Cancer germline predisposing variants and late mortality from subsequent malignant neoplasms among long-term childhood cancer survivors: a report from the St Jude Lifetime Cohort and the Childhood Cancer Survivor Study

Background Carriers of cancer predisposing variants are at an increased risk of developing subsequent malignant neoplasms among those who have survived childhood cancer. We aimed to investigate whether cancer predisposing variants contribute to the risk of subsequent malignant neoplasm-related late mortality (5 years or more after diagnosis). Methods In this analysis, data were included from two retrospective cohort studies, St Jude Lifetime Cohort (SJLIFE) and the Childhood Cancer Survivor Study (CCSS), with prospective follow-up of patients who were alive for at least 5 years after diagnosis with childhood cancer (ie, long-term childhood cancer survivors) with corresponding germline whole genome or whole exome sequencing data. Cancer predisposing variants affecting 60 genes associated with well-established autosomal-dominant cancer-predisposition syndromes were characterised. Subsequent malignant neoplasms were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 with modifications. Cause-specific late mortality was based on linkage with the US National Death Index and systematic cohort follow up. Fine-Gray subdistribution hazard models were used to estimate subsequent malignant neoplasm-related late mortality starting from the first biospecimen collection, treating non -subsequent malignant neoplasm-related deaths as a competing risk, adjusting for genetic ancestry, sex, age at diagnosis, and cancer treatment exposures. SJLIFE (NCT00760656) and CCSS (NCT01120353) are registered with ClinicalTrials.gov. Findings 12 469 (6172 male and 6297 female) participants were included, 4402 from the SJLIFE cohort (median follow-up time since collection of the first biospecimen 7 < middle dot > 4 years [IQR 3 < middle dot > 1-9 < middle dot > 4]) and 8067 from the CCSS cohort (median follow-up time since collection of the first biospecimen 12 < middle dot > 6 years [2 < middle dot > 2-16 < middle dot > 6]). 641 (5 < middle dot > 1%) of 12 469 participants carried cancer predisposing variants (294 [6 < middle dot > 7%] in the SJLIFE cohort and 347 [4 < middle dot > 3%] in the CCSS cohort), which were significantly associated with an increased severity of subsequent malignant neoplasms (CTCAE grade >= 4 vs grade < 4: odds ratio 2 < middle dot > 15, 95% CI 1 < middle dot > 18-4 < middle dot > 19, p=0 0085) 263 (2 < middle dot > 1%) subsequent malignant neoplasm-related deaths (44 [1 < middle dot > 0%] in the SJLIFE cohort; and 219 [2 < middle dot > 7%] in the CCSS cohort) and 426 (3 < middle dot > 4%) other-cause deaths (103 [2 < middle dot > 3%] in SJLIFE; and 323 [4 < middle dot > 0%] in CCSS) occurred. Cumulative subsequent malignant neoplasm-related mortality at 10 years after the first biospecimen collection in carriers of cancer predisposing variants was 3 < middle dot > 7% (95% CI 1 < middle dot > 2-8 < middle dot > 5) in SJLIFE and 6 < middle dot > 9% (4 < middle dot > 1-10 < middle dot > 7) in CCSS versus 1 < middle dot > 5% (1 < middle dot > 0-2 < middle dot > 1) in SJLIFE and 2 < middle dot > 1% (1 < middle dot > 7-2 < middle dot > 5) in CCSS in non -carriers. Carrying a cancer predisposing variant was associated with an increased risk of subsequent malignant neoplasm-related mortality (SJLIFE: subdistribution hazard ratio 3 < middle dot > 40 [95% CI 1 < middle dot > 37-8 < middle dot > 43]; p=0 < middle dot > 0082; CCSS: 3 < middle dot > 58 [2 < middle dot > 27-5 < middle dot > 63]; p < 0 < middle dot > 0001). Interpretation Identifying participants at increased risk of subsequent malignant neoplasms via genetic counselling and clinical genetic testing for cancer predisposing variants and implementing early personalised cancer surveillance and prevention strategies might reduce the substantial subsequent malignant neoplasm-related mortality burden.