Browsing by Author "Hoffman, Mary"

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    Ancestry and frequency of genetic variants in the general population are confounders in the characterization of germline variants linked to cancer
    (2020-05-06) Bobyn, Anna; Zarrei, Mehdi; Zhu, Yuankun; Hoffman, Mary; Brenner, Darren; Resnick, Adam C; Scherer, Stephen W; Gallo, Marco
    Abstract Background Pediatric high-grade gliomas (pHGGs) are incurable malignant brain cancers. Clear somatic genetic drivers are difficult to identify in the majority of cases. We hypothesized that this may be due to the existence of germline variants that influence tumor etiology and/or progression and are filtered out using traditional pipelines for somatic mutation calling. Methods In this study, we analyzed whole-genome sequencing (WGS) datasets of matched germlines and tumor tissues to identify recurrent germline variants in pHGG patients. Results We identified two structural variants that were highly recurrent in a discovery cohort of 8 pHGG patients. One was a ~ 40 kb deletion immediately upstream of the NEGR1 locus and predicted to remove the promoter region of this gene. This copy number variant (CNV) was present in all patients in our discovery cohort (n = 8) and in 86.3% of patients in our validation cohort (n = 73 cases). We also identified a second recurrent deletion 55.7 kb in size affecting the BTNL3 and BTNL8 loci. This BTNL3–8 deletion was observed in 62.5% patients in our discovery cohort, and in 17.8% of the patients in the validation cohort. Our single-cell RNA sequencing (scRNA-seq) data showed that both deletions result in disruption of transcription of the affected genes. However, analysis of genomic information from multiple non-cancer cohorts showed that both the NEGR1 promoter deletion and the BTNL3–8 deletion were CNVs occurring at high frequencies in the general population. Intriguingly, the upstream NEGR1 CNV deletion was homozygous in ~ 40% of individuals in the non-cancer population. This finding was immediately relevant because the affected genes have important physiological functions, and our analyses showed that NEGR1 expression levels have prognostic value for pHGG patient survival. We also found that these deletions occurred at different frequencies among different ethnic groups. Conclusions Our study highlights the need to integrate cancer genomic analyses and genomic data from large control populations. Failure to do so may lead to spurious association of genes with cancer etiology. Importantly, our results showcase the need for careful evaluation of differences in the frequency of genetic variants among different ethnic groups.
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    Characterizing the Genomic Heterogeneity of Pediatric Glioblastoma
    (2018-09-05) Hoffman, Mary; Gallo, Marco; Chan, Jennifer A. W.; Grewal, Savraj S.; Cobb, Jennifer A.
    Brain tumors are currently the most common cause of cancer-related deaths among children. With a 5-year survival rate of 20%, pediatric glioblastoma (pGBM) is a lethal brain tumor with no effective treatment options. Although pathologically indistinct from its adult counterpart, recent work has shown that pGBMs diverge at both the genetic and transcriptional level from the adult malignancy. Genomic analyses have identified a recurrent mutation in H3F3A, but this lesion is only present in a fraction of patients and has not contributed to the advancement of effective therapies. Using a longitudinal collection of primary and recurrent pGBMs with matched germlines, I have described a molecularly heterogeneous disease with extreme tumoral evolution. Perhaps my most striking finding is the presence of potentially deleterious structural variants in the patient germlines. Together, these findings suggest a novel hereditary component to tumor etiology which has not been previously described in this malignancy.