Identification of a Hypomorphic FANCG Variant in Bernese Mountain Dogs.

Bernese mountain dogs (BMDs), have an overall cancer incidence of 50%, half of which is comprised of an otherwise rare tumor, histiocytic sarcoma (HS). While recent studies have identified driver mutations in the MAPK pathway, identification of key predisposing genes has been elusive. Studies have identified several loci to be associated with predisposition to HS in BMDs, including near the MTAP/CDKN2A region, but no causative coding variant has been identified. Here we report the presence of a coding polymorphism in the gene encoding FANCG, near the MTAP/CDKN2A locus. This variant is in a conserved region of the protein and appears to be specific to BMDs. Canine fibroblasts derived from dogs homozygous for this variant are hypersensitive to cisplatin. We show this canine FANCG variant and a previously defined hypomorphic FANCG allele in humans impart similar defects in DNA repair. However, our data also indicate that this variant is neither necessary nor sufficient for the development of HS. Furthermore, BMDs homozygous for this FANCG allele display none of the characteristic phenotypes associated with Fanconi anemia (FA) such as anemia, short stature, infertility, or an earlier age of onset for HS. This is similar to findings in FA deficient mice, which do not develop overt FA without secondary genetic mutations that exacerbate the FA deficit. In sum, our data suggest that dogs with deficits in the FA pathway are, like mice, innately resistant to the development of FA.

Activating Mutations in PTPN11 and KRAS in Canine Histiocytic Sarcomas.

While the genetic contributions to the predisposition of Bernese mountain dogs (BMDs) to histiocytic sarcoma (HS) remains unclear, some insights into key genetic drivers have been gained. Our group recently reported a mutation in the PTPN11 gene (E76K). We have now identified a second missense mutation in PTPN11 (G503V), and a mutation in KRAS (Q61H) present in HS cell lines. These mutations are associated with malignancies in humans, and known to be gain-of-function mutations that result in activation of the mitogen-activated protein kinase (MAPK) pathway. The goal of the present study was to evaluate the prevalence of these mutations in a large sample of HS cases from BMDs and golden retrievers, and in lymphoma cases, from a cohort of BMDs. Mutations in PTPN11 were present in HS in 41/96 (43%) BMDs, and in 3/13 (23%) golden retrievers. PTPN11 mutations E76K and G503V did not coexist in the same neoplasm. The KRAS mutation was much less frequent, with a prevalence of 3.1% (3/96). We did not identify either PTPN11 nor KRAS mutations in any of the lymphoma samples. These results point out the potential relevance of PTPN11 and KRAS mutations as activators of the oncogenic MAPK pathway for canine HS, particularly in BMDs.

Use of a jugular vein graft in a modified Blalock-Taussig procedure in dogs.

OBJECTIVE: To determine whether autologous jugular veins provide functional grafts with high 30-day patency rates in an experimental model of systemic-to-pulmonary shunting performed with a modified Blalock-Taussig procedure. ANIMALS: 15 healthy Beagles. PROCEDURE: A segment of the left jugular vein was implanted between the left subclavian and pulmonary arteries. Echocardiograms were obtained prior to surgery, at day 4 to 7, and at day 30 after surgery. Selective angiograms were performed immediately after surgery and on day 30. Oximetric shunt calculations were made via terminal angiography prior to euthanasia. Gross and histologic evaluations of the grafts were conducted. RESULTS: Grafts were patent in 12 of 15 dogs 30 days after surgery as assessed via auscultation, color Doppler ultrasonography, angiography, and histologic examination. Echocardiographic analysis revealed compensatory eccentric left ventricular hypertrophy. Mean pulmonary-to-systemic flow ratio was 1.5:1. Histologic evidence of endothelialization of the anastomotic sites and vein graft arterialization was detectable at 30 days. CONCLUSIONS AND CLINICAL RELEVANCE: Autologous jugular vein grafts were effectively used to create a systemic-to-pulmonary shunt by use of a modified Blalock-Taussig procedure. High patency, ready accessibility, low cost, and theoretical adaptative remodeling during patient growth make autologous jugular vein grafts a valuable alternative to synthetic materials.

Evaluation of the effects of nephrotomy on renal function in clinically normal cats.

OBJECTIVE: To evaluate the effects of nephrotomy on renal function in clinically normal cats. ANIMALS: 20 specific-pathogen-free, 9- to 11-month-old female mixed-breed cats. PROCEDURE: Serum chemistry analyses, CBC determinations, urinalyses, microbiologic urine cultures, renal ultrasonography, abdominal radiography, and single-kidney and total glomerular filtration rate (GFR) determinations by use of renal scintigraphy and measurements of plasma disappearance of technetium 99m-diethylenetriaminepentaacetic acid were performed before surgery and at 3, 12, 26, 52, and 78 weeks after surgery in 10 cats that underwent unilateral nephrotomy and in 10 control cats that underwent a sham surgical procedure. RESULTS: Two cats (1 from each group) did not complete the study, and their data were eliminated from analyses. Unilateral nephrotomy resulted in a 10% to 20% reduction in mean single-kidney GFR, compared with that of nephrotomy contralateral control kidneys. However, mean total GFR in nephrotomy-group cats was not significantly different from that of sham-group cats. Over the 78 weeks of study, mean total GFR declined 34% and 40% in nephrotomy- and sham-group cats, respectively. Adverse events associated with nephrotomy included persistent microscopic hematuria, renal pelvis hyperechogenicity with distant shadowing on ultrasonographic evaluation, dilatation of renal pelves, and hydronephrosis. CONCLUSIONS AND CLINICAL RELEVANCE: Nephrotomy in normal functioning feline kidneys results in a modest relative reduction in renal function, compared with contralateral kidney controls, but has minimal effect on total GFR when compared with sham-operated control cats. However, any detrimental effects of nephrotomy may be magnified in cats with diseased kidneys, which may have little or no capacity for repair or compensation.