Mario Mosqueda
Mario Mosqueda
Mario Mosqueda
Helios Scholar
School: South Mountain Community College
Hometown: Phoenix, Arizona
Mentor: Sara Byron, Ph.D.
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Prevalence and Spectrum of Germline Mutations in the Beat Childhood Cancer Cohort

Despite improvements in standard of care and the introduction of novel therapeutics, cancer is still the number one cause of disease-related death among children over one year of age in the United States. Moreover, pediatric cancer survivors suffer from long term side effects caused by intensive chemotherapy, radiotherapy and surgery. Recent large-scale sequencing studies have reported that ~8% of pediatric cancer patients carry a pathogenic germline mutation in cancer-predisposing genes. Germline biomarkers can be used to personalize therapy, decrease cytotoxic side-effects, and improve the overall care of children with cancer. To address the clinical unmet needs in pediatric cancer, TGen, in collaboration with the Beat Childhood Cancer (BeatCC) consortium, is conducting a clinical trial testing molecular-guided therapy for pediatric patients with rare, relapsed and refractory cancers (NCT02162732). The BeatCC cohort consists of 160 patients with 42 different tumor types. Paired tumor/normal exome sequencing and tumor RNA sequencing were performed by the Ashion CLIA lab. Somatic variants were reported at the molecular tumor board and used to inform treatment recommendations. However, the unreported germline data for the 160 patients is available, including patients with rare tumor subtypes that may have an inherited component. Therefore, we assessed the prevalence and spectrum of germline variants across the BeatCC cohort. Thirteen cancer-predisposing genes were analyzed due to their known role in pediatric cancer or inherited cancer syndromes. Pathogenicity of identified germline variants was assessed using ClinVar classifications. Pathogenic or likely pathogenic variants were identified in 6.25% (10/160) of patients and encompassed BRCA2, MUTYH, PMS2 and TP53. Interestingly, five patients with distinct tumor types had the same pathogenic PMS2 variant, PMS2 L729fs (rs587779335). PMS2 L729fs is a frameshift mutation that results in a premature stop codon and inhibits the ability of PMS2 to repair DNA replication errors, which can lead to a high mutational burden. PMS2 L729fs has previously been identified in pediatric tumors and in patients with constitutional mismatch repair deficiency (CMMRD), a devastating predisposition syndrome characterized by the early onset of malignancies. There is growing evidence that patients with high mutation burden tumors and CMMRD may be sensitive to immunotherapies, pointing to the potential clinical relevance of our findings. In conclusion, we identified pathogenic germline variants in a subset of the pediatric cancer patients enrolled on the BeatCC clinical trial. Our findings suggest that assessing germline variants can reveal additional biomarkers to inform the therapeutic options for pediatric cancer patients.