Genetic Risk for Subsequent Neoplasms Among Long-Term Survivors of Childhood Cancer

Abstract

Purpose Childhood cancer survivors are at increased risk of subsequent neoplasms (SNs), but the germline genetic contribution is largely unknown. We assessed the contribution of pathogenic/likely pathogenic (P/LP) mutations in cancer predisposition genes to their SN risk. Patients and Methods Whole-genome sequencing (30-fold) was performed on samples from childhood cancer survivors who were ≥ 5 years since initial cancer diagnosis and participants in the St Jude Lifetime Cohort Study, a retrospective hospital-based study with prospective clinical follow-up. Germline mutations in 60 genes known to be associated with autosomal dominant cancer predisposition syndromes with moderate to high penetrance were classified by their pathogenicity according to the American College of Medical Genetics and Genomics guidelines. Relative rates (RRs) and 95% CIs of SN occurrence by mutation status were estimated using multivariable piecewise exponential regression stratified by radiation exposure. Results Participants were 3,006 survivors (53% male; median age, 35.8 years [range, 7.1 to 69.8 years]; 56% received radiotherapy), 1,120 SNs were diagnosed among 439 survivors (14.6%), and 175 P/LP mutations were identified in 5.8% (95% CI, 5.0% to 6.7%) of survivors. Mutations were associated with significantly increased rates of breast cancer (RR, 13.9; 95% CI, 6.0 to 32.2) and sarcoma (RR, 10.6; 95% CI, 4.3 to 26.3) among irradiated survivors and with increased rates of developing any SN (RR, 4.7; 95% CI, 2.4 to 9.3), breast cancer (RR, 7.7; 95% CI, 2.4 to 24.4), nonmelanoma skin cancer (RR, 11.0; 95% CI, 2.9 to 41.4), and two or more histologically distinct SNs (RR, 18.6; 95% CI, 3.5 to 99.3) among nonirradiated survivors. Conclusion The findings support referral of all survivors for genetic counseling for potential clinical genetic testing, which should be prioritized for nonirradiated survivors with any SN and for those with breast cancer or sarcoma in the field of prior irradiation.

Generalizability of “GWAS hits” in clinical populations: Lessons from childhood cancer survivors

“…All other 408 exclusion criteria, adjustment covariates, and case/phenotype definitions were identical to those applied 409 to the SJLIFE analysis. The SJLIFE genotype data used in this analysis was collected as a part of larger effort to 423 sequence whole genomes of SJLIFE participants 40 . Comprehensive details of DNA sample collection, 424 extraction, sequencing, quality control, and variant mapping have been described previously 40,41 .…”

“…The SJLIFE genotype data used in this analysis was collected as a part of larger effort to 423 sequence whole genomes of SJLIFE participants 40 . Comprehensive details of DNA sample collection, 424 extraction, sequencing, quality control, and variant mapping have been described previously 40,41 . Briefly, 425 sequencing for 3,006 samples was completed at the HudsonAlpha Institute for Biotechnology Genomic 426 Raw intensity data was processed with the "minfi" R package 51 , including sample and probe 473 quality controls, background correction, and normalization.…”

Speaking genomics to parents offered germline testing for cancer predisposition: Use of a 2‐visit consent model

“…Cancer July 15, 2019 In pediatric oncology, a significant proportion of children with cancer (9%-12%) [5][6][7] carry a germline mutation in 1 or more cancer predisposition genes prompting recommendations for the consideration of germline genetic testing. However, germline sequencing is not without its potential risks, and many professional guidelines recommend against broadly testing children for heritable genetic conditions that have no actionability in childhood.…”

Long‐term survivors of childhood, adolescent and young adult non‐Hodgkin lymphoma

“…A similar pattern has been observed when considering the contribution of SMNs to the total number of chronic conditions experienced per survivor, where NHL survivors have been reported to experience a lower cumulative burden of SMNs relative to many other survivor groups (Bhakta et al , ). Despite these findings, Wang et al () identified unique patterns and prevalence of pathogenic or likely pathogenic mutations in cancer predisposition genes in NHL survivors, suggesting that further work is necessary to understand the underlying aetiology of SMN risk, as well as potential genetic associations with other late adverse health effects.…”