Biology subjects

Post, G.

Publications and source records attributed to Post, G..

4 recordsLinked to original sources

bioRxiv2022

Identification of genomic alterations with clinical impact in canine splenic hemangiosarcoma

BackgroundCanine hemangiosarcoma (HSA) is an aggressive cancer of endothelial cells associated with short survival times. Understanding the genomic landscape of HSA is critical to developing more effective therapeutic strategies. ObjectivesTo determine the relationships between genomic and clinical features including treatment and outcome in canine splenic HSA. Animals109 dogs with primary splenic HSA treated by splenectomy that had tumor sequencing via the FidoCure(R) Precision Medicine Platform targeted sequencing panel. MethodsPatient signalment, weight, metastasis at diagnosis, treatment, and survival time were retrospectively evaluated. The incidence of genomic alterations in individual genes and their relationship to patient variables and outcome were assessed. ResultsSomatic mutations in TP53 (n = 45), NRAS (n = 20), and PIK3CA (n = 19) were most common. Survival was associated with metastases at diagnosis, germline variants in SETD2 and NOTCH1, and nominally with breed. Age at diagnosis was associated with NRAS mutations and breed. TP53 and PIK3CA mutations were found in larger dogs, germline SETD2 variants in smaller dogs. Doxorubicin (DOX) treatment did not significantly improve survival time, while targeted therapies had a significant early survival benefit. Conclusions and clinical importanceDOX treatment may provide limited clinical benefit for dogs with splenic HSA, while targeted therapy may provide early survival benefit. Genetic signatures associated with splenic HSA may be useful in guiding targeted therapy to improve outcomes. Germline variants, age, size, and breed may be useful prognostic factors and provide insight into the genomic landscape of the tumor.

genomics↗

bioRxiv2021

Shared hotspot mutations in spontaneously arising cancers position dog as an unparalleled comparative model for precision therapeutics

Naturally occurring canine cancers have remarkable similarities to their human counterparts. In order to determine whether these similarities occur at the molecular level, we investigated hotspot mutations in a variety of spontaneously arising canine cancers and found high concordance in oncogenic drivers between cancers in both species. These findings suggest that canines may present a powerful and complementary model for preclinical investigations for targeted cancer therapeutics. Through analysis of 708 client-owned dogs from 96 breeds (plus mixed breeds) with 23 common tumor types, we discovered mutations in 50 well-established oncogenes and tumor suppressors, and compared them to those reported in human cancers. TP53 is the most commonly mutated gene, detected in 30.81% of canine tumors overall and >40% in hemangiosarcoma and osteosarcoma. Canine tumors share mutational hotspots with human tumors in oncogenes including PIK3CA, KRAS, NRAS, BRAF, KIT and EGFR. Hotspot mutations with significant (P<0.0001) association to tumor type include NRAS G61R and PIK3CA H1047R in hemangiosarcoma, ERBB2 V659E in pulmonary carcinoma, and BRAF V588E in urothelial carcinoma. This work positions canines as excellent spontaneous models of human cancers that can help to investigate a wide spectrum of targeted therapies.

cancer biology↗

bioRxiv2021

Rad52 mediates class-switch DNA recombination to IgD

While the biology of IgD begins to be better understood, the mechanism of expression of this phylogenetically old and highly conserved Ig remains unknown. In B cells, IgD is expressed together with IgM as transmembrane receptor for antigen through alternative splicing of long primary VHDJH-C-s-m-C{delta}-s-m RNAs, which also underpin secreted (s)IgD. IgD is also expressed through class switch DNA recombination (CSR), as initiated by AID-mediated double-strand DNA breaks (DSBs) in S and {sigma}{delta}, and resolution of such DSBs by a still unknown mechanism. This synapses S with {sigma}{delta} region DSB resected ends leading to insertion of extensive S-S junction microhomologies, unlike Ku70/Ku86-dependent NHEJ which resolves DSB blunt ends in CSR to IgG, IgA and IgE with little or no microhomologies. Our previous demonstration of a novel role of Rad52 in a Ku70/Ku86-independent "short-range" microhomology-mediated synapsis of intra-S region DSBs led us to hypothesize that this homologous recombination DNA annealing factor is also involved in short-range microhomology-mediated alternative endjoining (A-EJ) recombination of S with {sigma}{delta}. We found that induction of IgD CSR by selected stimuli downregulated Zfp318 (the suppressor of C-s-m transcription termination), promoted Rad52 phosphorylation and Rad52 recruitment to S and {sigma}{delta}, leading to S-{sigma}{delta} recombination with extensive microhomologies, VHDJH-C{delta}s transcription and sustained IgD secretion. Rad52 ablation in mouse Rad52-/- B cells aborted IgD CSR in vitro and in vivo and dampened the specific IgD antibody response to OVA. Further, Rad52 knockdown in human B cells virtually abrogated IgD CSR. Finally, Rad52 phosphorylation was associated with high levels of IgD CSR and anti-nuclear IgD autoantibodies in lupus-prone mice and lupus patients. Thus, Rad52 effects CSR to IgD through microhomology-mediated A-EJ and in concert with Zfp318 modulation. This is a previously unrecognized, critical and dedicated role of Rad52 in mammalian DNA repair that provides a mechanistic underpinning to CSR A-EJ.

immunology↗

bioRxiv2017

Somatic inactivating PTPRJ mutations and dysregulated pathways identified in canine melanoma by integrated comparative genomic analysis

Canine malignant melanoma, a significant cause of mortality in domestic dogs, is a powerful comparative model for human melanoma, but little is known about its genetic etiology. We mapped the genomic landscape of canine melanoma through multi-platform analysis of 37 tumors (31 mucosal, 3 acral, 2 cutaneous, and 1 uveal) and 17 matching constitutional samples including long- and short-insert whole genome sequencing, RNA sequencing, array comparative genomic hybridization, single nucleotide polymorphism array, and targeted Sanger sequencing analyses. We identified novel predominantly truncating mutations in the putative tumor suppressor gene PTPRJ in 19% of cases. No BRAF mutations were detected, but activating RAS mutations (24% of cases) occurred in conserved hotspots in all cutaneous and acral and 13% of mucosal subtypes. MDM2 amplifications (24%) and TP53 mutations (19%) were mutually exclusive. Additional low-frequency recurrent alterations were observed amidst low point mutation rates, an absence of ultraviolet light mutational signatures, and an abundance of copy number and structural alterations. Mutations that modulate cell proliferation and cell cycle control were common and highlight therapeutic axes such as MEK and MDM2 inhibition. This mutational landscape resembles that seen in BRAF wild-type and sun-shielded human melanoma subtypes. Overall, these data inform biological comparisons between canine and human melanoma while suggesting actionable targets in both species.\n\nAUTHOR SUMMARYMelanoma, an aggressive cancer arising from transformed melanocytes, commonly occurs in pet dogs. Unlike human melanoma, which most often occurs in sun-exposed cutaneous skin, canine melanoma typically arises in sun-shielded oral mucosa. Clinical features of canine melanoma resemble those of human melanoma, particularly the less common sun-shielded human subtypes. However, whereas the genomic basis of diverse human melanoma subtypes is well understood, canine melanoma genomics remain poorly defined. Similarly, although diverse new treatments for human melanoma based on a biologic disease understanding have recently shown dramatic improvements in outcomes for these patients, treatments for canine melanoma are limited and outcomes remain universally poor. Detailing the genomic basis of canine melanoma thus provides untapped potential for improving the lives of pet dogs while also helping to establish canine melanoma as a comparative model system for informing human melanoma biology and treatment. In order to better define the genomic landscape of canine melanoma, we performed multi-platform characterization of 37 tumors. Our integrated analysis confirms that these tumors commonly contain mutations in canine orthologs of human cancer genes such as RAS, MDM2, and TP53 as well mutational patterns that share important similarities with human melanoma subtypes. We have also found a new putative cancer gene, PTPRJ, frequently mutated in canine melanoma. These data will guide additional biologic and therapeutic studies in canine melanoma while framing the utility of comparative studies of canine and human cancers more broadly.

cancer biology↗