Orru S, Manolakos E, Orru N, Kokotas H, Mascia V, Carcassi C, Petersen MB. High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis.

Recently, rare mutations in the TARDBP gene have been identified in familial and sporadic amyotrophic lateral sclerosis (ALS) patients. The purpose of this study was to characterize the genetic variability of the TARDBP gene in a cohort of Sardinian ALS patients. The coding region of the gene was analyzed in 97 unrelated patients previously tested negative for superoxide dismutase (SOD1) mutations. The p.Ala382Thr (c.1144G>A) mutation was found in 30 patients (30.9%). The mutation was predominant in familial ALS patients (FALS) as it was represented in 24 of 30 FALS cases (80%) (p < 0.0003). Six cases were apparently sporadic (9% of sporadic ALS patients). No further mutation of TARDBP was found in our cohort of ALS patients. Patients carrying the mutation showed spinal site of onset in 24 cases (80%), an average age at onset of 54.7 ± 11.1 years, not significantly different from patients not harboring TARDBP mutations (56.7 ± 9.6) and a female:male gender ratio of 1:1.1. The haplotype analysis carried out using eight microsatellite markers flanking the gene showed a founder effect for this mutation. Finally, we estimated the age-specific penetrance of the TARDBP p.Ala382Thr mutation in an additional sample of 47 carriers (20 affected and 27 unaffected). The average penetrance to 70 years was 60% (95% confidence interval 41–79%). A trend toward a higher penetrance in males was observed. Even in the presence of a causal mutation, most of the ALS clinical heterogeneity, however, draws upon from a multifactorial context.

High frequency of the TARDBP p.Ala382Thr mutation in Sardinian patients with amyotrophic lateral sclerosis

Role of KRAS, BRAF and PIK3CA mutations in pathogenesis of colorectal cancer (CRC) has been recently investigated worldwide. In this population-based study, we evaluated the incidence rates and distribution of such somatic mutations in genetically isolated population from Sardinia. From April 2009 to July 2011, formalin-fixed paraffin-embedded tissues (N = 478) were prospectively collected from Sardinian CRC patients at clinics across the entire island. Genomic DNA was isolated from tissue sections and screened for mutations in KRAS, BRAF, and PIK3CA genes by automated DNA sequencing. Overall, KRAS tumour mutation rate was 30% (145/478 positive cases). Distribution of mutation carriers was surprisingly different within the island: 87/204 (43%) in North Sardinia vs. 58/274 (21%) in Middle-South Sardinia (p<0.001). Among 384 CRC cases whose DNA was available, only one (0.3%) patient carried a mutation in BRAF gene; PIK3CA was found mutated in 67 (17%) patients. A significant inverse distribution of PIK3CA mutation rates was observed within Sardinian population: 19/183 (10%) cases from northern vs. 48/201 (24%) cases from central-southern island (p<0.001). This heterogeneity in frequencies of KRAS/PIK3CA somatic mutations is consistent with already-reported discrepancies in distribution of germline mutations for other malignancies within Sardinian population. Preliminary clinical evaluation of 118 KRAS wild-type patients undergoing anti-EGFR-based treatment indicated lack of role for PIK3CA in predicting response to therapy. Our findings support the hypothesis that differences in patients’ origins and related genetic backgrounds may contribute to even determine the incidence rate of somatic mutations in candidate cancer genes.

/pdf/prevalence-of-kras-braf-and-pik3ca-somatic-mutations-in-4ptnjsncnf.pdf

Prevalence of KRAS , BRAF , and PIK3CA somatic mutations in patients with colorectal carcinoma may vary in the same population: clues from Sardinia

Germline mutations in BRCA1 or BRCA2 genes have been demonstrated to increase the risk of developing breast cancer. Among the prognostic factors currently used in clinical practice, the disease stage and the receptor status play a crucial role in the management of breast carcinoma. Triple‑negative breast cancer (TNBC) has been classified as a disease subgroup that is negative for oestrogen, proges- terone and HER2 receptor expression, and presents a poor prognosis. The present study investigated the correlation between BRCA1/2 mutations and TNBC status in a large series (n=726) of breast cancer patients from Sardinia. The BRCA mutation screening was performed on genomic DNA from peripheral blood samples by denaturing high-perfor- mance liquid chromatography analysis and automated DNA sequencing. Overall, 21/726 (2.9%) patients carried a germ- line mutation in BRCA1 or BRCA2. The TNBC phenotype was significantly associated with the BRCA1 mutations (P<0.001), whereas no association was found with the BRCA2 mutations (P=0.837). With respect to patient origin within Sardinia, a significant inverse distribution of mutations was found; BRCA1 and BRCA2 mutations represented 86 and 93% of the mutated cases in Southern and Middle-Northern Sardinia, respectively (P<0.001). Patients from the geograph- ical area with BRCA1 mutation prevalence presented a TNBC incidence much higher than that observed in cases from the area with BRCA2 mutation prevalence (12 vs. 4%, respectively; P=0.037). These findings further confirmed that the occurrence of TNBC is significantly associated with the BRCA1 mutation carrier status and that a different 'genetic background' may have a phenotypic impact in the onset of breast cancer.

/pdf/triple-negative-breast-cancer-frequency-and-type-of-brca-1kc6cesm7q.pdf

Triple‑negative breast cancer frequency and type of BRCA mutation: Clues from Sardinia

Objective To summarize the knowledge about BRCA1 and BRCA2 germline mutation spectrum in Maghrebian countries. Methods We performed a systematic review of the literature to determine the impact of BRCA1 and BRCA2 mutations on hereditary breast/ovarian cancer in the Maghrebian population from Algeria, Morocco and Tunisia. We searched all available data published in Pubmed, Scopus, Cancerlit® databases and other scientific literatures sources. Results Pathogenic mutations in BRCA1 gene were detected by DNA sequencing in 17.43% (34/195) of analyzed breast/ovarian cancer families from Algeria, Morocco and Tunisia. One common mutation c.798_799delTT was identified in the BRCA1 gene with a frequency of 5.12%. Pathogenic BRCA2 mutations were identified in 11 out 146 families (7.53%). A new common BRCA2 pathogenic mutation c.7235_7236insG was detected in Algerian and Moroccan families. Conclusions The Maghrebian population from Algeria, Morocco and Tunisia has just been started to be extensively studied; consequently knowledge of the prevalence and spectrum of BRCA1 and BRCA2 mutations in these populations is getting dense. The implications of these new findings in regard to genetic testing and counseling are substantial for patients and families at risk.

BRCA1 and BRCA2 germline mutation spectrum in hereditary breast/ovarian cancer families from Maghrebian countries.

The alarming increase in the number of breast cancer patients worldwide and the increasing death rate indicate that the traditional and current medicines are insufficient to fight against it. The onset of chemo- and radioresistances and cancer stem cell-based recurrence make this problem harder, and this hour needs a novel treatment approach. Competent nanoparticle-based accurate drug delivery and cancer nanotheranostics like photothermal therapy, photodynamic therapy, chemodynamic therapy, and sonodynamic therapy can be the key to solving this problem due to their unique characteristics. These innovative formulations can be a better cargo with fewer side effects than the standard chemotherapy and can eliminate the stability problems associated with cancer immunotherapy. The nanotheranostic systems can kill the tumor cells and the resistant breast cancer stem cells by novel mechanisms like local hyperthermia and reactive oxygen species and prevent tumor recurrence. These theranostic systems can also combine with chemotherapy or immunotherapy approaches. These combining approaches can be the future of anticancer therapy, especially to overcome the breast cancer stem cells mediated chemo- and radioresistances. This review paper discusses several novel theranostic systems and smart nanoparticles, their mechanism of action, and their modifications with time. It explains their relevance and market scope in the current era. This article is categorized under: Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease.

Innovative nanotheranostics: Smart nanoparticles based approach to overcome breast cancer stem cells mediated chemo- and radioresistances.

Background: In recent years, numerous studies have assessed the prevalence of germline mutations in BRCA1 and BRCA2 genes in various cohorts. We here extensively investigated the prevalence and geographical distribution of BRCA1-2 mutations in the entire geneticallyhomogeneous Sardinian population. The occurrence of phenotypic characteristics which may be predictive for the presence of BRCA1-2 germline mutations was also evaluated. Methods: Three hundred and forty-eight breast cancer patients presenting a familial recurrence of invasive breast or ovarian carcinoma with at least two affected family members were screened for BRCA1-2 mutations by DHPLC analysis and DNA sequencing. Association of BRCA1 and BRCA2 mutational status with clinical and pathological parameters was evaluated by Pearson's Chi-Squared test. Results and Conclusion: Overall, 8 BRCA1 and 5 BRCA2 deleterious mutations were detected in 35/348 (10%) families; majority (23/35;66%) of mutations was found in BRCA2 gene. The geographical distribution of BRCA1-2 mutations was related to three specific large areas of Sardinia, reflecting its ancient history: a) the Northern area, linguistically different from the rest of the island

/pdf/a-role-of-brca1-and-brca2-germline-mutations-in-breast-4u2kyo8cds.pdf

A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population.

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A role of BRCA1 and BRCA2 germline mutations in breast cancer susceptibility within Sardinian population.