase that positively regulates the prosurvival AKT kinase and may modulate Wnt/β-catenin signaling; rs1381392 is not near any known genes, miRNAs, or regulatory elements, although it lies in a region recurrently deleted in lung cancer.
Ellis et al (173)Candidate gene (2 common functional p53-pathway variants, the MDM2 SNP309 and the tP53 codon 72)Case–control (healthy controls)YesDiscovery set: 80 cases; replication set: 91 casesNeither polymorphism alone influenced the risk of t-MDS/AML; however, an interactive effect was detected such that MDM2 TT TP53 Arg/Arg double homozygotes, and individuals carrying both a MDM2 G allele and a TP53 Pro allele, were at increased risk of t-MDS/AML (OR = 2.04; 95% CI, 1.20–3.48; Pinteraction = 0.009)
Allan et al (141)Candidate gene approach (polymorphisms in GSTM1, GSTT1, GSTP1)Case–controlNo89 cases; 420 patients with de novo AML; 1,022 healthy controlsIndividuals with at least one GSTP1 codon 105 Val allele were significantly overrepresented in t-AML cases compared with de novo AML cases (OR = 1.81; 95% CI, 1.11–2.94). Also, relative to do novo AML, the GSTP1 codon 105 allele occurred more often among t-AML patients with prior exposure to chemotherapy (OR = 2.66; 95% CI, 1.39–5.09), particularly among those with prior exposure to known GSTP1 substrates (OR = 4.34; 95% CI, 1.43–13.20) and not among t-AML patients with exposure to radiation alone.
Worrillow et al (134)Candidate gene (hMSH2–6 exon 13 polymorphism); evaluation of MSICase–controlNo; verification done by direct sequencing91 cases; 420 patients with de novo AML, 837 healthy controlsThe variant (C) hMSH2 allele was significantly overrepresented in t-AML cases that had previously been treated with O6-guanine alkylating agents, including cyclophosphamide and procarbazine, compared with controls (OR = 4.02; 95% CI, 1.40–11.37); 38% of the patients were MSI-positive; hMSH2 -6 exon 13 (C) allele confers a nondisabling DNA MMR defect and predisposes to development of t-AML via induction of DNA MMR mutations and high grade MSI.
Worrillow et al (137)Candidate gene [polymorphism of MLH1 (position -93, rs1800734)]Case–controlNo133 cases; 420 patients with de novo AML, 242 patients with primary HL, 1,177 healthy controlsCarrier frequency of MLH1 -93 variant was higher in patients who developed t-AML or secondary breast cancer after alkylating agents exposure for HL, compared with patients without alkylating agent exposure. The MLH1-93 variant allele was also overrepresented in t-AML cases when compared with de novo AML cases and was associated with increased risk of t-AML (OR = 5.31; 95% CI, 1.40–20.15) among patients exposed to alkylating agents
Seedhouse et al (166)Candidate gene (polymorphisms in XRCC1, XRCC3, XPD, NQO1)Case–controlNo34 cases; 134 patients with de novo AML; 178 healthy controlsPresence of at least one XRCC1 399Gln allele indicated a protective effect for the allele in controls compared with patients with t-AML (OR = 0.44; 95% CI, 0.20–0.93)
Jawad et al (154)Candidate gene [C/T-3′ untranslated region (UTR) polymorphism in HLX; polymorphism in RAD51 (135G/C-5′ UTR)]Case–controlNo42 cases; 166 patients with de novo AML; 189 healthy controlsPresence of the variant HLX1 allele significantly increased the risk of t-AML (OR = 3.36; 95% CI, 1.65–6.84). Polymorphism in RAD51 (135G/C-5′ UTR) also increased the risk of t-AML. Combined analysis revealed, a synergistic 9.5-fold increase (95% CI, 2.22–40.64) in risk for t-AML
Subsequent solid malignancies
Best et al (175)GWASCase—control (controls: cancer survivors with no SMNs)YesDiscovery set: 100 cases, 89 controls; replication set: 62 cases, 71 controlsTwo variants at chromosome 6q21 [rs4946728 (OR = 11.4; 95% CI, 3.23–40.25), rs1040411 (OR = 6.57; 95% CI, 3.19–13.52)] were associated with SMNs in childhood HL survivors, but not in adult-onset HL survivors. The variants comprise a risk locus associated with decreased basal expression of PRDM1 and impaired induction of PRDM1 protein after radiation exposure. PRDM1 encodes a zinc finger transcriptional repressor involved in cellular processes such as proliferation, differentiation, and apoptosis.
Mertens et al. (136)Candidate gene (polymorphisms in GSTM1, GSTT1, XRCC1)Cohort studyNo650 patients with HL (178 with subsequent malignancy)Individuals lacking GSTM1 were at increased risk of any subsequent malignancy (OR = 1.5; 95% CI, 1.0–2.3). A nonsignificant increased risk for thyroid cancer was observed in individuals lacking either GSTM1 (OR = 2.9; 95% CI, 0.8–10.9) or GSTT1 (OR = 3.7; 95% CI, 0.6–23.5). Individuals with the genotype of the arginine/glutamine polymorphism at codon 399 in the XRCC1 gene (R399)r showed a nonsignificant increased risk of breast cancer (OR = 1.4; 95% CI, 0.7–2.7).