Abstract. Tumor suppressor gene promoter CpG island methylation is a well-recognized mechanism in cancer pathogenesis, but its role in multiple myeloma (MM) is controversial. The present study investigated the methylation status and expression of

Fifteen female canines with mammary tumors and 6 normal females were used to study mutations in exons 4 to 8 of the p53 gene. DNA samples from the tumors, respective adjacent normal mammary tissue and mammary glands from healthy animals were sequenced and analyzed for the presence of mutations. Mutations were found in 71.8% of the samples and the most frequent were missense mutations. The most attacked exons in the mammary tumor were 5, 7 and 8, with 23.4, 31.6 and 23.4% mutations, respectively. Canine mammary tumors are related to mutations in gene p53 and mutations mostly occur in the region of the protein that is linked to the DNA in the cell nucleus, which can change the functionality of the cell and propitiate tumor growth. Despite being macroscopically normal, the mammary tissue adjacent to the tumors has mutations that can lead to recurrence if not removed together with the tumor.

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Background Multiple myeloma (MM) has been associated with several cytogenetic abnormalities (CA), contributing in heterogeneity of clinical outcome. CA are not always captured by conventional cytogenetic analysis (CGA), fluorescence in situ hybridization (FISH) has emerged as a useful assessment. CA that confer poor outcome include: t(4;14), t(14;16), 17p13 deletion, 13 deletion and complex karyotypes. No data regarding CA evaluated by FISH and its correlation with clinical outcome has been reported in Mexican population. Methods Prospective study carried between October 2006 and August 2012 in patients with newly diagnosed and untreated MM, were enrolled at our institution. Cytogenetic studies including CGA and FISH with probes for 17p13.1, 13q14.3, t(4;14), t(11;14), t(14;16), and in some cases IGH as screening test were performed. Clinical and laboratory data were collected. A high cytogenetic risk group (HCGRG) was considered for analysis which included patients with one or more of 17 deletion, 13 deletion, t(4;14), t(14;16) and complex karyotype excluding polyploidy. Continuous variables were described as medians and range, categorical variables as frequencies and proportions. Survival analysis was determined by Kaplan-Meier curves. Survival related prognostic factors were analyzed with the Cox proportional hazards regression model. Overall Survival (OS) was calculated from time of treatment initiation until death, patients that did not received therapy were excluded from the analysis. Progression-free survival (PFS) was calculated from the time of treatment initiation to the date of progression. Results Total of 73 patients were included. Baseline characteristics are shown in table 1. The median follow-up was 21 months (95% CI 1-70).Successful FISH was obtained in 100% of cases, CA by this method were detected in 40 patients (54.8%). CGA was useful for diagnosis in 53 cases (72.6%) with CA detected in 11 patients (20.8%). Related CA are shown in table 2. The median OS was 44 months (95% CI, 35.1-54.5) and PFS was 32.5 months (95% CI, 18.96-46.101). In the univariate analysis the variables associated with a shorter OS were: isotype (p =0.03; 95% CI 1.031-1.843), presence of bone plasmocytoma (BP) (p=0.015; 95% CI 1.29-10.68), FISH del13q14 (p=0.004; 95% CI 1.408-8.247), FISH IGH (p=0.028; 95% CI 1.097-5.087) and HCGRG (p=0.001; 95% CI 1.77-9.47). In the multivariate analysis isotype (p=0.033; 95% CI 1.029-2.009), presence of BP (p=0.010; 95% CI 1.48-18.33), FISH del13q14 (p=0.045; 95% CI 1.024-7.19) and patients in the HCGRG (p=0.002; 95% CI 1.84-13.757), were independent prognostic factors for OS. Variables associated with shorter PFS in the univariate analysis were: ISS (p=0.01, 95% CI 1.15-4.45), DS (p=0.01, 95% CI 1.09-2.47) and the presence of any CA (p=0.04, 95% CI 0.08-0.98). None were significant in the multivariate analysis. Conclusions This is the first report to show data about cytogenetics by CGA and FISH and its association with clinical outcomes in Mexico. Our distribution of CA is similar to the previously reported, except for 13 and 17 deletions, possibly due to different techniques and cut off values. The presence of BP and patients in HCGRG was associated to shorter OS. PFS and OS of patients in de HCGRG differs from other reports being significantly lower. This could be explained by our lack of access to drugs that overcome the negative prognosis of some CA, this is due to financial limitations. Our evaluation panel of CA is able to identify a group of patients with an unfavorable prognosis. It is mandatory to asses an alternative for financial protection for this group through a social program. TABLE 1. Baseline characteristics VARIABLE CATEGORY n (%) Total of patients 73 Age (years) 62 (35-87) Gender Male 33 (45.2) Isotype IgG IgA Kappa Lambda Biclonal 35 (47.9) 22 (30.1) 6 (8.2) 7 (9.6) 3 (4.1) ECOG PS 1 2 3 4 35 (47.9) 19 (26) 10 (13.7) 9 (12.3) ISS Stage I Stage II Stage III 11 (15.1) 16 (21.9) 46 (63) Durie Salmon (DS) Stage 1A Stage 1B Stage 2A Stage 2B Stage 3A Stage 3B 6 (8.2) 0 (0) 4 (5.5) 1 (1.4) 38 (52.1) 24 (32.9) Bone Plasmocytoma (BP) 11(15.1) Extramedullary disease 4 (5.4) TABLE 2. Cytogenetic abnormalities METHOD CATEGORY n (%) FISH 13q14 17p13 t(4;14) t(11;14) t(14;16) IGH >1 abnormality 19 (26) 16 (21.9) 8 (10.9) 5 (6.8) 6 (8.2) 26 (35.6) 11 (15) CGA del13 del17 Complex karyotype Polyploidy 4 (5.4) 3 (4.1) 8 (10.9) 7 (9.5) HCGRG 20 (27.4) Disclosures No relevant conflicts of interest to declare.