Unit of Medical Genetics

Catania, Italy

Unit of Medical Genetics

Catania, Italy
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Tavano F.,Casa Sollievo della Sofferenzah Hospital | Copetti M.,Unit of Biostatistics | Piepoli A.,Casa Sollievo della Sofferenzah Hospital | Carella M.,Unit of Medical Genetics | And 7 more authors.
Pancreas | Year: 2016

Adenocarcinomas of Vater's papilla (PVAC) may originate fromeither the pancreatic duct or the intestinal epithelium. Conflicting data have been reported about the frequency of the 2 anatomical entities and their influence on patients' prognosis. To ascertain the anatomical origin of PVAC in a family member of a Lynch syndrome kindred, we searched for microRNA (miRNA) expression profiles on resected tumor specimens. The support vector machine was trained on our previous miRNAs expression data sets of pancreatic and colorectal tissue samples and used to classify the site of origin of the tumor in our patient. The support vector machine worked by contrasting the profiles of miRNAs in patients with pancreatic ductal and colorectal cancers to that of our patient, which was finally classified as pancreatic ductal adenocarcinoma accordingly to alterations of 55 miRNAs. The PVAC might be originated from ductal epithelium rather than from the intestinal mucosa of the papilla in the case at issue. Alteration of miR-548b-3p, miR-551a, miR-21, miR-92a, miR-let-7i, and miR-181a∗ emerged as potentially associated with cancer genetic susceptibility in PVAC. © 2016 Wolters Kluwer Health, Inc. All rights reserved.


Casadei S.,University of Washington | Heikkinen T.,University of Helsinki | Pylkas K.,University of Oulu | Roberts J.,University of Cambridge | And 43 more authors.
New England Journal of Medicine | Year: 2014

BACKGROUND: Germline loss-of-function mutations in PALB2 are known to confer a predisposition to breast cancer. However, the lifetime risk of breast cancer that is conferred by such mutations remains unknown. METHODS: We analyzed the risk of breast cancer among 362 members of 154 families who had deleterious truncating, splice, or deletion mutations in PALB2. The age-specific breast-cancer risk for mutation carriers was estimated with the use of a modified segregation-analysis approach that allowed for the effects of PALB2 genotype and residual familial aggregation. RESULTS: The risk of breast cancer for female PALB2 mutation carriers, as compared with the general population, was eight to nine times as high among those younger than 40 years of age, six to eight times as high among those 40 to 60 years of age, and five times as high among those older than 60 years of age. The estimated cumulative risk of breast cancer among female mutation carriers was 14% (95% confidence interval [CI], 9 to 20) by 50 years of age and 35% (95% CI, 26 to 46) by 70 years of age. Breast-cancer risk was also significantly influenced by birth cohort (P < 0.001) and by other familial factors (P = 0.04). The absolute breast-cancer risk for PALB2 female mutation carriers by 70 years of age ranged from 33% (95% CI, 25 to 44) for those with no family history of breast cancer to 58% (95% CI, 50 to 66) for those with two or more first-degree relatives with breast cancer at 50 years of age. CONCLUSIONS: Loss-of-function mutations in PALB2 are an important cause of hereditary breast cancer, with respect both to the frequency of cancer-predisposing mutations and to the risk associated with them. Our data suggest the breast-cancer risk for PALB2 mutation carriers may overlap with that for BRCA2 mutation carriers. Copyright © 2014 Massachusetts Medical Society.


Varesco L.,Unit of Hereditary Cancer | Viassolo V.,Unit of Hereditary Cancer | Viel A.,Cancer Regional Center | Gismondi V.,Unit of Hereditary Cancer | And 18 more authors.
Breast | Year: 2013

Purpose: To evaluate in current practice the performance of BOADICEA and BRCAPRO risk models and empirical criteria based on cancer family history for the selection of individuals for BRCA genetic testing. Patients and methods: The probability of BRCA mutation according to the three tools was retrospectively estimated in 918 index cases consecutively undergone BRCA testing at 15 Italian cancer genetics clinics between 2006 and 2008. Results: 179 of 918 cases (19.5%) carried BRCA mutations. With the strict use of the criteria based on cancer family history 173 BRCA (21.9%) mutations would have been detected in 789 individuals. At the commonly used 10% threshold of BRCA mutation carrier probability, the genetic models showed a similar performance [PPV (38% and 37%), sensitivity (76% and 77%) and specificity (70% and 69%)]. Their strict use would have avoided around 60% of the tests but would have missed approximately 1 every 4 carriers. Conclusion: Our data highlight the complexity of BRCA testing referral in routine practice and question the strict use of genetic models for BRCA risk assessment. © 2013 Elsevier Ltd.


Loupakis F.,Unit of Medical Oncology 2 | Loupakis F.,Azienda Ospedaliero Pisana Instituto Toscano Tumori | Cremolini C.,Unit of Medical Oncology 2 | Salvatore L.,Unit of Medical Oncology 2 | And 15 more authors.
European Journal of Cancer | Year: 2014

Background BRAF V600E mutation plays a negative prognostic role in metastatic colorectal cancer (mCRC), leading to a median Progression Free Survival (PFS) of 4-6 months with first-line conventional treatments. Our group recently reported in a retrospective exploratory analysis of a phase II trial that FOLFOXIRI (5-FU/LV+Oxaliplatin+Irinotecan) plus bevacizumab might allow to achieve remarkable results in terms of PFS and Overall Survival (OS) also in this poor-prognosis subgroup. The aim of this work was to prospectively validate our retrospective finding. Patients and methods This phase II trial was designed to detect an increase in 6 month-Progression Free Rate (6 m-PFR) from 45% to 80% in a population of BRAF mutant mCRC patients treated with first-line FOLFOXIRI plus bevacizumab. Secondary end-points were PFS, OS, response rate (RR) and the analysis of outcome parameters in the pooled population consisting of both retrospectively and prospectively included patients. This trial is registered with ClinicalTrials.gov, number NCT01437618. Results Two-hundred-fourteen potentially eligible mCRC patients were screened for BRAF mutational status. Fifteen BRAF mutant patients (7%) were included in the validation cohort. At a median follow up of 25.7 months, 6 m-PFR was 73%. Median PFS and OS were 9.2 and 24.1 months, respectively. In the pooled population, at a median follow up of 40.4 months, 6 m-PFR was 84%. Median PFS and OS were 11.8 and 24.1 months, respectively. Overall RR and disease control rate were 72% and 88%, respectively. Conclusion Lacking randomised trials in this specific molecular subgroup, FOLFOXIRI plus bevacizumab might be a reasonable option for the first-line treatment of BRAF mutant mCRC patients. © 2013 Elsevier Ltd. All rights reserved.


Nicoloso M.S.,University of Texas M. D. Anderson Cancer Center | Sun H.,Chinese University of Hong Kong | Sun H.,Wistar Institute | Spizzo R.,University of Texas M. D. Anderson Cancer Center | And 16 more authors.
Cancer Research | Year: 2010

Single-nucleotide polymorphisms (SNP) associated with polygenetic disorders, such as breast cancer (BC), can create, destroy, or modify microRNA (miRNA) binding sites; however, the extent to which SNPs interfere with miRNA gene regulation and affect cancer susceptibility remains largely unknown. We hypothesize that disruption of miRNA target binding by SNPs is a widespread mechanism relevant to cancer susceptibility. To test this, we analyzed SNPs known to be associated with BC risk, in silico and in vitro, for their ability to modify miRNA binding sites and miRNA gene regulation and referred to these as target SNPs. We identified rs1982073-TGFB1 and rs1799782-XRCC1 as target SNPs, whose alleles could modulate gene expression by differential interaction with miR-187 and miR-138, respectively. Genome-wide bioinformatics analysis predicted ∼64% of transcribed SNPs as target SNPs that can modify (increase/decrease) the binding energy of putative miRNA::mRNA duplexes by >90%. To assess whether target SNPs are implicated in BC susceptibility, we conducted a case-control population study and observed that germline occurrence of rs799917-BRCA1 and rs334348-TGFR1 significantly varies among populations with different risks of developing BC. Luciferase activity of target SNPs, allelic variants, and protein levels in cancer cell lines with different genotypes showed differential regulation of target genes following overexpression of the two interacting miRNAs (miR-638 and miR-628-Sp). Therefore, we propose that transcribed target SNPs alter miRNA gene regulation and, consequently, protein expression, contributing to the likelihood of cancer susceptibility, by a novel mechanism of subtle gene regulation. ©2010 American Association for Cancer Research.


Yang X.R.,U.S. National Institutes of Health | Chang-Claude J.,Institute of Cancer Research | Goode E.L.,German Cancer Research Center | Nevanlinna H.,Mayo Medical School | And 128 more authors.
Journal of the National Cancer Institute | Year: 2011

Background Previous studies have suggested that breast cancer risk factors are associated with estrogen receptor (ER) and progesterone receptor (PR) expression status of the tumors. Methods We pooled tumor marker and epidemiological risk factor data from 35568 invasive breast cancer case patients from 34 studies participating in the Breast Cancer Association Consortium. Logistic regression models were used in case-case analyses to estimate associations between epidemiological risk factors and tumor subtypes, and case-control analyses to estimate associations between epidemiological risk factors and the risk of developing specific tumor subtypes in 12 population-based studies. All statistical tests were two-sided. Results In case-case analyses, of the epidemiological risk factors examined, early age at menarche (≤12 years) was less frequent in case patients with PR- than PR+ tumors (P =. 001). Nulliparity (P = 3 × 10 -6) and increasing age at first birth (P = 2 × 10-9) were less frequent in ER- than in ER+ tumors. Obesity (body mass index [BMI] ≥ 30 kg/m2) in younger women (≤50 years) was more frequent in ER-/PR- than in ER +/PR+ tumors (P = 1 × 10-7), whereas obesity in older women (>50 years) was less frequent in PR- than in PR+ tumors (P = 6 × 10-4). The triple-negative (ER-/PR-/HER2-) or core basal phenotype (CBP; triple-negative and cytokeratins [CK]5/6+ and/or epidermal growth factor receptor [EGFR]+) accounted for much of the heterogeneity in parity-related variables and BMI in younger women. Case-control analyses showed that nulliparity, increasing age at first birth, and obesity in younger women showed the expected associations with the risk of ER+ or PR + tumors but not triple-negative (nulliparity vs parity, odds ratio [OR] = 0.94, 95% confidence interval [CI] = 0.75 to 1.19, P =. 61; 5-year increase in age at first full-term birth, OR = 0.95, 95% CI = 0.86 to 1.05, P =. 34; obesity in younger women, OR = 1.36, 95% CI = 0.95 to 1.94, P =. 09) or CBP tumors. Conclusion sThis study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology. © 2011 The Author.

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