Cardiac and Nephrological Complications Related to the Use of Antiangiogenic and Anti-Programmed Cell Death Protein 1 Receptor/Programmed Cell Death Protein 1 Ligand Therapy.

The ability to undergo neoangiogenesis is a common feature with all cancers. Signaling related to vascular endothelial growth factors (VEGF) and their receptors (VEGFR) plays a key role in the process of tumor neoangiogenesis. A close relationship has been demonstrated between excessive VEGF levels and the induction of immunosuppression in the tumor microenvironment. The use of drugs blocking the VEGF function, apart from the anticancer effect, also result in adverse effects, in particular related to the circulatory system and kidneys. Cardiac toxicity associated with the use of such therapy manifests itself mainly in the form of hypertension, thromboembolic episodes and ischemic heart disease. In the case of renal complications, the most common symptoms include renal arterial hypertension, proteinuria and microangiopathy. Although these complications are reversible in 60-80% of cases after cessation of VSP (VEGF pathway inhibitor) therapy, in some cases they can lead to irreversible changes in renal function, whereas cardiac complications may be fatal. Also, the use of PD-1/PD-L1 inhibitors may result in kidney and heart damage. In the case of cardiac complications, the most common symptoms include myocarditis, pericarditis, arrhythmia, acute coronary syndrome and vasculitis, while kidney damage most often manifests as acute kidney injury (AKI), nephrotic syndrome, pyuria or hematuria. The decision whether to resume treatment after the occurrence of cardiovascular and renal complications remains a problem.

Canis MitoSNP database: a functional tool useful for comparative analyses of human and canine mitochondrial genomes.

Canis MitoSNP is a tool allowing assignment of each mitochondrial genomic position a corresponding position in the mitochondrial gene and in the structure of tRNA, rRNA, and protein. The main aim of this bioinformatic tool was to use data from other bioinformatic tools (TMHMM, SOPMA, tRNA-SCAN, RNAfold, ConSurf) for dog and human mitochondrial genes in order to shorten the time necessary for the analysis of the whole genome single nucleotide polymorphism (SNP) as well as amino acid and protein analyses. Each position in the canine mitochondrial genome is assigned a position in genes, in codons, an amino acid position in proteins, or a position in tRNA or rRNA molecules. Therefore, a user analysing changes in the canine and human mitochondrial genome does not need to extract the sequences of individual genes from the mitochondrial genome for analysis and there is no need to rewrite them into amino acid sequences to assess whether the change is synonymous or nonsynonymous. Canis mitoSNP allows the comparison between the human and canine mitochondrial genomes as well. The Clustal W alignment of the dog and human mitochondrial DNA reference sequences for each gene obtained from GenBank (NC_002008.4 dog, NC_012920.1 human) was performed in order to determine which position in the canine mitochondrial genome corresponds to the position in the human mitochondrial genome. This function may be useful for the comparative analyses. The tool is available at: https://canismitosnp.pl .

Mitochondrial DNA Changes in Respiratory Complex I Genes in Brain Gliomas.

Mitochondria are organelles necessary for oxidative phosphorylation. The interest in the role of mitochondria in the process of carcinogenesis results from the fact that a respiratory deficit is found in dividing cells, especially in cells with accelerated proliferation. The study included tumor and blood material from 30 patients diagnosed with glioma grade II, III and IV according to WHO (World Health Organization). DNA was isolated from the collected material and next-generation sequencing was performed on the MiSeqFGx apparatus (Illumina). The study searched for a possible relationship between the occurrence of specific mitochondrial DNA polymorphisms in the respiratory complex I genes and brain gliomas of grade II, III and IV. The impact of missense changes on the biochemical properties, structure and functioning of the encoded protein, as well as their potential harmfulness, were assessed in silico along with their belonging to a given mitochondrial subgroup. The A3505G, C3992T, A4024G, T4216C, G5046A, G7444A, T11253C, G12406A and G13604C polymorphisms were assessed as deleterious changes in silico, indicating their association with carcinogenesis.

Non-Small Cell Lung Cancer Treatment with Molecularly Targeted Therapy and Concurrent Radiotherapy-A Review.

Lung cancer is the leading cause of death worldwide for both men and women. Surgery can be offered as a radical treatment at stages I and II and selected cases of stage III (III A). Whereas at more advanced stages, combined modalities of treatment are applied: radiochemotherapy (IIIB) and molecularly targeted treatment (small molecule tyrosine kinase inhibitors, VEGF receptor inhibitors, monoclonal antibodies, and immunological treatment with monoclonal antibodies). Combination treatment, composed of radiotherapy and molecular therapy, is increasingly employed in locally advanced and metastatic lung cancer management. Recent studies have indicated a synergistic effect of such treatment and modification of immune response. The combination of immunotherapy and radiotherapy may result in the enhancement of the abscopal effect. Anti-angiogenic therapy, in combination with RT, is associated with high toxicity and should be not recommended. In this paper, the authors discuss the role of molecular treatment and the possibility of its concurrent use with radiotherapy in non-small cell lung cancer (NSCLC).

Mitochondrial DNA Changes in Genes of Respiratory Complexes III, IV and V Could Be Related to Brain Tumours in Humans.

Mitochondrial DNA changes can contribute to both an increased and decreased likelihood of cancer. This process is complex and not fully understood. Polymorphisms and mutations, especially those of the missense type, can affect mitochondrial functions, particularly if the conservative domain of the protein is concerned. This study aimed to identify the possible relationships between brain gliomas and the occurrence of specific mitochondrial DNA polymorphisms and mutations in respiratory complexes III, IV and V. The investigated material included blood and tumour material collected from 30 Caucasian patients diagnosed with WHO grade II, III or IV glioma. The mitochondrial genetic variants were investigated across the mitochondrial genome using next-generation sequencing (MiSeq/FGx system-Illumina). The study investigated, in silico, the effects of missense mutations on the biochemical properties, structure and functioning of the encoded protein, as well as their potential harmfulness. The A14793G (MTCYB), A15758G, (MT-CYB), A15218G (MT-CYB), G7444A (MT-CO1) polymorphisms, and the T15663C (MT-CYB) and G8959A (ATP6) mutations were assessed in silico as harmful alterations that could be involved in oncogenesis. The G8959A (E145K) ATP6 missense mutation has not been described in the literature so far. In light of these results, further research into the role of mtDNA changes in brain tumours should be conducted.

The Role of Mitochondria in Carcinogenesis.

The mitochondria are essential for normal cell functioning. Changes in mitochondrial DNA (mtDNA) may affect the occurrence of some chronic diseases and cancer. This process is complex and not entirely understood. The assignment to a particular mitochondrial haplogroup may be a factor that either contributes to cancer development or reduces its likelihood. Mutations in mtDNA occurring via an increase in reactive oxygen species may favour the occurrence of further changes both in mitochondrial and nuclear DNA. Mitochondrial DNA mutations in postmitotic cells are not inherited, but may play a role both in initiation and progression of cancer. One of the first discovered polymorphisms associated with cancer was in the gene NADH-ubiquinone oxidoreductase chain 3 (mt-ND3) and it was typical of haplogroup N. In prostate cancer, these mutations and polymorphisms involve a gene encoding subunit I of respiratory complex IV cytochrome c oxidase subunit 1 gene (COI). At present, a growing number of studies also address the impact of mtDNA polymorphisms on prognosis in cancer patients. Some of the mitochondrial DNA polymorphisms occur in both chronic disease and cancer, for instance polymorphism G5913A characteristic of prostate cancer and hypertension.

The role of immunotherapy and molecular­targeted therapy in the treatment of melanoma (Review).

Skin melanomas are malignant neoplasms originating from neuroectodermal melanocytes. Compared to other neoplasms, melanomas have a high rate of growth. Their incidence is highest in Australia and New Zealand, in high­income European countries (Switzerland, Norway, Sweden) and in the US. In Poland, the standardized incidence rate is approximately 5/100,000. Melanomas are typically highly radioresistant and chemoresistant. Before the era of immunotherapy, inoperable lesions were treated using chemotherapy based mainly on dacarbazine, temozolomide or fotemustine, which did not yield the expected results in terms of extending survival time or improving patient comfort. Therefore, there has emerged a need to seek other solutions. In most cases, the use of immunological treatment or targeted therapy has had a positive impact on survival time and relapse­free survival. However, these periods are still relatively short, hence the need for further research and improvement of treatment. The most promising strategies appear to be antibodies that block programmed death receptor­1 (PD­1) and programmed death receptor ligand­1 (PD­L1) molecules, anti­CTLA4 antibodies (cytotoxic T­lymphocyte antigen 4) and therapy with BRAF and MEK inhibitors.

Interstitial HDR Brachytherapy in the Treatment of Non-Melanocytic Skin Cancers around the Eye.

BACKGROUND: Eyelid tumors are rare skin cancers, the most common of which is basal cell carcinoma characterized primarily by local growth. In addition to surgery, radiotherapy is among the basic methods of treatment. External beam radiotherapy is associated with the risk of complications within ocular structures, especially the lens. In the case of interstitial brachytherapy, it is possible to administer a high dose to the clinical target volume (CTV), while reducing it in the most sensitive structures. METHODS: This paper presents the results of an analysis of 28 patients treated with interstitial high dose rate (HDR) brachytherapy for skin cancers of the upper and lower eyelid; medial and lateral canthus; and the cheek, nose and temples with the infiltration of ocular structures. The patients were treated according to two irradiation schedules: 49 Gy in 14 fractions of 3.5 Gy twice a day for 7 days of treatment, and 45 Gy in 5 Gy fractions twice a day for 5 days. The mean follow-up was 22 months (3-49 months). RESULTS: two patients (6%) had a relapse: a local recurrence within the irradiated area in one of them, and metastases to lymph nodes in the other. The most common early complication was conjunctivitis (74%), and the most common late complication was dry eye syndrome (59%). CONCLUSIONS: Interstitial HDR brachytherapy for skin cancers of the upper and lower eyelid; medial and lateral cants; and the cheek, nose and temples with infiltration of ocular structures is a highly effective, short and relatively low burden type of treatment.

The presence of particular criteria and noncriteria antiphospholipid antibodies in patients with uterine malignancies.

INTRODUCTION: Currently, there have been limited data on the presence of antiphospholipid antibodies (aPLs) in patients with uterine malignancies (UMs). OBJECTIVES: We aimed to determine whether criteria and noncriteria aPLs are present in patients with UMs and associated with the thrombotic risk, as compared with patients with noncancerous gynecological diseases (NCGDs). PATIENTS AND METHODS: The study involved 151 women scheduled for gynecological surgery. The patients were divided into the UM group (n = 70) and the NCGD group (n = 81). The Antiphospholipid 10 Dot assay was used to detect criteria and noncriteria aPLs before surgery. The study patients were considered positive for thrombosis if they exhibited signs of thrombosis within the 2­year follow­up period after surgery. RESULTS: Positive results for aPLs were obtained in 17/70 patients with UMs (24.3%) and in 6/81 patients with NCGDs (7.4%) (P = 0.008). Particular noncriteria aPLs (antiphosphatidic acid, antiphosphatidylserine, anti-annexin V, and antiprothrombin antibodies) yet no criteria aPLs (anticardiolipin and anti-ß2­glycoprotein I antibodies) were more frequently found in patients with UMs than in those with NCGDs. Thrombosis was diagnosed in 9/70 patients (12.9%) in the UM group and in 3/81 patients (3.7%) in the NCGD group (P = 0.03). CONCLUSIONS: Antiphospholipid antibodies were present at significant levels in patients with UMs. Noncriteria aPLs yet no criteria aPLs were more frequently found in patients with UMs than in those with NCGDs. The incidence of thrombosis was significantly higher in patients with UMs.

The Role of Prognostic Factors in Salivary Gland Tumors Treated by Surgery and Adjuvant Radio- or Chemoradiotherapy - A Single Institution Experience.

PURPOSE: Salivary gland neoplasms are rare cancers of the head and neck region. Radical treatment in tumors of large salivary glands is surgery. Adjuvant treatment depends on the presence of risk factors that worsen the prognosis, but the role of these factors in patients treated by surgery with radio- or radiochemotherapy still remains unclear. The aim of the study is assessment of treatment results and identification of the risk factors affecting the prognosis in patients with tumors of large salivary glands subjected to adjuvant radio- or radiochemotherapy. PATIENTS AND METHODS: The study included 126 patients with local stage large salivary gland cancer who were treated surgically with adjuvant radio- or radiochemotherapy. The study excluded inoperable patients, patients with distant metastases, patients in a poor general condition and patients with contraindications to adjuvant treatment. They were treated between 2006 and 2016 and evaluated in terms of OS (overall survival), CSS (cancer-specific survival), RFS (relapse-free survival) and LRFS (local relapse-free survival). RESULTS: During a 44-month follow-up, 5-OS, CSS, RFS and LRFS were 55%, 68%, 60% and 73%, respectively. Multivariate analysis showed that OS was influenced by the following parameters: WHO performance status, TNM stage (T and N parameters), radicality of surgery, histopathological type, applied method of radiotherapy planning and tumor volume. WHO performance status, T and N parameters of the TNM stage and large volume of elective area influenced CSS, and the T parameter of the TNM stage, the dose below 60Gy and tumor volume influenced RFS and LRFS. Chemoradiotherapy can be used in N-positive patients. CONCLUSION: The analysis indicates that the TNM grade, histopathological type, patient's condition, radicality of the procedure, technique and dose of radiotherapy are the most important prognostic factors in these patients.

Complications of radio- and radiochemotherapy in patients undergoing major salivary gland cancer surgery.

PURPOSE: The aim of this retrospective study was to present the prevalence of early and late radiation-induced reaction and factors affecting its formation and severity in patients after adjuvant radio- or radiochemotherapy in salivary gland cancer. MATERIAL AND METHODS: A total of 113 patients with early and 91 with late radiation-induced reaction, irradiated in 2006-2016 were enrolled in the study. The frequency of acute mucosal radiation-induced reaction, time of onset, intensity, healing time, as well as the incidence of late radiation-induced reaction from the skin and subcutaneous tissue were analyzed. Factors that could influence the development and intensity of reaction were identified. RESULTS: Acute severity and the presence of late radiation-induced reaction do not affect overall survival. Dosage in the tumor bed site, as well as the dosage in the nodal region, affect the severity of the acute radiation-induced mucosal reaction. The severity of the early radiation-induced reaction is higher in men, more advanced patients (higher T and N+ in TNM classification), irradiated into a larger area, and those in whom two-dimensional planning and complementary chemoradiotherapy were applied. The late reaction of the skin and subcutaneous tissue was dominated by patients irradiated in the nodal regions and those with a higher intensity of early radiation-induced reaction. CONCLUSIONS: Supplementary radiotherapy or radiochemotherapy in salivary gland cancer is associated with acceptable toxicity which has no effect on overall survival.

Heteroplasmic Mutations and Polymorphisms in the Cyb Gene of Mitochondrial DNA in Canine Mast Cell Tumours.

AIM: Identification of mutations and polymorphisms in the cytochrome b gene (Cyb) of mitochondrial DNA (mtDNA) in canine mast cell tumours and determinatiion of their association with the process of neoplastic transformation. MATERIALS AND METHODS: The samples comprised tumour tissues and blood obtained from 34 dogs of various breeds. Mutations and polymorphisms in the Cyb gene were detected using amplification and sequencing methods. RESULTS: Heteroplasmic mutations were detected at seven positions of mtDNA in 86% of the individuals. Blood and tumour heteroplasmy were recorded at five nucleotide positions of the Cyb gene, whereas tumour heteroplasmy was detected at two positions. Polymorphisms were detected at 14 Cyb gene positions in in the blood of 91% of dogs with mast cell tumours. CONCLUSION: The presence of numerous mutations and polymorphisms of Cyb in the blood and tumour tissues and the high frequency of heteroplasmy indicate their involvement in the process of neoplastic transformation in dogs.

Treatment of hepatic metastases with computed tomography-guided interstitial brachytherapy.

The aim of the present study was to evaluate the efficacy, safety and tolerability of local treatment of liver metastases of various types of cancer using brachytherapy with computed tomography (CT) imaging. Retrospective analysis of 61 patients with unresectable hepatic metastases treated with CT-guided interstitial high dose rate (HDR) brachytherapy of the liver between April 2014 and December 2016 was performed. Patients were treated with a single fractional dose of 15-25 Gy. Statistical analysis was performed on local relapse free survival (LRFS), progression free survival (PFS) and overall survival (OS) rates across the group. In the 6 and 12-month follow-up periods, the 6- and 12-month LRFS rates were 88.7 and 70.7%, PFS rates were 78.1 and 53.8% and the OS rates were 96.7 and 79.6%, respectively. In the Cox regression analysis, the 100% isodose was a statistically significant predictor of LRFS (P=0.01) and PFS (P=0.02), but it was not significant in OS (P=0.07). The 90% isodose was a statistically significant predictor of LRFS (P=0,03) but not significant in PFS (P=0.17) or OS (P=0.25). In all patients, no serious complications were observed. Overall, 30% of patients experienced pain at the injection site, and 50% exhibited nausea or vomiting. In 2 patients, minor subcapsular bleeding occurred without clinical significance, and 1 patient was diagnosed with a pneumothorax that was not clinically significant. Brachytherapy HDR with CT imaging is an effective and safe method of local treatment of liver metastases. The effectiveness of the treatment is probably dose-dependent, and increases with increasing dosage.

Application of molecular targeted therapies in the treatment of head and neck squamous cell carcinoma.

Despite the development of standard therapies, including surgery, radiotherapy and chemotherapy, survival rates for head and neck squamous cell carcinoma (HNSCC) have not changed significantly over the past three decades. Complete recovery is achieved in <50% of patients. The treatment of advanced HNSCC frequently requires multimodality therapy and involves significant toxicity. The promising, novel treatment option for patients with HNSCC is molecular-targeted therapies. The best known targeted therapies include: Epidermal growth factor receptor (EGFR) monoclonal antibodies (cetuximab, panitumumab, zalutumumab and nimotuzumab), EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, lapatinib, afatinib and dacomitinib), vascular endothelial growth factor (VEGF) inhibitor (bevacizumab) or vascular endothelial growth factor receptor (VEGFR) inhibitors (sorafenib, sunitinib and vandetanib) and inhibitors of phosphatidylinositol 3-kinase/serine/threonine-specific protein kinase/mammalian target of rapamycin. There are also various inhibitors of other pathways and targets, which are promising and require evaluation in further studies.

Retrospective Analysis of Intravaginal Brachytherapy in Adjuvant Treatment of Early Endometrial Cancer.

The aim of this study was to determine the role of adjuvant endovaginal brachytherapy HDR (High Dose Rate) or observation, as well as identification of risk factors of tumor recurrence. The study included 178 women after radical hysterectomy. All patients belonged to the group of low- and medium-risk stage I FIGO. Analysis consisted of 3-, 5-, and 10-year OS, DFS, and LRFS in both groups. Follow-up was more than 6.5 years. The 5-OS, 5-DFS, and 5-LRFS were 93%, 96%, and 98% in the treated group and 95%, 94%, and 96% in the observed group, respectively. These differences were not statistically significant. There was a statistically significant difference in 5-OS in the treated group, between low- and medium-risk subgroups (100% versus 87.55%, p = 0.018). There was a better prognosis among the patients with FIGO IA compared to FIGO IB (5-DFS, 97 versus 86%, p = 0.047). Among the risk factors, there were only statistically significant differences in the 5-OS, between the ages of ≤ 70 years and >70 years. Use of brachytherapy may affect the reduction in the number of local recurrences at the vaginal stump (6% versus 2%). This is particularly noticeable in the low-risk subgroup (9% versus 0%).

Identification of additional mitochondrial DNA mutations in canine mast cell tumours.

BACKGROUND: Research has revealed the presence of somatic mutations in mitochondrial DNA (mtDNA) of certain types of tumours. As this has not been studied for canine mast cell tumours, the aim of this study was to identify mutations in the hypervariable region of mtDNA in mast cell tumours in dogs and determine their association with the process of neoplastic transformation. RESULTS: Samples from 17 dogs with histopathologically confirmed mast cell tumours were analysed. The samples consisted of tumour tissues (n = 17), normal tissues (n = 17), and blood (n = 17). Amplicons of the displacement loop (D-loop) were sequenced and the obtained nucleotide sequences were subjected to bioinformatics analyses. Somatic mutations were detected in seven positions of the D-loop nucleotide sequences in 47 % of the dogs, while polymorphisms were identified in 94 % of the dogs. Most of these changes were homoplasmic, while heteroplasmy was detected in two individuals. Six new haplotypes were established as being characteristic for canine mast cell tumours. There was no association between the presence of the mutations and sex, haplotype, or malignancy grade assessed in 3 and 2-grade scales. CONCLUSIONS: Differences in the frequency of somatic mutations imply their direct association with the neoplastic transformation. However, their functional consequences and clinical significance are not clear. The mutations may be used for diagnosis and prognosis of canine mast cell tumours in the future.

Mitochondrial DNA polymorphism in genes encoding ND1, COI and CYTB in canine malignant cancers.

The aim of the study was to identify DNA changes in mitochondrial gene fragments: NADH dehydrogenase subunit 1 (ND1), cytochrome c oxidase subunit I (COI) and cytochrome b (CYTB) in tumor tissue, normal tissue and blood, and to define their association with the tumor type in dogs. Molecular analysis included 144 tests in total. A functional effect of the non-synonymous protein coding SNP was predicted. The presence of polymorphisms in all tested gene fragments in individual tissues of dogs was observed. Heteroplasmic changes were found in ND1 and CYTB in epithelioma glandulae sebacei and in CYTB in lymphoma centroblasticum. The results of in silico analysis show the impact of these alleles (COI: 507, ND1: 450, 216, CYTB: 748) on the functioning of proteins and thus their potential role in carcinogenesis. The possible harmful effects of changes in polypeptides in positions T193N, V98M, V118M and H196P were evaluated. It seems that polymorphisms occurring in cells can have a negative impact on functioning of proteins. This promotes disorders of the energy level in cells.

Novel mitochondrial mutations in the ATP6 and ATP8 genes in patients with breast cancer.

The role of the mitochondria in the process of carcinogenesis, mainly oxidative phosphorylation, mostly concerns their participation in the production of free radicals and ATP and in the process of apoptosis. The purpose of this study was to detect potential changes in the genes encoding the subunits 6 and 8 of the ATP synthase and their impact on the enzyme's biochemical properties, structure and function in patients with breast tumors. The tested material was mitochondrial DNA (mtDNA) isolated from specimens of ductal carcinoma (carcinoma ductale) Tp1-2Np0-1Mp0, blood and non-cancerous tissue of mammary gland (control), sampled from 50 patients who had been operated for breast cancer. In the case of missense-type changes in the mtDNA, protein prediction software was used to assess their effect on the biochemical properties of the protein, its structure and function. We identified 8 changes in the ATP6 gene in 36/50 examined breast cancer cell samples and 5 changes in the ATP8 gene (10/50). Most of them were homoplasmic changes of missense type. Four of the changes (A8439C, G8858C, C9130G and T9119G) had not been described in the literature before. The identified mutations and polymorphisms, especially those of missense type, can affect mitochondrial functions, especially if the conservative domain of the protein is concerned. Replacement of 'wild-type' mtDNA by mutated mtDNA can be an important event in carcinogenesis.

Mitochondrial NADH dehydrogenase polymorphisms are associated with breast cancer in Poland.

Complex I NADH-oxidoreductase-ubiquinone transports reducing equivalents from the reduced form of NADH to ubiquinone (coenzyme Q-CoQ). The purpose of this study was to analyze mutations in MT-ND1, MT-ND2, MT-ND3 and MT-ND6 genes and their effect on the biochemical properties, structure and functioning of proteins in patients with breast tumours. In research materials, in 50 patients, 28 total polymorphisms and five mutations were detected. Most detected polymorphisms (50 %, 14/28) were observed in MT-ND2 gene. Most of them were silent mutations. Five polymorphisms (m.G3916A, m.C4888T, m.A4918G, m.C5363T, m.C10283T) do not exist in the database. A total of five mutations in 13 patients (13/50) were detected, including two not described in the literature: m.C4987G and m.T10173C. It cannot be excluded that, through the mutations and polymorphism impact on the protein structure, they may cause mitochondrial dysfunction and contribute to the appearance of other changes in mtDNA. The results of our study indicate the presence of homological changes in the sequence of mtDNA in both breast cancer and in some mitochondrial diseases. Mutations in the examined genes in breast cancer may affect the cell and cause its dysfunction, as is the case in mitochondrial diseases.

Mitochondrial D-loop mutations and polymorphisms are connected with canine malignant cancers.

Abstract The aim of the conducted investigations was to identify differences in the D-loop nucleotide sequence between neoplastic tissue, normal tissue, and blood and to determine their correlation with the type of cancer in dogs. In 62.5% of the analyzed tumors of epithelial origin and 25% tumors of mesenchymal origin, substitution was detected within the D-loop sequence between the neoplastic tissue, normal tissue, and blood. Two mutations occurring in the carcinogenic process in position T15620C have been identified in epithelioma glandulae sebacei and carcinoma planoepithelialae keratodes. Blood and cancer heteroplasmy was diagnosed for carcinoma planoepithelialae keratodes and "Comedo" carcinoma. The results of the study indicate that polymorphic changes in the D-loop sequence promote carcinogenesis in dogs. Heteroplasmy diagnosed in blood and tumor cells and absence thereof in normal tissue may imply mtDNA recombination. High prevalence of mtDNA mutations in canine tumors may suggest mtDNA genetic instability, which is likely to play a role in carcinogenesis.