Thamm, D. | Search bioRxiv

bioRxiv2025

Comparative multi-omics analysis uncovers contrasting molecular profiles of canine and human thyroid carcinomas

Thyroid tumors represent 1-3% of canine cancers, with most tumors classified as follicular carcinomas and less frequently as medullary carcinomas. In comparison, only 10-15% of human thyroid cancers are follicular and 2% are medullary, with prevalent activating mutations in BRAF and NRAS, or RET, respectively. A cohort of canine thyroid carcinomas underwent histopathological (n=60 and paired molecular (n=30, WES and/or RNAseq) exploration. Clustering of tumor transcriptomes produced 2 groups; T1 and T2 clusters comprised of follicular thyroid carcinomas (FTC) and medullary thyroid carcinomas (MTC), respectively. Tumors were histologically typed as follicular, compact, and follicular-compact on blinded review, with most MTC classified as compact with rare follicular-compact appearance, while FTC displayed all 3 patterns. FTC samples had significantly elevated levels of ERBB2 and HER2 protein, and RET signaling was up-regulated in MTC. Recurrent somatic mutations in DNMT1, STAT2, SALL4, HSP90AA1, MEN1, MUC4, THRAP3, CDK4, NOTCH2, and THRAP3 were identified in at least 10% of samples. Individual variants were also identified in KRAS, ARAF, GNAS, and ERBB2. Additionally, we identified fusion genes that included TG, FGFR2, and PAX8. These data suggest that canine MTC, like their human counterparts, may be driven by RET signaling. In contrast, FTC show limited reliance on RAS/RAF signaling, prevalent in human TC, for oncogenic progression. Across the analyzed samples, 60% of tumors had mutations in at least one DNA repair-related pathway, suggesting that the accumulation of DNA damage may drive cancer progression in canine thyroid tumors. Elevated HER2 protein staining was associated with shorter progression free survival (PFS). Thyroid tumor size (>4.25 cm) was also associated with shorter overall survival and PFS, consistent with previous reports; however, metastasis at diagnosis was not correlated with outcome. Additional studies are warranted to explore the utility of these biomarkers to improve diagnosis and treatment of thyroid carcinoma in dogs.

cancer biology↗

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↗