Alise K. Blake

Recent studies reveal that a growing proportion of children with hematologic malignancies (HM) harbor germ line pathogenic or likely pathogenic variants (PV) in cancer-predisposing genes (CPG). Identifying these children is critical because the information gained guides leukemia therapy, family testing, and selection of related donors for hematopoietic cell transplantation (HCT). Nevertheless, it remains unclear how often children with HM being considered for HCT undergo genetic evaluation and whether germ line data are used to guide clinical practice. To address this gap, we reviewed the records of 286 children who underwent ≥1 HCT for HM at St. Jude Children's Research Hospital between 1 January 2017 and 31 December 2023. We examined the timeline of genetic evaluation, prevalence of germ line PV, and impact of PV on HCT outcomes. Overall, 227 (79%) children met with a genetic counselor before their first HCT, 192 underwent testing, and 142 had results returned before the HCT. Thirty-six patients (19%) harbored a germ line CPG PV, among whom 12 (6%) had PV aligning with their HM diagnosis. Of 5 patients who received an HCT from a PV-positive relative, 1 patient developed donor-derived leukemia. We observed no significant differences in time to neutrophil engraftment, cumulative incidence of relapse, or overall survival between patients with and without PV, although the cohort was heterogeneous with respect to the underlying PV. Given the high prevalence of PV in children with HM, prompt referral to genetics is warranted to ensure timely counseling and germ line testing to detect a hereditary predisposition and inform donor selection for HCT.

This study sought to understand the differences in how young adults with various cancer predisposition syndromes (CPS) feel toward disclosing their diagnosis to romantic partners. Young adults with a CPS completed a cross-sectional survey. Data analysis of 158 responses was performed via SPSS v 27.0 descriptive statistics. One-way ANOVA analyses, and post-hoc pairwise comparisons examining CPS, gender, and sexual orientation were performed. Individuals with Lynch syndrome favored disclosing later in a relationship compared to those with Li-Fraumeni syndrome (LFS) (p = 0.050). Individuals who identified as bisexual preferred disclosing more information about their CPS than those who identified as heterosexual (p = 0.035). Individuals with various CPS experience a myriad of feelings and attitudes surrounding dating and disclosure. This information can lead to better sensitivity and awareness of this topic by healthcare providers, ultimately improving the level of care given to these individuals.

PURPOSE: To determine whether transitioning from a two-visit consent process led by an expert consenter to a decentralized model of consenting using an educational video and a clinical care provider translated into sustained decisional satisfaction and comparable levels of understanding about genomic sequencing for cancer predisposition. MATERIALS AND METHODS: A total of 150 parents of children with cancer agreed to participate in this study approximately 4 weeks (±2 weeks) after a consent conversation for genomic sequencing using a decentralized model to assess their genetic knowledge and decision satisfaction. Results were compared with a cohort of parents (n = 121) consented with an expert consenter using a two-visit process consisting of an informational session followed by knowledge reinforcement 5 weeks (±3 weeks) after diagnosis. RESULTS: Among parents in the decentralized consent process, 94% recalled providing consent. However, 53% could not recall who conducted the consent conversation. Less than half (44%) recalled reviewing a copy of the consent form, and only 17% viewed the educational video. Overall, parents endorsed consenting to sequencing as the right choice (mean 4.4/5-point Likert) without decisional regret (1.5 of 5). Parents who consented through the decentralized process did not significantly differ in genetic knowledge from the baseline preconsent genetic knowledge assessment for the comparison sample. Only 56% of parents who consented through the decentralized process answered at least 75% of the knowledge questions correctly ( P < .001), compared with 82% of parents who consented through the expert consenter model. CONCLUSION: While the decentralized consenting processes translated into lower knowledge scores, parents maintained high levels of decisional satisfaction. Further research is warranted to maximize knowledge exchange and ensure values-aligned consent in decentralized models.

PURPOSE: Recent studies reveal that 5%-18% of children with cancer harbor pathogenic variants in known cancer-predisposing genes. However, DNA damage repair (DDR) genes, which are frequently somatically altered in pediatric tumors, have not been systematically examined as a source of novel cancer-predisposing signals. METHODS: To address this gap, we interrogated 189 DDR genes for presence of germline predisposing variants (PV) among 5,993 childhood cancer cases and 14,477 adult noncancer controls (discovery cohort). PV were determined using a tiered approach incorporating ClinVar annotations, InterVar classification, and in silico tools (REVEL, CADD, and MetaSVM). Using logistic and firth regression, we identified genes with PV statistically enriched in the germline of children with tumors and replicated findings among 1,497 additional childhood cancer cases across three independent cohorts. RESULTS: Analysis across all cases with cancer revealed enrichment of TP53 PV. Cancer-specific analyses confirmed known associations including germline TP53 PV in adrenocortical carcinoma, high-grade glioma (HGG), and medulloblastoma (MB), PMS2 in HGG and non-Hodgkin lymphoma (NHL), MLH1 in HGG, BRCA2 in NHL, and BARD1 in neuroblastoma. In addition, four novel associations were uncovered, including BRCA1 in ependymoma, SPIDR in HGG, SMC5 in MB, and SMARCAL1 in osteosarcoma (OS). Importantly, the SMARCAL1 :OS association was significant in the discovery (6/230, 2.6%, false discovery rate [FDR] _logistic = 0.0189) as well as all three replication cohorts (Childhood Cancer Survivor Study: 8/275, 2.9%; P _Fisher < .0001; Cancer Predisposition Syndrome-German Childhood Cancer Registry: 4/135, 3%, P _Fisher = .002; Individualized Therapy for Relapsed Malignancies in Childhood: 4/217, 1.8%, P _Fisher = .012). The remaining wild-type SMARCAL1 allele was deleted in three of four OS tumors with available data. CONCLUSION: Our study confirms the relevance DDR genetic variation in pediatric cancer risk and establishes SMARCAL1 as a novel OS predisposing gene, providing insights into tumor biology and creating opportunities to optimize care for patients with this challenging tumor.

Supplementary Figure 3. HRD Sum scores from ScarHRD analysis for biallelic, monoallelic, or no loss of HR genes in aoCPG and control samples.

Supplementary Figure 1. Signature exposures in 21 samples with aoCPG variants

Supplementary Figure 2. Molecular features of tumors harboring pathogenic aoCPG variants showing the full range of additional somatic second hits.

Supplemental Table 3. Total cohort of 78 Patients with thyroid carcinoma, including those who did and did not undergo genetic testing.