Clonal hematopoiesis of indeterminate potential in the companion dog

Sebastian, Kimberley; Özer, Hatice Gülçin; Howard, Cory; Chadsey, Laura; Lozanski, Arletta; Doong, Tzyy-Jye; Orwick, Shelley; Lozanski, Gerard; Ma, Wenjuan; Kisseberth, William C.; Byrd, John C.; Harrington, Bonnie K.

doi:10.1038/s41375-022-01520-5

Cited by 4 publications

(1 citation statement)

References 9 publications

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“…Additionally, these studies have shown that the co-occurrence of CHIP-associated CNVs and SNVs was associated with a higher cumulative incidence of leukemia than the exclusive occurrence of either type of genomic alteration. A recent study using blood samples from cancer-diagnosed dogs found that a small percentage (4.3%; 4/93) of subjects had genomic alterations (SNVs) in genes that have been associated with CHIP in human patients; however, no tumor tissue samples were available to confirm that these alterations did not in fact originate from the cancer itself, and no comparisons were made between WBC-derived gDNA and plasma-derived cfDNA [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

Detection of Age-Related Somatic Alterations in Canine Blood Using Next-Generation Sequencing-Based Liquid Biopsy: An Analysis of over 4800 Dogs

Kruglyak¹,

O'Kell²,

Cohen³

et al. 2023

Veterinary Sciences

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Age-related somatic genomic alterations in hematopoietic cell lines have been well characterized in humans; however, this phenomenon has not been well studied in other species. Next-generation sequencing-based liquid biopsy testing for cancer detection was recently developed for dogs and has been used to study the genomic profiles of blood samples from thousands of canine patients since 2021. In this study, 4870 client-owned dogs with and without a diagnosis or suspicion of cancer underwent liquid biopsy testing by this method. Copy number variants detected exclusively in genomic DNA derived from white blood cells (WBC gDNA-specific CNVs) were observed in 126 dogs (2.6%; 95% CI: 2.2–3.1); these copy number variants were absent from matched plasma cell-free DNA, and from tumor tissue in dogs with concurrent cancer. These findings were more common in older dogs and were persistent in WBC gDNA in over 70% of patients, with little to no change in the amplitude of the signal across longitudinal samples. Many of these alterations were observed at recurrent locations in the genome across subjects; the most common finding was a partial loss on CFA25, typically accompanied by a partial gain on the same chromosome. These early findings suggest that age-related somatic alterations may be present at an appreciable frequency in the general canine population. Further research is needed to determine the clinical significance of these findings.

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Section: Discussionmentioning

confidence: 99%

Detection of Age-Related Somatic Alterations in Canine Blood Using Next-Generation Sequencing-Based Liquid Biopsy: An Analysis of over 4800 Dogs

Kruglyak¹,

O'Kell²,

Cohen³

et al. 2023

Veterinary Sciences

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Precision preclinical modeling to advance cancer treatment

Gutmann,

Boehm,

Karlsson

et al. 2024

JNCI: Journal of the National Cancer Institute

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A new era of cancer management is underway in which treatments are being developed for the entire continuum of the disease process. The availability of genetically engineered and naturally occurring preclinical models serve as instructive platforms for evaluating therapeutic mechanisms. However, a major clinical challenge is that the entire malignancy process occurs across multiple scales including genetic mutations, malignant changes in cell behavior, dysregulated tumor microenvironments, and systemic adaptations in the host. A multi-disciplinary group of investigators coalesced at the National Cancer Institute Oncology Models Forum (NCI-OMF) with the overall goal to provide updates on the use of precision preclinical models of cancer. The benefits and limitations of preclinical models were discussed in order to identify strategies for maximizing opportunities in modeling that could inform future cancer prevention and treatment approaches. Our shared perspective is that the continuum of single cell, multi-cell, organoid, and in situ models are remarkable resources for the clinical challenges ahead. We provide a roadmap for parsing already available models and include preliminary recommendations for the application of next generation preclinical modeling in cancer intervention.

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Clonal hematopoiesis, somatic mosaicism, and age-associated disease

Evans

Walsh

2023

Physiological Reviews

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Somatic mosaicism - the occurrence of multiple genetically distinct cell clones within the same tissue - is an evitable consequence of human aging. The hematopoietic system is no exception to this, where studies have revealed the presence of expanded blood cell clones carrying mutations in preleukemic driver genes and/or genetic alterations in chromosomes. This phenomenon is referred to as clonal hematopoiesis and is remarkably prevalent in elderly individuals. Whilst clonal hematopoiesis represents an early step towards a hematological malignancy, most individuals will never develop a blood cancer. Somewhat unexpectedly, epidemiological studies have found that clonal hematopoiesis is associated with an increase in risk of all-cause mortality and age-related disease, particularly of the cardiovascular system. Studies using murine models of clonal hematopoiesis have begun to shed light on this relationship, suggesting that driver mutations in mature blood cells can causally contribute to aging and disease by augmenting inflammatory processes. Here we provide an up-to-date review of clonal hematopoiesis within the context somatic mosaicism and aging and describe recent epidemiological studies which have reported associations with age-related disease. We will also discuss the experimental studies which have provided important mechanistic insight into how driver mutations promote age-related disease and how this knowledge could be leveraged to treat individuals with clonal hematopoiesis.

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Clonal hematopoiesis of indeterminate potential in the companion dog

Cited by 4 publications

References 9 publications

Detection of Age-Related Somatic Alterations in Canine Blood Using Next-Generation Sequencing-Based Liquid Biopsy: An Analysis of over 4800 Dogs

Detection of Age-Related Somatic Alterations in Canine Blood Using Next-Generation Sequencing-Based Liquid Biopsy: An Analysis of over 4800 Dogs

Precision preclinical modeling to advance cancer treatment

Clonal hematopoiesis, somatic mosaicism, and age-associated disease

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