TY - JOUR
T1 - Polygenic Risk and Chemotherapy-Related Subsequent Malignancies in Childhood Cancer Survivors
T2 - A Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study Report
AU - Im, Cindy
AU - Sharafeldin, Noha
AU - Yuan, Yan
AU - Wang, Zhaoming
AU - Sapkota, Yadav
AU - Lu, Zhanni
AU - Spector, Logan G.
AU - Howell, Rebecca M.
AU - Arnold, Michael A.
AU - Hudson, Melissa M.
AU - Ness, Kirsten K.
AU - Robison, Leslie L.
AU - Bhatia, Smita
AU - Armstrong, Gregory T.
AU - Neglia, Joseph P.
AU - Yasui, Yutaka
AU - Turcotte, Lucie M.
N1 - Publisher Copyright:
© American Society of Clinical Oncology.
PY - 2023/9/20
Y1 - 2023/9/20
N2 - PURPOSEChemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases.PATIENTS AND METHODSSMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models.RESULTSA total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P =.048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P <.01), anthracyclines (20% v 8%; HR, 2.86; P <.001), epipodophyllotoxins (23% v 1%; HR, 12.20; P <.001), or platinums (46% v 7%; HR, 8.58; P <.01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P <.01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors.CONCLUSIONA pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.
AB - PURPOSEChemotherapeutic exposures are associated with subsequent malignant neoplasm (SMN) risk. The role of genetic susceptibility in chemotherapy-related SMNs should be defined as use of radiation therapy (RT) decreases.PATIENTS AND METHODSSMNs among long-term childhood cancer survivors of European (EUR; N = 9,895) and African (AFR; N = 718) genetic ancestry from the Childhood Cancer Survivor Study and St Jude Lifetime Cohort Study were evaluated. An externally validated 179-variant polygenic risk score (PRS) associated with pleiotropic adult cancer risk from the UK Biobank Study (N > 400,000) was computed for each survivor. SMN cumulative incidence comparing top and bottom PRS quintiles was estimated, along with hazard ratios (HRs) from proportional hazards models.RESULTSA total of 1,594 survivors developed SMNs, with basal cell carcinomas (n = 822), breast cancers (n = 235), and thyroid cancers (n = 221) being the most frequent. Although SMN risk associations with the PRS were extremely modest in RT-exposed EUR survivors (HR, 1.22; P =.048; n = 4,630), the increase in 30-year SMN cumulative incidence and HRs comparing top and bottom PRS quintiles was statistically significant among nonirradiated EUR survivors (n = 4,322) treated with alkylating agents (17% v 6%; HR, 2.46; P <.01), anthracyclines (20% v 8%; HR, 2.86; P <.001), epipodophyllotoxins (23% v 1%; HR, 12.20; P <.001), or platinums (46% v 7%; HR, 8.58; P <.01). This PRS also significantly modified epipodophyllotoxin-related SMN risk among nonirradiated AFR survivors (n = 414; P <.01). Improvements in prediction attributable to the PRS were greatest for epipodophyllotoxin-exposed (AUC, 0.71 v 0.63) and platinum-exposed (AUC,0.68 v 0.58) survivors.CONCLUSIONA pleiotropic cancer PRS has strong potential for improving SMN clinical risk stratification among nonirradiated survivors treated with specific chemotherapies. A polygenic risk screening approach may be a valuable complement to an early screening strategy on the basis of treatments and rare cancer-susceptibility mutations.
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U2 - 10.1200/JCO.23.00428
DO - 10.1200/JCO.23.00428
M3 - Article
C2 - 37459583
AN - SCOPUS:85171600175
SN - 0732-183X
VL - 41
SP - 4381
EP - 4393
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 27
ER -
