TABLE 7.

Genetic susceptibility to subsequent malignant neoplasms

Gene / Variant	Methods	Results	Comment / Conclusion
PRDM142 PRDM1 encodes PR domain zinc finger protein 1 also known as BLIMP-1. Increased Blimp-1 expression in immune system cells leads to proliferation and differentiation of antibody secreting plasma cells. Blimp-1 is also considered a ‘master regulator’ of hematopoietic stem cells.	• Discovery set was 100 CCSs individuals treated for HL who subsequently developed SMNs and 89 individuals treated for HL who did not develop SMNs. European descent with diagnosis of HL at 10–20 years of age • Treated similarly with 25–44 Gy RT chemotherapy with an alkylating agent • Radiation exposure was to the site at which the subsequent SMN developed • Distribution and frequency of sites exposed to RT similar between cases and controls • Controls from all HL cases without SMN followed for 27 years ≥ treatment for HL	• Three SNPs achieved genome-wide significance: rs4946728, rs1040411 and rs8083533 • rs4946728 (P=1.09 × 10−8, ORallelic = 4.22; 95%CI = 2.53–7.05).and rs1040411 mapped to chromosome 6q21, between ATG5 and PRDM1. • rs8083533 mapped to 18q11.2, intronic to TAF4B (encoding transcription initiation factor TFIID subunit 4B) (P=4.98 × 10−8, ORallelic 3.78, 95% CI 2.31–6.18) • Gender, age at diagnosis, year of HL diagnosis, gonadal RT (in females) and alkylating chemotherapy exposure, had no effect on the observed associations	• Survivors of pediatric HL are at risk for RT-induced SMNs • Two variants at chromosome 6q21 associated with SMNs in survivors of HL treated with RT as children but not as adults. The variants comprise a risk locus associated with decreased basal expression of PRDM1 and impaired induction of the PRDM1 after RT • Data suggest gene-exposure interaction that may implicate PRDM1 in the etiology of RT-induced SMNs.
FGFR243 FGFR2 also known as CD332 (cluster of differentiation 332) is a receptor for fibroblast growth factor. Member of fibroblast growth factor receptor family. Extracellular portion interacts with fibroblast growth factors, setting in motion cascade of downstream signals, ultimately influencing mitogenesis and differentiation. FGFR2 is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor.	• 2 case-control series: • Discovery: 449 women with HL treated with supradiaphragmatic RT in UK at age <36 years: 140 had BC after HL treatment (the “cases”) and 309 had had no solid cancer after HL (the “controls”) • Replication: 244 female Dutch HL patients treated with supradiaphragmatic RT at age <41 years: 92 cases and 152 controls.	• Genotype frequencies of rs1219648 significantly different between cases vs. controls. • Overrepresentation of the minor, G allele, in HL patients with BC (OR 1.73; P=000273). Association dose-dependent; highest risks if homozygous for G allele • OR > for BC in relation to FGFR2 genotype in the general population (1.26 per allele) • Effect greater if <20 years when first treated (OR 1.70, 95%CI 1.16–2.50) than ≥20 years (OR 1.48, 95%CI 1.09–2.00), and if had not received an alkylating agent or ≥5-Gy pelvic radiotherapy	• Women treated at young ages with supradiaphragmatic RT for HL have a highly increased risk of BC. • rs1219648, which annotates the FGFR2 gene associated with risk in discovery and replication (combined per-allele OR 1.59, 95%CI 1.26–2.02; P=0.0001) • Evidence genetic variation in FGFR2 influences RT-induced BC risk.
PROX1; TAGLN44 • PROX1: Transcription factor involved in cell fate determination, gene transcriptional regulation and progenitor cell regulation in a number of organs. Plays critical role in embryonic development and functions as a key regulatory protein in neurogenesis and the development of other organs. • TAGLN: Encodes transgelin, a transformation and shapechange sensitive actin crosslinking/gelling protein found in fibroblasts and smooth muscle. Down-regulation of expression may be early and sensitive marker of transformation. Functional role unclear.	• Genome-wide association study of BC in female CCS, pooling two cohorts with detailed treatment data and systematic, long-term follow-up • 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up • 16 958 466 high-quality variants for analysis	• CCS who received exposure to breast of ≥10 gray, a locus on 1q41 was associated with subsequent BC risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls] = 0.46, hazard ratio 1.92, 95%CI 1.49–2.44, P=7.09 × 10−9) • Potentially promising associations for rs74949440, 11q23, TAGLN, RAF controls = 0.02, P=5.84 × 10−8	• Strong evidence germline genetics outside high-risk syndromes could modify effect of RT on BC risk in CCSs
HRT2A45 HTR2A encodes one of the receptors for serotonin, a multifunctional neurotransmitter with roles in many physiologic processes such as sleep, hormone secretion, and appetite	• GWAS of subsequent BCC in European CCS treated with RT • Evaluated genome-wide significant SNPs (P < 5 × 10−8) Discovery cohort (401 and 2,330 control); independent cohort (97 case patients and 1,082 control)	• Discovery cohort did not identify variants reaching genome-wide significance; however, 14 SNPs on HTR2A showed strongest associations (adjusted HRs ~1.50; P<1 × 10−6) • Further studies showed genome-wide significance for 11/14 HTR2A SNPs • Strongest association for rs633737 (HR = 2.25; P=5.99 × 10−9 , P-value based on 100 million permutations [Pperm] < 1 × 10−8) • High among leukemia and HL survivors • Association of HTR2A with BCC attenuated (HRs 1.30–1.36) and/or not statistically significant (P>0.51) among survivors not in low-risk subgroup/periods (<40 yrs of age; treated when ≥10 yrs)	• Results suggest HTR2A-BCC association among CCS treated with RT may be more pronounced in individuals <40 years old and those ≥10 years old when treated • Possibly because key nongenetic factors, (RT exposure, years sun exposure, and aging) are less influential relative to the older age of survivors treated at a younger age (≤10 years old).
60 genes associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance46	• WGS performed on samples from CCS ≥5 years since initial cancer diagnosis. • Looked for germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance	• 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received RT), 1,120 SMNs diagnosed in 439 survivors (14.6%), and 175 P/LP mutations identified in 5.8% (95%CI 5.0–6.7%) • Among survivors who received RT mutations associated with significantly increased rates of; • BC (RR 13.9, 95%CI, 6.0–32.2) • Sarcoma (RR 10.6, 95%CI, 4.3–26.3) • Among survivors who did not received RT mutations associated with significantly increased rates of; • Any SMN (RR 4.7, 95%CI, 2.4–9.3) • BC (RR 7.7, 95%CI, 2.4–24.4) • Nonmelanoma skin cancer (RR 11.0, 95%CI, 2.9–41.4) • ≥2 histologically distinct SMNs (RR 18.6, 95%CI, 3.5–99.3)	• Findings support referral of all CCSs for potential clinical genetic testing, with priority for survivors who did not receive RT and have any SMN and for those with BC or sarcoma in the field of prior RT

Abbreviations: 95%CI, 95% confidence interval; BC, breast cancer; BCC, basal cell carcinoma; CCSs, childhood cancer survivors; GWAS, Genome-wide association study; HL, Hodgkin lymphoma; OR, odds ratio; P/LP, pathogenic/likely pathogenic; RT, radiation therapy; SMN, second malignant neoplasms; SNPs, single-nucleotide polymorphisms; WGS, whole genome sequencing