Biology subjects

Lana, S. E.

Publications and source records attributed to Lana, S. E..

3 recordsLinked to original sources

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↗

bioRxiv2023

Integrated analysis of canine soft tissue sarcomas identifies recurrent mutations in TP53, KMT genes and PDGFB fusions

Canine soft tissue sarcomas (STS) are a heterogenous group of malignant tumors arising from mesenchymal cells of soft tissues. This simplified collective of tumors most commonly arise from subcutaneous tissues, are treated similar clinically, and conventionally exclude other sarcomas with more definitive anatomical, histological, or biological features. Histologically, canine STS sub-types are difficult to discern at the light microscopic level due to their overlapping features. Thus, genomic, and transcriptomic profiling of canine STS may prove valuable in differentiating the diverse sub-types of mesenchymal neoplasms within this group. To this purpose we sought to characterize the transcript expression and genomic mutation profiles of canine STS. To delineate transcriptomic sub-types, hierarchical clustering was used to identify 4 groups with district expression profiles. Using the RNAseq data, we identified three samples carrying driver fusions of platelet derived growth factor B (PDGFB) and collagen genes. Sensitivity to imatinib was evaluated in a canine STS cell line also bearing a PDGFB fusion. Using whole exome sequencing, recurrent driver variants were identified in the cancer genes KMT2D (21% of the samples) and TP53 (21%) along with copy number losses of RB1 and CDKN2A. Gene amplifications and resulting transcript increases were identified in genes on chromosomes 13, 14, and 36. A subset of STS was identified with high T-cell infiltration. This multi-omics approach has defined canine STS sub-types at a molecular level for comparison to their human counterparts, to improve diagnosis, and may provide additional targets for therapy.

cancer biology↗

bioRxiv2021

Multi-omics approach identifies germline regulatory variants associated with hematopoietic malignancies in retriever dog breeds

Histiocytic sarcoma is an aggressive hematopoietic malignancy of mature tissue histiocytes with a poorly understood etiology in humans. A histologically and clinically similar counterpart affects flat-coated retrievers (FCRs) at unusually high frequency, with 20% developing the lethal disease. The similar clinical presentation combined with the closed population structure of dogs, leading to high genetic homogeneity, makes dogs an excellent model for genetic studies of cancer susceptibility. To determine the genetic risk factors underlying histiocytic sarcoma in FCRs, we conducted multiple genome-wide association studies (GWASs), identifying two loci that confer significant risk on canine chromosomes (CFA) 5 (Pwald=4.83x10-9) and 19 (Pwald=2.25x10-7). We subsequently undertook a multi-omics approach that has been largely unexplored in the canine model to interrogate these regions, generating whole genome, transcriptome, and chromatin immunoprecipitation sequencing. These data highlight the PI3K pathway gene PIK3R6 on CFA5, and proximal candidate regulatory variants that are strongly associated with histiocytic sarcoma and predicted to impact transcription factor binding. The CFA5 association colocalizes with susceptibility loci for two hematopoietic malignancies, hemangiosarcoma and B-cell lymphoma, in the closely related golden retriever breed, revealing the risk contribution this single locus makes to multiple hematological cancers. By comparison, the CFA19 locus is unique to the FCR and harbors risk alleles associated with upregulation of TNFAIP6, which itself affects cell migration and metastasis. Together, these loci explain ~35% of disease risk, an exceptionally high value that demonstrates the advantages of domestic dogs for complex trait mapping and genetic studies of cancer susceptibility.

genetics↗