Joshua Schiffman

University of Utah | UOU · Department of Pediatrics

Cancer is pervasive across multicellular species. Are there any patterns that can explain differences in cancer prevalence across species? Using 16,049 necropsy records for 292 species spanning three clades (amphibians, sauropsids and mammals) we found that neoplasia and malignancy prevalence increases with adult weight and decreases with gestation...

Approximately 20 TP53 retrogenes exist in the African and Asian elephant genomes (Loxodonta Africana, Elephas Maximus) in addition to a conserved TP53 gene that encodes a full-length protein. Elephant TP53-RETROGENE 9 (TP53-R9) encodes a p53 protein (p53-R9) that is truncated in the middle of the canonical DNA binding domain. This C-terminally trun...

Cancer genetics has to date focused on epithelial malignancies, identifying multiple histotype-specific pathways underlying cancer susceptibility. Sarcomas are rare malignancies predominantly derived from embryonic mesoderm. To identify pathways specific to mesenchymal cancers, we performed whole-genome germline sequencing on 1644 sporadic cases an...

Introduction Neutrophil extracellular traps (NETs) clear pathogens but may contribute Q8 pathogenically to host inflammatory tissue damage during sepsis. Innovative therapeutic agents targeting NET formation and their potentially harmful collateral effects remain understudied. Methods We investigated a novel therapeutic agent, neonatal NET-Inhibit...

Li-Fraumeni syndrome (LFS) is a hereditary cancer predisposition syndrome associated with germline TP53 pathogenic variants. Here, we perform whole-genome sequence (WGS) analysis of tumors from 22 patients with TP53 germline pathogenic variants. We observe somatic mutations affecting Wnt, PI3K/AKT signaling, epigenetic modifiers and homologous reco...

Based on current studies, the incidence of Ewing sarcoma (ES) varies significantly by race and ethnicity, with the disease being most common in patients of European ancestry. However, race/ethnicity has generally been self-reported rather than formally evaluated at a population level using DNA evidence. Additionally, mitochondrial dysfunction is a...

Germline pathogenic variants in cancer susceptibility genes are identified in up to 18% of all children with cancer. Because pediatric cancer predisposition syndromes (CPS) themselves are rare and underrecognized, there are limited data to guide the diagnosis and management of affected children and at-risk relatives. Furthermore, the care of affect...

Soft tissue sarcoma (STS) most often occurs sporadically, but can also arise in the setting of a germline cancer predisposition syndrome (CPS). There is significant diversity amongst STS diagnoses as these tumors exhibit a variety of histologies, occur in all age groups, and can occur in any location in the body. This diversity is also reflected in...

Reproductive tumors can impact conception, pregnancy, and birth in mammals. These impacts are well documented in humans, while data in other mammals are limited. An urgent need exists to understand the reproductive impact of these lesions in endangered species, because some endangered species have a documented high prevalence of reproductive tumors...

Background: Li-Fraumeni syndrome (LFS) is an autosomal dominant cancer predisposition syndrome. Approximately 80% of individuals with LFS harbor a germline TP53 pathogenic variant rendering them susceptible to a wide spectrum of early-onset malignancies. A comprehensive surveillance regimen termed the ‘Toronto Protocol’, has recently been adopted f...

More knowledge is needed regarding germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. Here, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance of these variants. We carried out European-focused a...

Rhabdomyosarcoma (RMS) is a well-described cancer in Li-Fraumeni Syndrome (LFS), resulting from germline TP53 pathogenic variants (PVs). RMS exhibiting anaplasia (anRMS) have been associated with a high rate of germline TP53 PVs. This study provides an updated estimate of the prevalence of TP53 germline PVs from a large cohort of patients (n=239) e...

More knowledge is needed around the role and importance of specific genes in germline predisposition to Ewing sarcoma to inform biological investigation and clinical practice. In this study, we evaluated the enrichment of pathogenic germline variants in Ewing sarcoma relative to other pediatric sarcoma subtypes, as well as patterns of inheritance o...

Introduction: Primary care providers (PCPs) and oncologists lack time and training to appropriately identify patients at increased risk for hereditary cancer using family health history (FHx) and clinical practice guideline (CPG) criteria. We built a tool, "ItRunsInMyFamily" (ItRuns) that automates FHx collection and risk assessment using CPGs. Th...

Background Family health history (FHx) is an effective tool for identifying patients at risk of hereditary cancer. Hereditary cancer clinical practice guidelines (CPG) contain criteria used to evaluate FHx and to make recommendations for genetic consultation. Comparing different CPGs used to evaluate a common set of FHx provides insight into how we...

Background Inherited germline TP53 pathogenic and likely pathogenic variants (gTP53) cause autosomal dominant multicancer predisposition including Li-Fraumeni syndrome (LFS). However, there is no known association of prostate cancer with gTP53. Objective To determine whether gTP53 predisposes to prostate cancer. Design, setting, and participants...

PURPOSE Molecular tumor profiling is becoming a routine part of clinical cancer care, typically involving tumor-only panel testing without matched germline. We hypothesized that integrated germline sequencing could improve clinical interpretation and enhance the identification of germline variants with significant hereditary risks. MATERIALS AND M...

Importance Li-Fraumeni syndrome is a cancer predisposition syndrome that is associated with a high, lifelong risk of a broad spectrum of cancers that is caused by pathogenic TP53 germline variants. A definition that reflects the broad phenotypic spectrum that has evolved since the gene discovery is lacking, and mechanisms leading to phenotypic diff...

Childhood leukemia is the most common pediatric malignancy, diagnosed in nearly a third of pediatric cancer patients. Awareness and identification of the hereditary component of childhood leukemia continues to increase. Childhood leukemia, especially acute lymphoblastic leukemia (ALL), has been attributed to a dysregulated immune system with differ...

Importance Alterations in the IKZF1 gene drive B-cell acute lymphoblastic leukemia (B-ALL) but are not routinely used to stratify patients by risk because of inconsistent associations with outcomes. We describe a novel deletion in 22q11.22 that was consistently associated with very poor outcomes in patients with B-ALL with IKZF1 alterations. Objec...

In studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we exp...

Background Advances in genetics and sequencing technologies are enabling the identification of more individuals with inherited cancer susceptibility who could benefit from tailored screening and prevention recommendations. While cancer family history information is used in primary care settings to identify unaffected patients who could benefit from...

Background CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine multigenera...

10532 Background: CNS tumors are the most common solid tumors and the deadliest cancers in children. Approximately 10% of children with a CNS tumor harbor a hereditary cancer syndrome (HCS), but many will not be tested for a HCS. The Utah Population Database (UPDB) contains comprehensive cancer registry data for Utah families and can determine mult...

Ewing Sarcoma (ES) is the second most common primary bone tumor in children and adolescents. There are few known epidemiological or genetic risk factors for ES. Numerous reports describe incidence rates and trends within the United States, but international comparisons are sparse. We used the Cancer Incidence in Five Continents (CI5) data to estima...

Disease susceptibility and resistance are important factors for the conservation of endangered species, including elephants. We analyzed pathology data from 26 zoos and report that Asian elephants have increased neoplasia and malignancy prevalence compared with African bush elephants. This is consistent with observed higher susceptibility to tuberc...

Cells losing the ability to self-regulate in response to damage are a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because dam...

BACKGROUND Identifying patients at risk of hereditary cancer based on their family health history is a highly nuanced task. Frequently, patients at risk are not referred for genetic counseling because providers lack time and training to collect and assess family health history. Consequently, patients at risk are not receiving the genetic counseling...

Wild elephant populations are declining rapidly due to rampant killing for ivory and body parts, range fragmentation, and human-elephant conflict. Wild and captive elephants are further impacted by viruses, including highly pathogenic elephant endotheliotropic herpesviruses. Moreover, while the rich genetic diversity of the ancient elephant lineage...

PURPOSE Rhabdomyosarcoma (RMS) is the most common pediatric soft-tissue sarcoma and accounts for 3% of all pediatric cancer. In this study, we investigated germline sequence and structural variation in a broad set of genes in two large, independent RMS cohorts. MATERIALS AND METHODS Genome sequencing of the discovery cohort (n = 273) and exome seq...

Bone and soft tissue sarcomas collectively make up 12% of all pediatric malignancies. While there have been significant improvements in treatment for these sarcomas, mortality and morbidity are still high. There is also a substantial heterogeneity in the etiologies and biology of bone and soft tissue sarcomas, making these malignancies difficult to...

Background Several cancer-susceptibility syndromes are reported to underlie pediatric rhabdomyosarcoma (RMS); however, there have been no systematic efforts to characterize the heterogeneous genetic etiologies of this often-fatal malignancy. Methods We performed exome-sequencing on germline DNA from 615 patients with newly diagnosed RMS consented...

OBJECTIVE: Coronavirus disease 2019 (COVID-19) is associated with derangement in biomarkers of coagulation and endothelial function and has been likened to the coagulopathy of sepsis. However, clinical laboratory metrics suggest key differences in these pathologies. We sought to determine whether plasma coagulation and fibrinolytic potential in pat...

Objective To identify needs in a clinical decision support tool development by exploring how primary care providers currently collect and use family health history (FHH). Design Survey questionnaires and semi-structured interviews were administered to a mix of primary and specialty care clinicians within the University of Utah Health system (40 su...

PURPOSE The ubiquitous adoption of electronic health records (EHRs) with family health history (FHH) data provides opportunities for tailoring cancer screening strategies to individuals. We aimed to enable a standards-based clinical decision support (CDS) platform for identifying and managing patients who meet guidelines for genetic evaluation of h...

Purpose: We developed a Web-based chatbot (ItRunsInMyFamily.com) to help individuals collect their family health history (FHx) and determine their risk for hereditary cancer. The purpose of the current study was to assess the characteristics of users and identify opportunities to improve the FHx collection tool. Methods: During Family Health His...

Cells losing the ability to self-regulate in response to damage is a hallmark of cancer. When a cell encounters damage, regulatory pathways estimate the severity of damage and promote repair, cell cycle arrest, or apoptosis. This decision-making process would be remarkable if it were based on the total amount of damage in the cell, but because dama...

Many animals have evolved toxins to defend themselves from predators and hunt prey. These toxins have been honed over millions of years by the unique selective pressures on each organism leading to a vast array of potent bioactive compounds, many of which have therapeutic potential. Animal extracts have been used for medicinal purposes for thousand...

Introduction: Tumor profiling is becoming a more routine part of clinical care. Many academic centers and commercial entities offer tumor sequencing of cancer-related genes without matched germline profiling. We hypothesize that tumor-only sequencing may limit full clinical interpretation and have decreased sensitivity to identify significant germl...

As precision medicine becomes a mainstay in health care, the use of health information technology (IT) platforms will play an important role in the delivery of services across the cancer care continuum. Currently, there is both limited understanding about perceptions of health IT tools and barriers to their use among cancer genetic counselors. We a...

COVID-19 affects millions of patients worldwide with clinical presentation ranging from isolated thrombosis to acute respiratory distress syndrome (ARDS) requiring ventilator support. Neutrophil extracellular traps (NETs) originate from decondensed chromatin released to immobilize pathogens and can trigger immunothrombosis. We studied the connectio...

Early‐onset breast cancer is the most common malignancy in women with Li‐Fraumeni syndrome, caused by germline TP53 pathogenic variants. It has repeatedly been suggested that breast tumors from TP53 carriers are more likely to be HER2+ than those of non‐carriers, but this information has not been incorporated into variant interpretation models for...

Disease susceptibility and defense are important factors in conservation, particularly for elephants. We report that in addition to endotheliotropic herpesvirus and tuberculosis, Asian elephants are also more susceptible to cancer than African elephants. To determine mechanisms underlying elephant traits including disease resistance, we analyzed ge...

Background Health information technology (IT) is becoming increasingly utilized by cancer genetic counselors (CGCs). We sought to understand the current engagement, satisfaction, and opportunities to adopt new health IT tools among CGCs. Methods We conducted a mixed‐mode survey among 128 board‐certified CGCs using both closed‐ and open‐ended quest...

Cancer is a common diagnosis in many mammalian species, yet they vary in their vulnerability to cancer. The factors driving this variation are unknown, but life history theory offers potential explanations to why cancer defense mechanisms are not equal across species. Here we report the prevalence of neoplasia and malignancy in 37 mammalian species...

Background: There are few reports of the association of other cancers with Ewing sarcoma in patients and their relatives. We use a resource combining statewide genealogy and cancer reporting to provide unbiased risks. Methods: Using a combined genealogy of 2.3 million Utah individuals and the Utah Cancer Registry (UCR), relative risks (RRs) for...

Background, Rationale and Experimental Approach Oncogenic fusions are generated via chromosomal rearrangements resulting in an exchange of coding or regulatory DNA sequences. These mutations play an important role in disease onset and subsequent cancer progression, however the exact timing and mechanisms by which they arise are unknown. Through the...

Li-Fraumeni syndrome (LFS) is a familial cancer predisposition syndrome (CPS) caused by germline mutations in , associated with a high frequency of sarcomas, breast cancers, adrenocortical carcinomas and CNS tumours. Recently, our group and others have identified distinct mutational signatures, defined by the spectrum and context of somatic mutatio...

Li-Fraumeni syndrome (LFS) is a familial cancer predisposition syndrome (CPS) caused by germline mutations in , associated with a high frequency of sarcomas, breast cancers, adrenocortical carcinomas and CNS tumours. Recently, our group and others have identified distinct mutational signatures, defined by the spectrum and context of somatic mutatio...

Background, Rationale and Experimental Approach Oncogenic fusions are generated via chromosomal rearrangements resulting in an exchange of coding or regulatory DNA sequences. These mutations play an important role in disease onset and subsequent cancer progression, however the exact timing and mechanisms by which they arise are unknown. Through the...

Introduction Advances in treatments for Hodgkin Lymphoma (HL) have significantly increased survival of childhood and adult patients; however, the leading cause of death in HL survivors is due to secondary malignancy following HL treatment [1,2]. Among women treated for HL, breast cancer (BC) is the most common secondary malignancy [3]. We explored...

Importance Birth defects affect approximately 1 in 33 children. Some birth defects are known to be strongly associated with childhood cancer (eg, trisomy 21 and acute leukemia). However, comprehensive evaluations of childhood cancer risk in those with birth defects have been limited in previous studies by insufficient sample sizes. Objectives To i...

e13137 Background: Identifying individuals with inherited cancer susceptibility is critical for optimal cancer prevention and screening. Family history is a significant predictor of inherited risk. Algorithms to extract and analyze family histories in electronic health records (EHRs) provide an opportunity for enhanced identification. Methods: Algo...

1517 Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Spor...

Background. Family health history (FHH) can be used to identify individuals at elevated risk for familial cancers. Risk criteria for common cancers rely on age of onset, which is documented inconsistently as structured and unstructured data in electronic health records (EHRs). Objective. To investigate a natural language processing (NLP) approach t...

Introduction Patients with germline TP53 pathogenic variants (Li–Fraumeni syndrome [LFS]) are at extremely high lifetime risk of developing cancer. Recent data suggest that tumor surveillance for patients with LFS may improve survival through early cancer detection. The objective of this study was to assess the cost‐effectiveness of a cancer survei...

BODY: Objective: There is a strong genetic component to sarcomas and they are more common in hereditary cancer syndromes. The most recognised genetic drivers are germline mutations in theTP53 gene (Li Fraumeni syndrome) but other risk genes include NF1/2, Rb, SDH genes and BRCA2. A polygenic contribution to sarcoma risk has also been recognised. We...

Histone deacetylase (HDAC) inhibition has sporadic clinical efficacy in urothelial carcinoma; the genomic basis for clinical response is not known. In two separate phase I clinical trials testing pharmacokinetic aspects of HDAC inhibitors in advanced solid tumors, we identified one patient with advanced urothelial carcinoma who had a complete respo...

Objectives People with Li-Fraumeni syndrome (LFS) have a 90% lifetime risk of cancer due to mutations in the tumor suppressor gene, TP53. LFS patients experience invasive, expensive screening for early cancer detection. An inexpensive, blood-based assay does not currently exist in clinical practice to monitor an LFS patient’s cancer risk. Periphera...

Looping together genes in cancer A subset of human cancers are characterized by aberrant fusion of two specific genes. In some cases, the activity of the resultant fusion protein drives tumor growth. Most fusion genes in cancer appear to arise from simple reciprocal chromosomal translocations. Anderson et al. found that the characteristic fusion ge...

Elephant immunology is an emerging field of study. While we still have much to learn about how the elephant immune system differs from the immune systems of other animals and what advantages or disadvantages these differences may provide, our knowledge of the elephant immune system continues to increase as we work to understand disease mechanisms t...

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are rare tumors, generally high-grade, and comprise ~ 5-10% of soft tissue sarcomas. Over two-thirds of MPNSTs metastasize, and upwards of 40% clinically recur. Etiologic risk factors for MPNSTs are historically understudied. There is evidence to suggest MPNST incidence differs across r...

Mutations in succinate dehydrogenase complex genes predispose to familial paraganglioma-pheochromocytoma syndrome (FPG) and gastrointestinal stromal tumors (GIST). Here we describe cancer patients undergoing agnostic germline testing at Memorial Sloan Kettering Cancer Center and found to harbor germline SDHA mutations. Using targeted sequencing cov...

The tumor suppressor protein p53 compiles information about cellular stressors to make decisions on whether the cell should survive or undergo apoptosis. However, the p53 response depends on the source of damage, displaying a 'digital' oscillatory response after ionizing radiation (IR) damage and a proportional non-oscillatory response following UV...

Background: Racial predilection to pediatric cancer exists; however optic pathway glioma (OPG) risk differences by race/ethnicity are undefined. We estimated differences in OPG incidence across racial/ethnic groups in a multi-state cancer surveillance registry in the United States. Methods: OPG data were obtained from the Surveillance, Epidemiol...

The Inaugural Symposium on Childhood Cancer Health Disparities was held in Houston, Texas, on November 2, 2016. The symposium was attended by 109 scientists and clinicians from diverse disciplinary backgrounds with interests in pediatric cancer disparities and focused on reviewing our current knowledge of disparities in cancer risk and outcomes for...

Family health history (FHx) is one of the most important pieces of information available to help genetic counselors and other clinicians identify risk and prevent disease. Unfortunately, the collection of FHx from patients is often too time consuming to be done during a clinical visit. Fortunately, there are many electronic FHx tools designed to he...