Table 2.

Role of Genetic Susceptibility in the Development of therapy-related solid subsequent malignant neoplasms

Study	GWAS vs. Candidate gene	Study design	Replication study	Results
Any solid
Best et al****, 201170	SMN GWAS	Case-control Cases (discovery: n=100; replication: n=62): childhood and adult-onset primary cancers Cancer controls (discovery: n=89; replication: n=71): childhood and adult-onset cancer survivors (matched on primary diagnosis)	Yes	Two variants at chromosome 6q21 (rs4946728 [OR=11.4, 95%CI, 3.2–40.3]; rs1040411 [OR=6.6, 95%CI, 3.2–13.5]) were associated with SMNs in childhood HL survivors. The variants comprise a risk locus associated with decreased basal expression of PRDM1 and impaired induction of PRDM1 protein after radiation exposure.
Mertens et al*, 200493	Candidate gene GSTM1, GSTT1, XRCC1	Cohort study Cohort (n=650): Childhood HL survivors of which 178 patients were diagnosed with SMNs	No	Individuals lacking GSTM1 were at increased risk of any SMN (OR=1.5, 95%CI, 1.0–2.3).
Radiation-related breast cancer
Bernstein et al***, 201023	Candidate gene Full mutation screen of ATM gene	Case control Cases (n=708): breast cancer patients with contralateral breast cancer (adult-onset) Controls (n=1397): U/L breast cancer (adult-onset)	No	Among women who carried a rare, deleterious ATM missense variant, radiation exposure was associated with a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01–0.99 Gy: RR=2.8, 95%CI, 1.2–6.5; ≥1 Gy: RR=3.3, 95%CI, 1.4–8.0) or compared with unexposed women who carried the same deleterious missense variant (0.010.99 Gy: RR=5.3, 95%CI: 1.6–17.3; ≥1.0 Gy: RR=5.8, 95% CI: 1.8–19.0, Ptrend=0.04)
Brooks et al***, 201294	Candidate gene CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1	Case-control Cases (n=649): breast cancer patients with contralateral breast cancer (adult-onset) Controls (n=1284): U/L breast cancer (adult-onset)	No	Carriers of a RAD50 haplotype exposed to ≥1 gray had an increased risk of contralateral breast cancer compared with unexposed carriers (RR=4.3, 95% CI, 1.9–9.6) with an excess relative risk per Gray=2.1 (95% CI, 0.6–5.3)
Radiation-associated meningioma
Hosking et al***, 201174	Family-based association test (FBAT)	Family-based association study 15 families segregating radiation-associated meningioma using high-density SNP arrays (adults)	No	The strongest haplotype associations were attained at 18q21.1 (p=7.5 × 10−5), 18q21.31 (p=2.8 × 10−5) and 10q21.3 (p=1.6 × 10−4). The 18q21.1 and 10q21.3 associations provide support for variation in PIAS2, KATNAL2, TCEB3C, TCEB3CL, CTNNA3 genes as risk factors for radiation- associated meningioma.
Head and Neck Cancer
Gal et al*, 200585	Candidate gene XRCC1 Arg399Gln, XRCC3 Thr241Met, XPD Lys751Gln, MGMT Leu84Phe, Val143Ile	Cohort study Cohort (n=246): 18–65 yo with oral cancer; 88 developed a head and neck SMN	No	A significant increased risk of SMNs (all sites combined; upper airway digestive tract sites; head and neck squamous cell carcinomas) was observed among XRCC3 241 Met allele homozygotes (HR=2.65–3.44, p<0.02).
Jin et al***, 201386	Candidate gene P53, p73, p14ARF, MDM2, MDM4	Cohort study Cohort (n=1283): Adults with squamous cell carcinoma of the head and neck diagnosed between 1995 and 2007; of these 120 developed an SMN	No	SMN risk increased with increasing number of risk genotypes (Ptrend<0.0001). Compared with the low risk group (0–3 combined risk genotypes), both the medium-risk (4–5 combined risk genotypes) and high-risk (6–9 combined risk genotypes) groups had significantly increased risk of SMNs (HR: 1.6, 95% CI: 1.0–2.6; HR: 3.0, 95%CI, 1.8–5.0, respectively)
Zhang, et al***. 2012,87	Candidate gene p53 codon 72 and p73 G4C14-to-A4T14	Cohort study Cohort (n=1269)of adults with squamous cell carcinoma of the head and neck; of these 109 developed an SMN	No	Patients with p53 WP + PP and p73 GC/GC genotypes had an increased risk of SMNs compared with the corresponding p53 WW and p73 GC/T + AT/AT genotypes. After combining the 2 polymorphisms, a significantly increased risk of SMN was observed in the high risk group (p53 P carriers and p73 GC/GC) compared with the low risk group (p53 WW and p73 AT carriers).
Radiation-associated papillary carcinoma of thyroid gland
Akulevich*, 200990	Candidate gene ATM, XRCC1, TP53, XRCC3, MTF1	Case-control Cases (n=123): Childhood primary cancers Healthy controls (596): Children	No	In the analyses of ATM/TP53 (rs1801516/rs664677/rs609429/rs1042522) combinations, the GG/TC/CG/GC genotype was associated with radiation-induced papillary thyroid carcinoma (OR=2.1, 95% CI, 1.2–3.8)

^*The study populations included primarily children

^**The study populations included primarily adults, although some children were also included

^***The study populations included primarily adults

^****The study population includes an equal mix of children and adults