malignant histiocytosis in bernese mountain dogs

malignant histiocytosis in bernese mountain dogshow to edit file in docker container

Hematological investigations at time of diagnosis revealed anemia, which was listed as severe for 41 dogs (66%), and thrombocytopenia in 56% of the cases (22 dogs). AKC-Canine Health Foundation (grant 936b to B.H., E.C. (This figure appears in color in the online version of Journal of Heredity .). The mean age at diagnosis was 6 years and 6 months (range = 211 years). But most of the HSs were localized, and, as expected, the presence of metastasis was associated with shorter survival times ( Fidel et al. Histiocytic disorders in human are classified according to the cell of origin as dendritic cellrelated disorders and macrophage-related disorders ( Schmitz and Favara 1998 ). In 1986, Moore and Rosin first described a series of 13 cases of malignant histiocytosis, reported to originate from the same family ( Moore 1984 ; Moore et al. The histopathological evaluation revealed tumor in poorly demarcated masses composed of a pleomorphic population of large round uni- or multinucleated neoplastic cells ( Figure 2 ). Only 7 dogs received chemotherapy, with lomustine being the most commonly used drug. To study the mode of inheritance, we have used a subset of 160 dogs, and to avoid biases, only full sibships with known HS status were used. The life span after diagnosis has been estimated to be 49 days. By comparison, only 2 cases have shown close relatives that were affected by reactive nonneoplastic histiocytosis. (1993) reported associations of LCH and malignant neoplasms including malignant lymphoma or Hodgkins disease, as we observed in our population. The club was founded in 1907 with 6 registered officially used for reproduction. Dogs are indeed an exceptional model for studying the genetic bases of cancer ( Cadieu and Ostrander 2007 ). Furthermore, the number of affected dogs in siblings with 1 or 2 affected parents is lower than expected for a monogenic transmission mode leading us to rule out a fully autosomal recessive mode of inheritance as proposed by Padgett et al. Among them, 18 cases of malignant mast cell tumor (51%), 6 cases of malignant lymphoma (17%), 6 cases of mammary adenocarcinoma (17%), and 3 cases of malignant melanoma (9%) have been recorded. The oldest dog was born in 1931, the youngest in 2007. This is also in favor of a major role of the genetic background of the BMD breed in the neoplastic transformation of dendritic cells. The absence of sex predisposition, also noticed by Padgett et al. To get insight into these mechanisms, targeted gene expression analyses have been performed, excluding candidate genes such as KIT , FLT3 , and MET ( Zavodovskaya et al. In addition, with the plan of selecting the best population for genetic investigation, we have conducted a prospective study in order to collect an extensive pedigree and to define the epidemiological, clinical, and pathological features of HS in this BMD population. This could be explained by the involvement of several genes with environmental factors possibly acting on the age of onset and/or the severity of the disease. Abnormal pulmonary auscultation has been detected in 31% of the dogs, with polypnea (10 cases, 40%), rattle and abnormal pulmonary sounds (7 cases, 28%), dyspnea (6 cases, 24%), tachypnea (5 cases, 23%), shortness of breath (3 cases, 12%), and discordance (1 case, 4%). 2000 ) particularly cancer ( Cadieu and Ostrander 2007 ). The second study reported responses to lomustine. Identifying causative genes in dogs may help to highlight predisposing genes in human and/or at least common pathways and genes. The intensive selection performed in breeds can lead to a loss of genetic diversity, as shown by Calboli at al. Histopathological and immunohistochemical features of HS. Furthermore, 35 dogs (39%) have first- or second-degree relatives affected with malignant neoplastic diseases other than HS. Among the remaining 206 dogs, 48 individuals were older than 10 years without evidence of HS or other cancers (20 males and 28 females) and were considered to be healthy controls. Whole-genome linkage scans as well as association studies using a case/control analysis, in parallel with expression profiling of neoplastic versus normal histiocytes, are all underway. 2005 ). 2002 ; Gross et al. The questionnaire investigated epidemiological, clinical, and pathological features including identification of the dog (identity sex, age, etc.) The number of affected offspring expected in these 21 families under a recessive model was computed considering 3 different probabilities of being affected for parents of unknown status: pk = 0.20, pk = 0.25, and pk = 0.3. 2009. Book Review: An Intrepid Ecological Geneticists Pursuit of Industrial Melanism, A chromosome-scale genome assembly of the okapi (. The American Genetic Association. 2004 ). Moreover, pedigree analysis and clinical study showed the presence of other cancers in HS-affected dogs or relatives. When parental status was unknown, we considered them as affected with a probability pk and unaffected with a probability 1 pk ( pk is the estimation of the prevalence of the disease in the breed). 2006 ). These results show that the fully recessive model did not explain the segregation of the disease observed in these families. Mean age at diagnosis did not differ significantly between males and females (Fisher's Exact test). In the subset of 21 nuclear families, analyzed in detail for the segregation analysis, 12 mast cell tumors (7.5%), 5 lymphomas (frequency 3.1%), and 5 melanocytic tumors (frequency 3.1%) were found (data not shown). Although HS is clearly overrepresented in the BMD, its mode of inheritance is not well understood, and the genes likely to be involved are unknown. Qualitative differences between populations were tested using the chi-square test with a significance level set at 5% for each analysis. A total of 17.8% of the cases were diagnosed after the age of 8 years and only 3.4 after the age of 10 years, which highlights the importance of long-term follow-up for the clinical status of the controls. We thank the very cooperative French BMD Club association Franaise des Bouviers suisses, the Italian Societ Italiana Bovaro del Bernese, and the Belgian and Swiss club of BMDs; the numerous veterinarians for providing us with clinical data and samples; and the many dog owners and breeders who provided samples and genealogical data of their dogs. ); Italian Societ Italiana Bovaro del Bernese club and Swiss Mountain Dogs International Working Group (Alberto Vittoni Award to B.H. All data were entered into a confidential database. A portion of 650 dogs of the BMD family segregating HS. Flat coated and golden retrievers, for example, are reported to be less frequently affected, and, in these 2 breeds, the sarcoma is generally localized and not disseminated as is observed in the BMD ( Affolter and Moore 2002 ; Fidel et al. Studying dogs with naturally occurring cancers is likely to provide a valuable perspective different from that generated by the study of rodent cancers alone, often obtained after induction ( Paoloni and Khanna 2007 ). Among the 327 dogs sampled in France and Europe, 121 BMDs were affected by HS. The BMD population was originally developed from the Berne region of Switzerland. Indeed, about 4 million new cancer diagnoses are recorded in dogs within the United States every year ( Khanna et al. A small number of samples with limiting amounts of DNA were whole genome amplified using the V1 genomiphi kit (GE Healthcare Bio-Sciences Corp). A pedigree of 327 BMDs (144 males, 183 females) was developed from the 800 French and European dogs ( Figure 3 ). Moreover, as in many dog breeds, the use of popular sires and inbreeding reduces diversity. This strategy increases the likelihood of finding significant association. We have collected 800 BMDs of which 200 are affected by HS. Skin and subcutis involvement was reported in 16 affected dogs (19%), 10 of them presenting multicentric lesions ( Figure 1 ). We found HS as a highly aggressive neoplastic disease of adult dogs (mean age at diagnosis 6.5 years) that affects males and females with an equal frequency. The aim of our research project is to identify the genetic causes of this highly aggressive cancer in dogs with consideration of the underlying comparative genetics. Forty-six offspring were affected, representing 39% of the 118 offspring from the set. A total of 46.5% of the affected dogs were living outdoors and 39.4% indoors, and presence of known or suspected carcinogens in the dog's environment was not identified, except for 2 cases in which toxic products (fertilizers and paint) were indicated. The BMD breed, as many others, was developed at the beginning of the 20th century with very few founders. At death, the majority of dogs demonstrate high levels of neoplastic infiltration in the lungs, spleen, liver and lymph nodes, with frequent associated hematologic abnormalities such as thrombocytopenia and anemia ( Moore and Rosin 1986 ). Comparison of the expected proportion of affected offspring in the 21 nuclear families under a fully recessive model and the observed proportion ( pk is the estimation of the prevalence of the disease in the breed). ( Affolter and Moore 2002 ; Fidel 2006). Dogs were initially exported to other European countries in the 1920s and brought to the United States in 1926 ( http://www.akc.org/breeds/bernese_mountain_dog/history.cfm ), the present population being largely derived from the original set of 6 males. Affected dogs (cases) are defined as less than 7.5 years of age at diagnosis with HS. Dogs older than 10 years that have not been diagnosed with any other cancer were considered as healthy; the other unaffected dogs were considered as unknown status. A large BMD pedigree of 327 dogs, 121 of which are affected, was assembled. The human equivalents of HS could encompass 2 types of aggressive proliferation of dendritic cells: disseminated LCH, which is an accumulation of tissue histiocytes in multiple organs and is generally associated with extensive multiorgan failure, and/or dendritic cellrelated HS, which is a very rare malignancy featuring cells with a dendritic phenotype ( Schmitz and Favara 1998 ). 1986; Affolter and Moore 2000 ; Affolter and Moore 2006). It furthers the University's objective of excellence in research, scholarship, and education by publishing worldwide, This PDF is available to Subscribers Only. In agreement with previous reports, the prognosis of BMDs with HS was very poor in our population as was response to treatment ( Skorupski et al. Genomic DNA was extracted from 5 ml of blood collected into ethylene diamine tetraacetic acid using the nucleon BACC 3 kit (GE Healthcare Bio-Sciences Corp, Piscataway, NJ) and the Nucleospin kit (Macherey Nagel). Histiocytic proliferative disorders are rare in humans, precluding the possibility of an efficient study of the genetic components of these diseases ( Arico and Danesino 2001 ). In France, 80% of HS diagnoses occur in BMDs, yet the BMD is only the 13th most popular breed and represents 1.8% of dogs registered in 2007 in France ( http://www.scc.asso.fr ). Illustration of the popular sire effect in the population of French BMDs: Only 5.4% of sires participate to the next generation (dogs in the rectangle), of which only 0.78% of sires (dog in the square) produce more than 50 % of the next generation (generation n + 1). Due to the lack of familial cases in humans, and the low frequency of the disease overall, the physiopathology of LCH and its genetic components are still unknown. This population has been used in the present study for the evaluation of the epidemiology, pathology, and transmission mode of HS in the BMD breed. HS, in our BMD population, displayed reproducible presentation and clinical course. For each dog, pedigree data were collected on ancestors, and a family of 21146 dogs (9989 males and 11457 females) was constructed. Despite their variable morphology, the tumor cells displayed a consistent phenotype with expression of the leukocyte antigen CD18 and the absence of expression of the lymphocytic markers CD3 and CD79, respectively, specific of T-cell and B-cell lineages ( Figure 2 ). These argue in favor of the use of the HS model in order to help to elucidate the complex mechanisms of the human LCH. Although the expected proportion of affected offspring under a fully recessive model is not very sensitive to the values of HS prevalence, the significance of the t -test is only strictly achieved when the prevalence equals 30%. To minimize the effect of pedigree time depth, we calculated consanguinity average for dogs born between 1998 and 2004 to be 3.2%. Less than 10% of the dogs lived longer than 4 months, and 61 dogs (79%) were euthanazied. Search for other works by this author on: Canine cutaneous and systemic histiocytosis: reactive histiocytosis of dermal dendritic cells, Localized and disseminated histiocytic sarcoma of dendritic cell origin in dogs. The average time between 2 generations was 3.7 years with a standard deviation of 1.2 years. 1996 ). To better characterize the physiopathology and epidemiology, an in-depth analysis of 89 BMD cases has been performed. Canine histiocytic proliferative disorders are a group of heterogeneous diseases that include reactive disorders such as cutaneous and systemic histiocytosis and neoplasias such as cutaneous histiocytoma and localized or disseminated histiocytic sarcoma (HS), the latter previously called malignant histiocytosis ( Moore 1984 ; Moore and Rosin 1986 ; Rosin et al. 1995 ), and by analyzing the inheritance of histiocytosis in 127 affected BMDs, they reported that the disease was inherited in the BMD ( Padgett et al. Pathological features of disseminated HS: multiple tumor masses affecting the skin, lung, and spleen. 1996; Arico and Danesino 2001) could not be postulated for dogs. 2006 ). Disseminated HS progresses rapidly to death or euthanasia, but localized HSs of the subcutis or joint are less devastating. (1996) . 2008 ). All dogs for which parental DNA was available were tested for parental compatibility using a set of informative microsatellite markers. Most HS cases in BMDs have been reported to be of dendritic antigen-presenting cell origin even though a distinctive neoplastic proliferation of macrophages has been recently described in dogs ( Affolter and Moore 2002 ; Moore et al. Using a subset of 160 BMDs, encompassing 21 complete sibships, we now propose an oligogenic transmission mode of the disease. Of those 121 dogs, 89 with pathological reports had been collected between 2005-01-01 and 2008-11-01. (This figure appears in color in the online version of Journal of Heredity .). Involvement of multiple organ systems at the time of presentation was present in 55% of the dogs (37 cases). This was the first description of a possible familial presentation or a related disease in dogs. Canine genetics offers new mechanisms for the study of human cancer, Population structure and inbreeding from pedigree analysis of purebred dogs, Histiocytose langerhansienne: mise au point, Association of Langerhans cell histiocytosis with malignant neoplasms, Langerhans cell histiocytosis: a pathologic combination of oncogenesis and immune 670 dysregulation, Histiocytic sarcomas in flat-coated retrievers: a summary of 37 cases (November 1998March 2005), The dog: a powerful model for studying genotype-phenotype relationships, Tumors of the hemolymphatic system. Immunostaining was performed on formalin-fixed and paraffin-embedded tumor tissues, and a diagnosis of HS was confirmed when tumor cells display morphological features consistent with an HS and were CD18 positive (hematopoietic in origin) and CD3 and CD79 negative (excluding T-cell and B-cell lymphomas, respectively). Naturally occurring cancers in pet dogs and humans have been shown to share many common features, including tumor genetics, molecular mechanisms of oncogenesis, histological appearance, and biological behavior. The most commonly reported clinical symptoms were anorexia (92% of the cases), asthenia and weakness (90%), weight loss (88%), and hyperthermia (43%). An increased number of hematopoietic cancers in BMDs was also found by Ramsey et al. It is clearly higher than the observed proportion in all cases, although the significance of the t -test comparing them is only strictly achieved ( P value < 0.05) when pk = 0.30. 1996 ; Affolter and Moore 2002 ). We calculated inbreeding coefficients within the pedigree, defining the probability that for any locus of an individual both 2 alleles descend from the same ancestral genotype. Langerhans cell histiocytosis: is there a role for genetics? ), therapeutics, and follow-up. Differences between populations were analyzed statistically using Fisher's Exact test. A surgical procedure was performed in 39 dogs, either for diagnosis purpose or as a therapeutic procedure. Right: neoplastic cells expressing the leukocyte CD18 marker (immunoperoxidase reaction, diaminobenzidine as chromogen, hematoxylin counterstaining); bar=30 m. 1986 ). The expected proportion of affected offspring under a fully recessive model is not very sensitive to the values of pk . For 19 dogs, corticosteroid therapy was associated with antibiotics (cefalixin, quinolone, amoxicillin, neomycin, etc.) Quantitative epidemiological features are described as the mean 1 standard deviation. Diagnosis must be made by a licensed veterinarian or veterinary oncologist. This was close to values described by Calboli et al. or anabolic steroid. For the pedigree constitution, more than 800 blood and tissue samples were collected by a network including oncologist practitioners, the veterinary schools, veterinary pathology laboratories, and veterinarians throughout France and close European countries. Among the 19 therapeutic surgeries, 13 (68%) consisted of splenectomy. To test whether a fully recessive model could explain the transmission of the disease, nuclear families with at least 2 phenotyped offspring, one of them being affected, were selected. It is possible that genes involved in the malignant neoplastic proliferation of dendritic cells in HS could also promote the neoplastic transformation of other hematopoietic cell lineages or that genes more generally involved in neoplastic transformation are fixed in the BMD breed. A subset of 327 was selected to construct a pedigree segregating the disease. The unaffected (control) dogs are all older than 10 years and have never been diagnosed with any form of cancer. In 82% of the cases, there was involvement of internal organs, primarily, the spleen, the lungs and mediastinum, internal lymph nodes, and the liver, with one or several distinctive tumor mass(es) ( Figure 1 ). In the BMD breed, small founding population and popular sire effects have enriched risk alleles for HS, where the estimated frequency of the risk allele is now 25%. Other cancers observed in the sampled dogs included 13 lymphomas (7 males, 6 females), 18 mast cell tumors (7 males and 11 females), and 6 melanomas (5 males and 1 female). (This figure appears in color in the online version of Journal of Heredity .). A total of 121 dogs (58 males and 63 females) had a clinical diagnosis of HS, and among those, 98 (47 males, 51 females) had a histopathology report. We also thank the pathology laboratories who actively participated by sending us all pathology reports (particularly the LAPVSO, Toulouse, France, and Idexx Alfort laboratory, Alfortville, France). Skin of the thorax and forelegs was involved in 10 cases, head and neck in 6, and abdomen and hind legs in 6. Interestingly, in human, Egeler et al. Malignant dendritic cellrelated disorders are indeed rare in human beings, and their nosology, etiology, and pathogenesis remain largely undefined ( Arico and Danesino 2001 ). In these cases, the spleen was the most frequently involved organ (28 cases, 76%) followed by the lung and mediastinum (27 cases, 67%), the liver (24 cases, 65%), and the lymph nodes (16 cases, 43%). These homogenous features are probably related to common physiopathologic mechanisms of oncogenesis in most if not all the cases. 2007 ). Coughing was recorded in 19% of affected dogs. There were, however, few reports of therapeutic trials and survival rates in dogs with HS. 2007 ; Jones et al. A 21146-dog multigenerational pedigree, connecting 327 BMD sampled dogs from France, with known phenotypes was constructed by investigations performed between 2001-01-01 and 2007-07-01. For permissions, please email: journals.permissions@oxfordjournals.org. In France, a few champion males born in the 1980s have produced 400 puppies. If any of these males were affected or were carriers, it could easily explain the fact that the disease has spread so rapidly and in so few generations. Lungs and spleen are reported to be most frequent site of primary tumor (Rosin and Moore 1986; Affolter and Moore 2002 ). It is ranked 15th in 2006 with 2900 new registrations per year in France ( http://www.scc.asso.fr ). (2008) (0.0240.071) but is likely still an underestimation as the data is missing for many founders of this pedigree. In fact, 2 studies reported that appropriate treatment can improve survival. Conditioning on the phenotyped parent, we computed for each family the expected number of affected offspring under a fully recessive model. We collected DNA samples and clinical information from 800 BMDs, of which 200 are affected by HS. Studying such complex diseases as cancers in dogs allows access to large and well-documented pedigrees and numerous samples. A spontaneous animal model of malignant LCH is expected to enhance research efforts and may represent a powerful tool, particularly for exploring the role of genetic predisposition to the disease. Reference Genome of the California Sheephead. Chapter 3, Single-nucleotide-polymorphism-based association mapping of dog stereotypes, Efficient mapping of Mendelian traits in dogs through genome-wide association, Genome sequence, comparative analysis and haplotype structure of the domestic dog, Systemic histiocytosis of Bernese mountain dogs, Malignant histiocytosis of Bernese mountain dogs, Canine hemophagocytic histiocytic sarcoma: a proliferative disorder of CD11dp macrophages, Inheritance of histiocytosis in Bernese mountain dogs, Canine genomics and genetics: running with the pack, Canine population structure: assessment and impact of intra-breed stratification on SNP-based association studies, Malignant histiocytosis in three Bernese mountain dogs, Malignant histiocytosis in Bernese Mountain dogs, Nosology and pathology of Langerhans Cell Histiocytosis, Cytokine genes single nucleotide polymorphism (SNP) screening analyses in canine malignant histiocytosis, CCNU for the treatment of dogs with histiocytic sarcoma, Evaluation of dysregulation of the receptor tyrosine kinases Kit, Flt3, and Met in histiocytic sarcomas of dogs. Unaffected dogs were declared controls if they were older than 10 years and had never been diagnosed with any form of cancer. With substantial recent progress in veterinary medicine, dogs live longer and are affected by many cancer types. (This figure appears in color in the online version of Journal of Heredity .).

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