Germline Cancer-Predisposing Variants and Increased Risk of Late Mortality From Subsequent Malignant Neoplasms in Long-Term Childhood Cancer Survivors

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In an analysis from the St. Jude Lifetime Cohort (SJLIFE) and Childhood Cancer Survivor Study (CCSS) reported in The Lancet Oncology, Chen et al found that among long-term survivors of childhood cancers, carriers of germline cancer-predisposing variants were at an increased risk of late mortality from subsequent malignant neoplasms.

Study Details

The retrospective cohort study included patients from SJLIFE and CCSS cohorts who survived for ≥ 5 years after their original cancer diagnosis, with germline whole-genome or whole-exome sequencing data; data were analyzed for presence of cancer-predisposing variants affecting 60 genes. The primary outcome measure was subsequent malignant neoplasm–related late mortality from time of first biospecimens collection.

Key Findings

A total of 12,469 survivors were included in the analysis: 4,402 from the SJLIFE cohort, with a median follow-up since collection of first biospecimen of 7.4 years (interquartile range [IQR] = 3.1–9.4 years); and 8,067 from the CCSS cohort, with a median follow-up since collection of first biospecimen of 12.6 years (IQR = 2.2–16.6 years). Germline cancer-predisposing variants were carried by 641 survivors overall (5.1%), including 294 (6.7%) in the SJLIFE cohort and 347 (4.3%) in the CCSS cohort.

Subsequent malignant neoplasms developed among 8.8% of cancer-predisposing variant carriers vs 6.6% of noncarriers in the SJLIFE cohort and in 16.4% of carriers vs 10.4% of noncarriers in the CCSS cohort. Cancer-predisposing variant carriers had an increased risk of more-severe subsequent malignant neoplasms (odds ratio [OR] for grade ≥ 4 vs < 4 = 2.15, 95% confidence interval [CI] = 1.18–4.19, P = .0085) in the combined cohort. Odds ratios were 2.54 (95% CI = 0.83–10.44, P = .12) in the SJLIFE cohort and 2.01 (95% CI = 0.98–4.53, P = .050) in the CCSS cohort.

Cumulative subsequent malignant neoplasm–related mortality at 10 years after first biospecimen collection was 3.7% (95% CI = 1.2%–8.5%) among cancer-predisposing variant carriers vs 0.5% (95% CI = 1.0%–2.1%) among noncarriers in the SJLIFE cohort and 6.9% (95% CI = 4.1%–10.7%) among carriers vs 2.1% (95% CI = 1.7%–2.5%) among noncarriers in the CCSS cohort. Cancer-predisposing variant carriers had a significantly increased risk of subsequent malignant neoplasm–related mortality vs noncarriers in the combined cohorts (subdistribution HR = 3.64, 95% CI = 23.6–5.32, P < .0001), the SJLIFE cohort (subdistribution HR = 3.40, 95% CI = 1.37–8.43, P = .0082), and the CCSS cohort (subdistribution HR = 3.58, 95% CI = 2.27–5.63, P < .0001).

The investigators concluded, “Identifying participants at increased risk of subsequent malignant neoplasms via genetic counseling and clinical genetic testing for cancer predisposing variants and implementing early personalized cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm–related mortality burden.”

Zhaoming Wang, PhD, of the Department of Epidemiology and Cancer Control, St. Jude Children’s Research Hospital, Memphis, is the corresponding author for The Lancet Oncology article.

Disclosure: The study was funded by the American Lebanese Syrian Associated Charities and U.S. National Institutes of Health. For full disclosures of the study authors, visit

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