Background Minimal residual disease (MRD) after induction therapy is one of the strongest prognostic factors in childhood acute lymphoblastic leukemia (ALL), and MRD-directed treatment intensification improves survival. Little is known about the effects of inherited genetic variants on inter-patient variability in MRD. Methods A genome-wide association study (GWAS) was performed on 2,597 children on the Children’s Oncology Group (COG) AALL0232 trial for high-risk B-ALL. Association between genotype and end-of-induction MRD levels was evaluated for 863,370 single nucleotide polymorphisms (SNPs), adjusting for genetic ancestry and treatment strata. Top variants were further evaluated in a validation cohort of 491 patients from the COG P9905/6 ALL trials. The independent prognostic value of SNPs was determined in multivariable analyses. All statistical tests were two-sided. Results In the discovery GWAS, we identified a genome-wide significant association at the GATA3 locus (rs3824662, odds ratio [OR] = 1.58, 95% confidence interval [CI] = 1.35 to 1.84, P = 1.15 × 10-8 as a dichotomous variable). This association was replicated in the validation cohort (P = .003, MRD as a dichotomous variable). The rs3824662 risk allele independently predicted ALL relapse after adjusting for age, white blood cell count and leukemia DNA index (P = .04 and .007 in the discovery and validation cohort, respectively) and remained prognostic when the analyses were restricted to MRD-negative patients (P = .04 and .03 for the discovery and validation cohorts, respectively). Conclusion Inherited GATA3 variant rs3824662 strongly influences ALL response to remission induction therapy and is associated with relapse. This work highlights the potential utility of germline variants in upfront risk stratification in ALL.

Paragangliomas are rare neuroendocrine neoplasms in the vagina, and their molecular pathogenesis has not been documented. We report a case of vaginal paraganglioma in a 15-yr-old adolescent girl who presented with irregular heavy menses and anemic symptoms. Examination under anesthesia revealed a polypoid mass of 3 cm size in the left anterior vaginal wall, which was resected piecemeal. Histology showed a circumscribed nodular tumor with typical nested morphology of paraganglioma and no significant nuclear atypia. Immunohistochemically the tumor cells were diffusely positive for synaptophysin and chromogranin while being negative for cytokeratin, accompanied by S100-positive sustentacular cells. SDHB immunohistochemistry demonstrated the absence of cytoplasmic staining in the tumor cells with preserved staining in sustentacular cells, raising the possibility of a germline mutation in the genes encoding subunits of succinate dehydrogenase. Sanger sequencing for all the exons and exon-flanking intronic regions of the SDHB gene revealed no mutation, but further investigation with multiplex ligation-dependent probe amplification identified a heterozygous deletion of exon 1 of the SDHB gene in the patient and her mother, confirming the diagnosis of SDHB-related hereditary paraganglioma-pheochromocytoma syndrome. The patient had no evidence of disease upon imaging surveillance and follow-up for 56 mo. A review of the published cases of vaginal paraganglioma seems to suggest a relatively young age of presentation, commonly encountered as incidental findings in asymptomatic patients or presenting with abnormal vaginal bleeding. The association between vaginal paraganglioma and germline SDHB mutation has not been reported. We believe this case illustrates the clinical significance of SDHB immunohistochemistry and genetic testing for this rare vaginal neoplasm.

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