High hyperdiploidy (HD) is the most common cytogenetic subtype of childhood acute lymphoblastic leukemia (ALL), and a higher incidence of HD has been reported in ALL patients with congenital cancer syndromes. We assessed the frequency of predisposing germline mutations in 57 HD‐ALL patients from the California Childhood Leukemia Study via targeted sequencing of cancer‐relevant genes. Three out of 57 patients (5.3%) harbored confirmed germline mutations that were likely causal, in NBN, ETV6, and FLT3, with an additional six patients (10.5%) harboring putative predisposing mutations that were rare in unselected individuals (<0.01% allele frequency in the Exome Aggregation Consortium, ExAC) and predicted functional (scaled CADD score ≥ 20) in known or potential ALL predisposition genes (SH2B3, CREBBP, PMS2, MLL, ABL1, and MYH9). Three additional patients carried rare and predicted damaging germline mutations in GAB2, a known activator of the ERK/MAPK and PI3K/AKT pathways and binding partner of PTPN11‐encoded SHP2. The frequency of rare and predicted functional germline GAB2 mutations was significantly higher in our patients (2.6%) than in ExAC (0.28%, P = 4.4 × 10−3), an observation that was replicated in ALL patients from the TARGET project (P = .034). We cloned patient GAB2 mutations and expressed mutant proteins in HEK293 cells and found that frameshift mutation P621fs led to reduced SHP2 binding and ERK1/2 phosphorylation but significantly increased AKT phosphorylation, suggesting possible RAS‐independent leukemogenic effects. Our results support a significant contribution of rare, high penetrance germline mutations to HD‐ALL etiology, and pinpoint GAB2 as a putative novel ALL predisposition gene.

Background Racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented, however little is known about the determinants of diagnostic delays in pediatric leukemia in the United States. The primary objective of this study is to identify factors contributing to delays preceding a pediatric leukemia diagnosis. Methods This qualitative study utilized in-depth semi-structured interviews. Parents and/or patients within two years of receiving a new acute leukemia diagnosis were asked to reflect upon their family’s experiences preceding the patient’s diagnosis. Subjects were purposively sampled for maximum variation in race, ethnicity, income, and language. Interviews were analyzed using inductive theory-building and the constant comparative method to understand the process of diagnosis. Chart review was conducted to complement qualitative data. Results Thirty-two interviews were conducted with a diverse population of English and Spanish speaking participants from two tertiary care pediatric cancer centers. Parents reported feeling frustrated when their intuition conflicted with providers’ management decisions. Many felt laboratory testing was not performed soon enough. Additional contributors to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining appointments, and financial disincentives to seek urgent or emergent care. Reports of difficulty obtaining timely appointments and financial concerns were disproportionately raised among low-income Black and Hispanic participants. Comparatively, parents with prior healthcare experiences felt better able to navigate the system and advocate for additional testing at symptom onset. Conclusions While there are disease-related factors contributing to delays in diagnosis, it is important to recognize there are multiple non-disease-related factors that also contribute to delays. Evidence-based approaches to reduce outcome disparities in pediatric cancer likely need to start in the primary care setting where timeliness of diagnosis can be addressed.

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Introduction: The stark racial and ethnic disparities in outcomes for Black and Hispanic children with acute leukemia have been well documented. Socioeconomic status (SES) also has been implicated in contributing to worse outcomes. However, little is known about the role access to care plays in acute leukemia disparities. The primary objective of this study is to characterize patient and parent experiences and to identify factors contributing to delays preceding an acute leukemia diagnosis. Methods: Patients ages 0-32 years who were within 12 months of receiving a new diagnosis of acute leukemia at Children's Hospital of Philadelphia (CHOP) or University of California, San Francisco (UCSF) were purposively sampled for maximum variation. We conducted in-depth semi-structured interviews, in which caregivers (defined as a parent or guardian) and/or patients were asked to reflect upon their family's experience leading up to the patient's diagnosis of acute leukemia. Interviews were coded using AtlasTi and analyzed for emerging themes using inductive theory-building and the constant comparative method to understand the process of leukemia diagnosis. Results: A total of 23 in-depth interviews (with 20 parents and 3 patients) were conducted with a diverse population of participants; 3 self-identified as Black, 5 self-identified as Hispanic, 1 self-identified as mixed race/ethnicity, and 10 reported low income. Parents reported feeling frustrated when their intuition conflicted with the management decisions made by physicians during initial clinical visits (Table 1). Many parents felt that medical providers did not perform laboratory testing soon enough. Additional factors that contributed to delays included misattribution of vague symptoms to more common diagnoses, difficulties in obtaining an appointment with a pediatrician, and financial disincentives to seek urgent or emergent care. In contrast, parents who had experience with the healthcare system prior to the leukemia diagnosis, as either healthcare professionals or through previous medical histories, felt they were in a better position to navigate the system and advocate for blood testing at initial symptom onset. Reports of difficulty seeing a medical professional as well as financial concerns were disproportionately raised among low-income Black or Hispanic study participants. Conclusions: Interviews with patients and their parents yielded a deeper understanding of the key reasons for diagnostic challenges in pediatric acute leukemia. Implicit racial bias may affect clinical decision-making and exacerbate physician-parent tensions. Our data also suggest that socioeconomic disparities could potentially contribute to a prolonged timeline preceding an acute leukemia diagnosis. By identifying factors associated with a prolonged diagnostic interval, and their contribution to disparities in pediatric acute leukemia diagnosis, our findings highlight the need to improve leukemia diagnosis for patients who have prolonged symptoms due to barriers in accessing appropriately responsive care. Disclosures No relevant conflicts of interest to declare.