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Italy has a monitoring system for genetic testing, consisting in a periodic census of clinical and laboratory activities performed in the country. The experience is limited, however, concerning the translation of genomic testing for complex diseases into clinical practice. For the first time the Italian Ministry of Health has introduced a policy strategic plan on genomics and predictive medicine within the 2010–2012 National Prevention Plan. This achievement was supported by the Italian Network for Public Health Genomics (GENISAP) and will likely contribute to the integration of public health genomics into health care in the country. Our experience might be of interest not only in Italy, but in other high-income countries, struggling to keep a healthy economy and healthy citizens.

Contains fulltext : 70182.pdf (Publisher’s version ) (Closed access) Genetic testing often results in the finding of a variant whose clinical significance is unknown. A number of different approaches have been employed in the attempt to classify such variants. For some variants, case-control, segregation, family history, or other statistical studies can provide strong evidence of direct association with cancer risk. For most variants, other evidence is available that relates to properties of the protein or gene sequence. In this work we propose a Bayesian method for assessing the likelihood that a variant is pathogenic. We discuss the assessment of prior probability, and how to combine the various sources of data into a statistically valid integrated assessment with a posterior probability of pathogenicity. In particular, we propose the use of a two-component mixture model to integrate these various sources of data and to estimate the parameters related to sensitivity and specificity of specific kinds of evidence. Further, we discuss some of the issues involved in this process and the assumptions that underpin many of the methods used in the evaluation process.

Mutation-predicting models can be useful when deciding on the genetic testing of individuals at risk and in determining the cost effectiveness of screening strategies at the population level. The aim of this study was to evaluate the performance of a newly developed genetic model that incorporates tumor microsatellite instability (MSI) information, called the AIFEG model, and in predicting the presence of mutations in MSH2 and MLH1 in probands with suspected hereditary non-polyposis colorectal cancer. The AIFEG model is based on published estimates of mutation frequencies and cancer penetrances in carriers and non-carriers and employs the program MLINK of the FASTLINK package to calculate the proband's carrier probability. Model performance is evaluated in a series of 219 families screened for mutations in both MSH2 and MLH1, in which 68 disease-causing mutations were identified. Predictions are first obtained using family history only and then converted into posterior probabilities using information on MSI. This improves predictions substantially. Using a probability threshold of 10% for mutation analysis, the AIFEG model applied to our series has 100% sensitivity and 71% specificity.

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Head and neck squamous cell carcinomas (SCCs) seem to follow a multistep process of carcinogenesis in which chemical and/or viral agents are associated with specific genetic alterations. The prevalence of human papillomavirus (HPV) infection and the amplification of the cyclin D1 (CCND1) gene were evaluated in a series of 75 laryngeal SCCs by PCR with HPV consensus primers and Southern blot analysis with a CCND1-specific probe, respectively. HPV DNA was detected in 22 of 75 (29.3%) tumors, and it belonged almost exclusively to the highly oncogenic HPV-16, HPV-18, and HPV-33. CCND1 gene amplification was found in 15 of 75 (20%) tumors, and it was associated with HPV infection in a statistically significant manner (chi2 = 20.3; P0.001). Because the viral oncoproteins E6 and E7 from high-risk HPV types are known to promote genomic rearrangements, these findings suggest that amplification of the CCND1 gene in laryngeal SCCs may occur as a consequence of the genomic instability associated with HPV infection. In turn, amplified CCND1, either alone or in conjunction with a direct action of the viral oncoproteins E6 and E7, could lead to a perturbation of the cell cycle. This model could explain the involvement of high-risk HPV types in laryngeal carcinogenesis.

Background Multiple myeloma (MM) is the most relevant hematologic tumor in the elderly population. Median age at diagnosis is 70 years; 37% of patients are older than 75 years and 30% of patients present at diagnosis at least one co-morbid condition. The introduction of novel agents, bortezomib, thalidomide and lenalidomide, have changed the treatment paradigm of elderly MM, but side effects are frequent and full-drug doses less tolerated. Up to 90% of at least one serious adverse event (AE), with a subsequent 40% of drug discontinuation has been reported. Aims. A retrospective analysis evaluating 1435 individual patient data from 4 European phase III trials was conducted. We analyzed the impact of age, organ damage, treatment-related AEs and drug discontinuation as predictors of outcome. Methods. Patients with newly diagnosed MM, not eligible for autologous transplantation due to age (≥65 years) or co-morbidities, received melphalan-prednisone (MP), MP-thalidomide (MPT), MP-bortezomib (VMP), bortezomib-thalidomide-prednisone (VTP) or VMP-thalidomide (VMPT). Patients enrolled in the GISMM-2001 MP vs. MPT (331 patients), HOVON 49 MP vs. MPT (333 patients), GEM05MAS VMP vs. VTP (260 patients) and GIMEMA MM0305 VMP vs. VMPT (511 patients) trials were included in this meta-analysis. Trials were registered at ClinicalTrials.gov or controlled-trials.com. Results. Of the 1435 patients analysed, 332 did not receive novel agents (MP), 332 received thalidomide (MPT), 387 bortezomib (VMP), 384 thalidomide and bortezomib (VTP/ VMPT). Patients ≥75 years were 36%, equally distributed in the 4 groups. The proportion of patients with ISS III was lower in the MP group; renal failure was higher in the MP and MPT groups, due to less stringent selection of these protocols. The incidence of any grade 3-4 non-hematologic AEs was 29%, higher in MPT (43%) compared with VMP (24%) or VTP/VMPT (32%) groups. The most frequent were infections (10%), peripheral neuropathy (8%), cardiac (6%) and gastro-intestinal complications (5%). Drug discontinuation for toxicity was 27%, higher in MPT (35%) compared with VMP (16%) or VTP/VMPT (29%) groups.After a median follow-up of 33 months (95% Confidence Interval [CI] 10-56 months), 513/1435 patients (36%) died, the median overall survival was 50 months (95% CI 46-60 months). The causes of death were disease progression (76%) and toxic effects (24%), mainly infections, cardiac complications, second primary malignancies, and venous thromboembolism. The risk of death was increased in patients ≥75 years (Hazard Ratio [HR] 1.44, 95% CI 1.20-1.72, P

Aims and Background Colorectal carcinoma patients from hereditary non-polyposis colorectal cancer families are suggested to have a better prognosis than sporadic colorectal carcinoma cases. Since the majority of hereditary non-polyposis colorectal cancer-related colorectal carcinomas are characterized by microsatellite instability due to germline mutations in DNA mismatch repair genes, this is consistent with the prolonged survival observed in sporadic microsatellite instability-positive colorectal carcinoma compared to microsatellite stable cases. However, a fraction of colorectal carcinoma cases belongs to families that, despite fulfilling the clinical criteria for hereditary non-polyposis colorectal cancer, do not carry mismatch repair gene mutations. Our aim was to verify to what extent the genotypic heterogeneity influences the prognosis of hereditary non-polyposis colorectal cancer patients. Methods A survival analysis was performed on 526 colorectal carcinoma cases from 204 Amsterdam Criteria-positive hereditary non-polyposis colorectal cancer families. Enrolled cases were classified as MLH1-positive, MSH2-positive and mutation-negative, according to the results of genetic testing in each family. Results Five-year survival rates were 0.73 (95% CI, 0.66-0.80), 0.75 (95% CI, 0.66-0.84) and 0.62 (95% CI, 0.55-0.68) for MLH1-positive, MSH2-positive and mutation-negative groups, respectively (logrank test, P = 0.01). Hazard ratio, computed using Cox regression analysis and adjusted for age, sex, tumor site and stage, was 0.71 (95% CI, 0.51-0.98) for the mutation-positive compared to the mutation-negative group. Moreover, in the latter group, patients with microsatellite instability-positive colorectal carcinomas showed a better outcome than microsatellite stable cases (5-year survival rates, 0.81 and 0.60, respectively; logrank test, P = 0.006). Conclusions Our results suggest that the prognosis of hereditary non-polyposis colorectal cancer-related colorectal carcinoma patients depends on the associated constitutional mismatch repair genotype.

Mutations of the mismatch repair (MMR) genes MLH1 and MSH2 are associated with hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant autosomal dominant condition characterized by hypermutability of short tandemly repeated sequences in tumor DNA. Mutations of another MMR gene, MSH6, seem to be less common than MLH1 and MSH2 defects, and have been mostly observed in atypical HNPCC families, characterized by a weaker tumor family history, higher age at disease onset, and low degrees of microsatellite instability (MSI), predominantly involving mononucleotide runs. We have investigated the MSH6 gene sequence in the peripheral blood of 4 HNPCC and 20 atypical HNPCC probands. Two frameshift mutations within exon 4 were detected in 2 patients. One mutation was found in a proband from a typical HNPCC family, who had developed a colorectal cancer (CRC), a gastric cancer and a rectal adenoma. The CRC and the adenoma showed mild MSI limited to mononucleotide tracts, while the gastric carcinoma was microsatellite stable. The other mutation was detected in an atypical HNPCC proband, whose CRC showed widespread MSI involving both mono- and dinucleotide repeats. The phenotypic variability associated with MSH6 constitutional mutations represents a complicating factor for the optimization of strategies aimed at identifying candidates to MSH6 genetic testing.

BACKGROUND: Homologous recombination repair (HRR) enables fault-free repair of double-stranded DNA breaks. HRR deficiency is predicted to occur in around half of high-grade serous ovarian carcinomas. Ovarian cancers harbouring HRR deficiency typically exhibit sensitivity to poly-ADP ribose polymerase inhibitors (PARPi). Current guidelines recommend a range of approaches for genetic testing to identify predictors of sensitivity to PARPi in ovarian cancer and to identify genetic predisposition. DESIGN: To establish a European-wide consensus for genetic testing (including the genetic care pathway), decision making and clinical management of patients with recently diagnosed advanced ovarian cancer, and the validity of biomarkers to predict the effectiveness of PARPi in the first-line setting. The collaborative European experts' consensus group consisted of a steering committee (n = 14) and contributors (n = 84). A (modified) Delphi process was used to establish consensus statements based on a systematic literature search, conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. RESULTS: A consensus was reached on 34 statements amongst 98 caregivers (including oncologists, pathologists, clinical geneticists, genetic researchers, and patient advocates). The statements concentrated on (i) the value of testing for BRCA1/2 mutations and HRR deficiency testing, including when and whom to test; (ii) the importance of developing new and better HRR deficiency tests; (iii) the importance of germline non-BRCA HRR and mismatch repair gene mutations for predicting familial risk, but not for predicting sensitivity to PARPi, in the first-line setting; (iv) who should be able to inform patients about genetic testing, and what training and education should these caregivers receive. CONCLUSION: These consensus recommendations, from a multidisciplinary panel of experts from across Europe, provide clear guidance on the use of BRCA and HRR deficiency testing for recently diagnosed patients with advanced ovarian cancer. ispartof: ANNALS OF ONCOLOGY vol:33 issue:3 pages:276-287 ispartof: location:England status: published

Genomic testing expansion is accompanied by an increasing need for genetic counselling and intrafamilial communication. Genetic counselling can play an important role in facilitating intrafamilial communication and relationships. We conducted a cross-sectional, multicenter study including 252 Italian women, using a questionnaire divided in two sections, the first one to be filled after the pre-test counselling and the second after receiving BRCA test results. We assessed the factors influencing intrafamilial disclosure of genetic information for hereditary breast and ovarian cancer, family members with whom probands are more prone to share genetic information, and the perceived understanding of information received by counselees during genetic counselling. Women were accompanied to the counselling more often by their husband/partner. Among those with a positive BRCA test result, 49% intended to communicate it to their offspring and 27% to their husband/partner. Younger women, those living with their husband/partner, and those who described family communication as open/profound and spontaneous/sincere had a higher probability of being accompanied during genetic counselling and discuss about it with relatives. Spontaneous/sincere or open/profound family communication and joyful/happy familial relationships were associated with the decision to undergo genetic testing as a responsibility towards relatives. Women had a good understanding of counselling contents (mean score 9.27 in a scale 1-10). Genetic counselling providers should consider that genetic information disclosure does not depend only on the clarity of the information provided, but also on pre-existing intrafamilial communication and relationships, family structure and marital status, indicating the need for a personalised approach accounting for these factors.

This multicenter, open-label phase 2 trial determined the safety and efficacy of carfilzomib, a novel and irreversible proteasome inhibitor, in combination with cyclophosphamide and dexamethasone (CCyd) in patients with newly diagnosed multiple myeloma (NDMM) ≥65 years of age or who were ineligible for autologous stem cell transplantation. Patients (N 5 58) received CCyd for up to 9 28-day cycles, followed by maintenance with carfilzomib until progression or intolerance. After a median of 9 CCyd induction cycles (range 1-9), 95% of patients achieved at least a partial response, 71% achieved at least a very good partial response, 49% achieved at least a near complete response, and 20% achieved stringent complete response. After a median follow-up of 18 months, the 2-year progression-free survival and overall survival rates were 76% and 87%, respectively. The most frequent grade 3 to 5 toxicities were neutropenia (20%), anemia (11%), and cardiopulmonary adverse events (7%). Peripheral neuropathy was limited to grades 1 and 2 (9%). Fourteen percent of patients discontinued treatment because of adverse events, and 21% of patients required carfilzomib dose reductions. In summary, results showed high complete response rates and a good safety profile. This trial was registered at clinicaltrials.gov as #NCT01346787. © 2014 by The American Society of Hematology.

Objectives The risk of uniparental disomy (UPD) occurrence associated with the prenatal finding of balanced nonhomologous Robertsonian translocations (NHRTs) has been estimated only on limited empirical data. The aim of the study was to verify the estimate of the general risk, to get narrower confidence intervals by cumulating the data and to obtain risk estimates for specific translocation types. Methods We tested for UPD 160 prenatal specimens referred to the participant centers after the cytogenetic finding of NHRT. Results One case of upd(14)mat was found, associated with a 45,XX,der(14;22)mat fetal karyotype. The general empirical risk of UPD occurrence in NHRT carrier fetuses, corrected for the actual number of chromosomes analyzed, was 0.76% (95% CI 0.02–4.25%). Cumulative data with previous studies gives a general risk of UPD associated with NHRT of 0.80% (95% CI 0.17–2.34%). The UPD risk for the specific NHRT der(13;14) did not significantly differ from that of the other NHRTs taken together. Conclusion The present survey confirms the previously estimated risk of occurrence of UPD in offspring of NHRT carriers as a low, but not negligible risk, worth being investigated in prenatal diagnosis. Copyright © 2004 John Wiley & Sons, Ltd.

Creutzfeldt-Jakob disease (CJD) is a transmissible neurodegenerative disorder characterized by the accumulation of the amyloid protein PrP in the CNS. Two coding polymorphisms of the PrP gene (PRNP) are a methionine (Met) to valine (Val) change at codon 129, and a deletion in the octapeptide coding region. In the United Kingdom, homozygosity at codon 129 appears to be associated with a predisposition to develop CJD. However, in Japan, where allelic frequencies and genotype distribution are significantly different, such an association has not been demonstrated. To determine whether such deletion(s) or codon 129 polymorphisms of PRNP predispose to the development of CJD in Italian patients, 31 sporadic CJD patients with no known PRNP mutations, and 186 unrelated control subjects were studied. Genotypic frequencies at codon 129 in these Italian CJD patients revealed a significant excess of methionine alleles, and a different genotype distribution in comparison with the normal Italian population. Deletions of a 24-bp segment located in the PrP octapeptide coding region were found in two control subjects, but in none of the sporadic CJD patients. These data suggest that Met homozygosity at codon 129 may contribute, with other environmental or endogenous factors, to CJD development.