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P Radice

Publications and source records attributed to P Radice.

At least 19 recordsLinked to original sources
PubMed2006

Methyl group metabolism gene polymorphisms as modifier of breast cancer risk in Italian BRCA1/2 carriers.

BRCA1 and 2 are major cancer susceptibility genes but their penetrance is highly variable. The folate metabolism plays an important role in DNA methylation and its alterated metabolism is associated with cancer risk. The role of allele variants 677T and 1298C (MTHFR gene) and 2756G (MS gene) has been investigated as potentially modifying factors of BRCA gene penetrance, evaluated as age at first diagnosis of cancer, in 484 BRCA1/BRCA2 carriers and in 108 sporadic breast cancer cases as a control group. The genotype analysis has been performed by means of PCR/RFLP's. The analysis of association between a particular genotype and disease risk was performed using Cox Regression with time to breast or ovarian cancer onset as the end-point. The presence of 677T allele confers an increased risk of breast cancer in BRCA1 carriers (P = 0.007) and the presence of 1298C allele confers an increased risk of breast cancer in sporadic cases (P = 0.015).

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed2005

Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies.

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.

Adult↗
PubMed2005

Classification of BRCA1 missense variants of unknown clinical significance.

BACKGROUND: BRCA1 is a tumour suppressor with pleiotropic actions. Germline mutations in BRCA1 are responsible for a large proportion of breast-ovarian cancer families. Several missense variants have been identified throughout the gene but because of lack of information about their impact on the function of BRCA1, predictive testing is not always informative. Classification of missense variants into deleterious/high risk or neutral/low clinical significance is essential to identify individuals at risk. OBJECTIVE: To investigate a panel of missense variants. METHODS AND RESULTS: The panel was investigated in a comprehensive framework that included (1) a functional assay based on transcription activation; (2) segregation analysis and a method of using incomplete pedigree data to calculate the odds of causality; (3) a method based on interspecific sequence variation. It was shown that the transcriptional activation assay could be used as a test to characterise mutations in the carboxy-terminus region of BRCA1 encompassing residues 1396-1863. Thirteen missense variants (H1402Y, L1407P, H1421Y, S1512I, M1628T, M1628V, T1685I, G1706A, T1720A, A1752P, G1788V, V1809F, and W1837R) were specifically investigated. CONCLUSIONS: While individual classification schemes for BRCA1 alleles still present limitations, a combination of several methods provides a more powerful way of identifying variants that are causally linked to a high risk of breast and ovarian cancer. The framework presented here brings these variants nearer to clinical applicability.

Adolescent↗
PubMed2004

Putative common origin of two MLH1 mutations in Italian-Quebec hereditary non-polyposis colorectal cancer families.

Hereditary non-polyposis colorectal cancer (HNPCC) is one of the most common inherited cancer syndromes, accounting for 3-5% of all cases of colorectal cancer. In most HNPCC families, the disease is caused by a germline mutation in MLH1 or MSH2. In some populations, founder mutations appear to explain a substantial fraction of HNPCC. We report here the identification and preliminary characterization of two putative MLH1 founder mutations. The mutation MLH1c.1831delAT was shown to segregate in two Quebec families of Italian origin who fulfilled the Amsterdam criteria for HNPCC. Haplotype analysis using five intragenic microsatellite/single nucleotide polymorphism markers spanning MLH1 on chromosome 3 showed that these two unrelated families share an identical haplotype. In addition, two other Italian kindred whose affected members carry MLH1g.IVS6 + 3A>G also share a common haplotype, suggesting that, similarly, the latter mutation has a common origin. These mutations are the first putative founder MLH1 mutations to be identified in HNPCC kindred of Italian origin.

Adaptor Proteins, Signal Transducing↗
PubMed2003

Multiple approach to the exploration of genotype-phenotype correlations in familial adenomatous polyposis.

PURPOSE: Familial adenomatous polyposis (FAP), caused by a mutation in the APC gene, is a colorectal cancer predisposition syndrome associated with several other clinical conditions. The severity of the FAP is related to the position of the inherited mutation in the APC gene. We analyzed a large series of FAP patients to identify associations among major clinical manifestations and to correlate the mutation site with specific disease manifestations. MATERIALS AND METHODS: APC mutations were identified in 953 FAP patients from 187 families. We used unconditional logistic regression models and a method involving generalized estimating equations to investigate the association between genotype and phenotype. We used multiple correspondence analysis to represent the interrelationships of a multiway contingency table of the considered variables. RESULTS: APC germline mutations were located between codons 156 and 2011 of the APC gene. Mutations spanning the region between codons 543 and 1309 were variable, but strongly associated with congenital hypertrophy of retinal pigment epithelium. Mutations between codons 1310 and 2011 were associated with a six-fold risk of desmoid tumors relative to the low-risk reference region (159 to 495). Mutations at codon 1309 were associated with early development of colorectal cancer. Mutations between codons 976 and 1067 were associated with a three- to four-fold increased risk of duodenal adenomas. The cumulative frequency of extracolonic manifestations was highest for mutations between codons 976 and 1067, followed by mutations between 1310 and 2011. CONCLUSION: Analysis of the relation between APC mutation site and phenotype identifies subgroups of FAP patients at high risk for major extracolonic disease, which is useful for surveillance and prevention.

Adenoma↗
PubMed2003

Average risks of breast and ovarian cancer associated with BRCA1 or BRCA2 mutations detected in case Series unselected for family history: a combined analysis of 22 studies.

Germline mutations in BRCA1 and BRCA2 confer high risks of breast and ovarian cancer, but the average magnitude of these risks is uncertain and may depend on the context. Estimates based on multiple-case families may be enriched for mutations of higher risk and/or other familial risk factors, whereas risk estimates from studies based on cases unselected for family history have been imprecise. We pooled pedigree data from 22 studies involving 8,139 index case patients unselected for family history with female (86%) or male (2%) breast cancer or epithelial ovarian cancer (12%), 500 of whom had been found to carry a germline mutation in BRCA1 or BRCA2. Breast and ovarian cancer incidence rates for mutation carriers were estimated using a modified segregation analysis, based on the occurrence of these cancers in the relatives of mutation-carrying index case patients. The average cumulative risks in BRCA1-mutation carriers by age 70 years were 65% (95% confidence interval 44%-78%) for breast cancer and 39% (18%-54%) for ovarian cancer. The corresponding estimates for BRCA2 were 45% (31%-56%) and 11% (2.4%-19%). Relative risks of breast cancer declined significantly with age for BRCA1-mutation carriers (P trend.0012) but not for BRCA2-mutation carriers. Risks in carriers were higher when based on index breast cancer cases diagnosed at <35 years of age. We found some evidence for a reduction in risk in women from earlier birth cohorts and for variation in risk by mutation position for both genes. The pattern of cancer risks was similar to those found in multiple-case families, but their absolute magnitudes were lower, particularly for BRCA2. The variation in risk by age at diagnosis of index case is consistent with the effects of other genes modifying cancer risk in carriers.

Adult↗
PubMed2002

Prevalence of the E1317Q variant of the APC gene in Italian patients with colorectal adenomas.

Loss of APC is an initial, rate-limiting event in inherited and sporadic colorectal tumorigenesis. Rare germline APC mutations have been identified in patients with multiple colorectal adenomas. Recently, the E1317Q APC variant has been associated with a predisposition to the development of multiple colorectal adenomas. In this study, the prevalence of the E1317Q variant was examined in 182 patients with single or multiple colorectal adenomas, and in 235 controls. In all, E1317Q was identified in two of 182 patients with adenomatous polyps (1.1%) and in two of 235 controls (0.8%) (p = 0.59). The risk of harboring adenoma(s) among subjects bearing the E1317Q variant was 1.29 (95% CI 0.09-18.0). No difference in the prevalence of E1317Q between cases with single (2.0%) or multiple colorectal adenomas (0.7%) and controls (0.8%) was found. None of the subjects with a family history of colorectal cancer carried the E1317Q variant. In conclusion, our results confirm that only a very small fraction of colorectal adenomas may be associated with the presence of E1317Q.

Adenoma↗
PubMed2002

Mutations of BRCA genes in hereditary breast and ovarian cancer.

BRCA1 and BRCA2 are the main genetic elements associated with hereditary susceptibility to breast and ovarian cancer that have been isolated to date. DNA analysis can identify carriers of mutations in these genes, who, accordingly, can benefit by adequate clinical programs for the reduction of cancer risk. Unfortunately, the analysis is complicated by the complexity of associated mutation spectra. The procedure for mutation testing in BRCA genes and its limitations are discussed.

Breast Neoplasms↗
PubMed2001

Detection of germline BRCA1 mutations by Multiple-Dye Cleavase Fragment Length Polymorphism (MD-CFLP) method.

We describe the Multiple-Dye Cleavase Fragment Length Polymorphism (MD-CFLP) method set up for a sensitive and preliminary rapid screening of BRCA1 mutations. We analysed exons 11 and 16, which are known to cover slightly more than 70% of the whole coding region of the gene, subdivided into 4 amplicons and labelled with different fluorescent dUTPs. MD-CFLP was first utilised on a panel of 30 DNA samples in which the presence of single-base substitutions or small deletions/insertions had been previously identified by direct sequencing as gold standard, in order to define the optimal conditions in terms of PCR amplification and temperature of digestion. In a second step, we blindly analysed 21 DNA samples by MD-CFLP to verify its reliability. The sensitivity and specificity of MD-CFLP were both 100% in the first study, and 80% and 94%, respectively, in the blind sample assay. Our results demonstrate the capability of the MD-CFLP method to detect DNA sequence alterations in fragments of more than 1 kb. We conclude that CFLP is a powerful tool in mutational analysis, offering reliable results in a shorter time and at a lower cost than conventional methods, and its potential can be enhanced when internal fluorescent labelling and laser detection are used.

BRCA1 Protein↗
PubMed2001

Genotype and phenotype factors as determinants of desmoid tumors in patients with familial adenomatous polyposis.

Desmoids represent the most important cause of death, after colorectal cancer, in patients affected with familial adenomatous polyposis (FAP), an inherited disease due to mutations in the APC gene. The aims of our study were to estimate the risk of developing desmoids in FAP patients and to evaluate the association between desmoids and different risk factors. The occurrence of desmoids, colorectal cancer and other extra-colonic manifestations were assessed in 897 FAP patients, 653 of whom were also investigated for APC mutations. Odds ratios (OR) and corresponding 95% confidence intervals (CI) were computed using an unconditional multiple logistic regression model. Desmoids developed in 107 patients (11.9%), with a cumulative risk of 20.6%. Females had a significantly higher risk than males (OR = 2.1; 95% CI 1.4-3.1). Family history of desmoids (OR = 8.75; 95% CI 5.66-13.51), osteomas (OR = 2.9; 95% CI 1.8-4.8) and epidermoid cysts (OR = 1.8; 95% CI 1.1-3.2) was also significantly associated with the occurrence of disease. Subjects with APC mutations beyond codon 1444 had a 12-fold increased risk, compared with patients with mutations located upstream. Mutations beyond codon 1309 conferred a 17-fold higher risk, compared with mutations upstream codon 452. Multivariate analysis identified as independent predictors mutation beyond codon 1444 (OR = 6.2; 95% CI 2.5-15.8), family history of desmoids (OR = 5.8; 95% CI 3.1-10.6), female gender (OR = 2.1; 95% CI 1.1-3.8) and the presence of osteomas (OR = 1.9; 95% CI 1.1-3.4). Our results indicate that integrating genetic and clinical data is helpful in defining subgroups of patients at higher risk for desmoids, who may benefit from specific prevention programs.

Adenomatous Polyposis Coli↗
PubMed2001

Refinement within single yeast artificial chromosome clones of a minimal region commonly deleted on the short arm of chromosome 7 in Wilms tumours.

Cytogenetic and molecular data indicate an involvement of genes mapped to the proximal portion of the short arm of chromosome 7 (7p) in Wilms tumours (WTs). We have analysed 38 WTs using a panel of eight microsatellite markers mapped to proximal 7p. Loss of heterozygosity (LOH) in tumour, compared with matched constitutional DNA, was identified in eight cases. To define better the minimal region commonly deleted in these tumours, they were analysed with nine additional markers, mapped within the region of interest. One tumour (case 30) showed LOH for only one marker (D7S510), while maintaining heterozygosity for the two immediately flanking loci (D7S555 and D7S668). This result was confirmed by fluorescence in situ hybridisation analysis, which showed that in the majority (65%) of nuclei from tumour 30 hybridising with a bacterial artificial chromosome clone containing the D7S510 locus, only one signal was visible. Noticeably, both markers defining the limits of the observed deleted region are simultaneously present within two distinct overlapping yeast artificial chromosome (YAC) clones mapped to chromosome bands 7p13-p14. This suggests that the maximum length of the missing DNA fragment was approximately 1.3 Mb, corresponding to the length of the smaller of the two YAC clones. In all other cases that showed LOH, the deletion encompassed the 7p13-p14 region. For this reason, we speculate that the identified interval contains a gene whose inactivation is important for the development of at least a fraction of WTs.

Child↗
PubMed2001

Evidence of a founder mutation of BRCA1 in a highly homogeneous population from southern Italy with breast/ovarian cancer.

Several genes have been involved in the pathogenesis of hereditary breast/ovarian cancer (BOC), but mutations in the BRCA1 gene are by far the most recurrent. In this study, we report the identification of a founder mutation in a geographically and historically homogeneous population from Calabria, a south Italian region. A screening performed on 24 patients from unrelated families highlighted the high prevalence of a 5083del19 alteration in the BRCA1 gene, which accounts for 33% of the overall gene mutations. The same mutation was also detected in 4 patients, all of Calabrian origin, referred to us by research centres from the north of Italy. Allelotype analysis, performed on probands and unaffected family members revealed the presence a common allele, therefore suggesting a founder effect due to a common ancestor. Our findings underscore the importance of ethnic background homogeneity in patients' selection and highlight the usefulness of founder mutations as a potential tool for optimisation of preclinical diagnosis in gene carriers and therapeutic approaches in affected individuals.

Adult↗
PubMed2000

A novel zinc finger gene is fused to EWS in small round cell tumor.

Ewing sarcoma family of tumors share recurrent translocations that fuse EWS from 22q12 to five different members of transcription factors namely FLI-1, ERG, ETV1, E1AF and FEV. Different classes of DNA binding proteins, ATF1, WT1 and CHOP are fused to EWS generating distinct tumor phenotypes: clear cell sarcoma, desmoplastic small round cell tumor, and myxoid liposarcoma, respectively. We have cloned a novel gene located at 22q12 fused to EWS by a submicroscopic inversion of 22q in a small round cell sarcoma showing a translocation (t(1;22)(p36.1;q12). The gene, designated ZSG (Zinc finger Sarcoma Gene), is a putative Cys2-His2 zinc finger protein which contains a POZ transcriptional repressor-like domain at the N-terminus. The rearrangement involves intron 8 of EWS and exon 1 of ZSG creating a chimeric sequence containing the transactivation domain of EWS fused to zinc finger domain of ZSG. This product lacks the transcriptional repressor domain at the N-terminus of ZSG. A rearrangement of the second ZSG allele was also found in tumor cells. This is the first example of an intra-chromosomal rearrangement of chromosome 22, undetectable by cytogenetics, activating EWS in soft tissue sarcoma.

Adolescent↗
PubMed2000

Microsatellite instability in colorectal-cancer patients with suspected genetic predisposition.

Hereditary non-polyposis colorectal cancer (HNPCC) is a dominantly inherited syndrome linked to DNA-mismatch-repair (MMR) gene defects, which also account for microsatellite instability (MSI) in tumour tissues. Diagnosis is based mainly on family history, according to widely accepted criteria (Amsterdam Criteria: AC). Aim of this work was to assess MSI in colorectal-cancer patients with suspected genetic predisposition, and to verify whether MSI represents a tool to manage MMR gene (hMSH2 and hMLH1) mutation analysis. We investigated 13 microsatellites (including the 5 NCI/ICG-HNPCC markers) in 45 patients with suspected hereditary predisposition (including 16 subjects from HNPCC families fulfilling the AC). We found MSI-H (high frequency of instability, i.e., in > or =30% of the markers) in 85% of the HNPCC patients and in 16% of the non-HNPCC subjects. The 5 NCI/ICG-HNPCC microsatellites proved to be the most effective in detecting MSI, being mononucleotide repeats the most unstable markers. We investigated the association between hMSH2- and hMLH1 gene mutations and MSI. Our results indicate that AC are highly predictive both of tumour instability and of MMR-gene mutations. Therefore, as the most likely mutation carriers, HNPCC subjects might be directly analyzed for gene mutations, while to test for MSI in selected non-HNPCC patients and to further investigate MMR genes in MSI-H cases, appears to be a cost-effective way to identify subjects, other than those from kindred fulfilling AC, who might benefit from genetic testing.

Adult↗
PubMed2000

Genotype and phenotype factors as determinants for rectal stump cancer in patients with familial adenomatous polyposis. Hereditary Colorectal Tumors Registry.

OBJECTIVE: To identify factors influencing the occurrence of cancer in the rectal remnant in patients with familial adenomatous polyposis (FAP) after colectomy and ileorectal anastomosis (IRA). SUMMARY BACKGROUND DATA: The risk for rectal cancer in patients with FAP after colectomy and IRA remains a major concern. METHODS: Between 1955 and 1997, 371 patients (206 men, 165 women) from the Registry of Hereditary Colorectal Tumors underwent colectomy and IRA as a primary surgical procedure. Survival was estimated using the Kaplan-Meier method. Cox proportional hazard models were fitted to assess the relative excess risk of rectal cancer and to control for confounding factors. A multivariate analysis was performed to assess the relation between cancer risk in the rectum and sex, age, number of rectal polyps, colon cancer, and APC germline mutation. RESULTS: Median follow-up was 81 months. Eighty-nine patients (24%) had colon cancer at the time of surgery. The APC mutation was found in 200 patients. In 27 patients, cancer developed in the retained rectum 1 to 26 years after surgery. The incidence of rectal carcinoma appears to increase with time: at 10, 15, and 20 years after surgery, the cumulative risk was 7.7%, 13.1%, and 23.0%, respectively. Multivariate analysis identified as independent predictors the presence of colon cancer at IRA and a mutation occurring between codons 1250 and 1464; both factors increased the risk nine times. CONCLUSIONS: The presence of cancer at IRA and APC mutation type are the most important risk factors for the future development of cancer in the rectal remnant in patients with FAP.

Adenomatous Polyposis Coli↗
PubMed2000

Recurrent germline mutation in MSH2 arises frequently de novo.

INTRODUCTION: An intronic germline mutation in the MSH2 gene, A-->T at nt942+3, interferes with the exon 5 donor splicing mechanism leading to a mRNA lacking exon 5. This mutation causes typical hereditary non-polyposis colorectal cancer (HNPCC) and has been observed in numerous probands and families world wide. Recurrent mutations either arise repeatedly de novo or emanate from ancestral founding mutational events. The A-->T mutation had previously been shown to be enriched in the population of Newfoundland where most families shared a founder mutation. In contrast, in England, haplotypes failed to suggest a founder effect. If the absence of a founder effect could be proven world wide, the frequent de novo occurrence of the mutation would constitute an unexplored predisposition. METHODS: We studied 10 families from England, Italy, Hong Kong, and Japan with a battery of intragenic and flanking polymorphic single nucleotide and microsatellite markers. RESULTS: Haplotype sharing was not apparent, even within the European and Asian kindreds. Our marker panel was sufficient to detect a major mutation arising within the past several thousand generations. DISCUSSION: As a more ancient founder is implausible, we conclude that the A-->T mutation at nt942+3 of MSH2 occurs de novo with a relatively high frequency. We hypothesise that it arises as a consequence of misalignment at replication or recombination caused by a repeat of 26 adenines, of which the mutated A is the first. It is by far the most common recurrent de novo germline mutation yet to be detected in a human mismatch repair gene, accounting for 11% of all known pathogenic MSH2 mutations.

Colorectal Neoplasms, Hereditary Nonpolyposis↗
PubMed1999

Survival of patients with hereditary colorectal cancer: comparison of HNPCC and colorectal cancer in FAP patients with sporadic colorectal cancer.

Conflicting data exist on the prognosis of hereditary colorectal cancer. HNPCC patients, in particular, are often reported to have a better survival. We examined 2,340 colorectal-cancer patients treated in our Institution: 144 HNPCC patients (Amsterdam Criteria), 161 FAP patients and 2,035 patients with sporadic cancer. Data on hereditary-cancer patients treated between 1980 and 1995 was collected in a registry. The 2,035 sporadic colorectal-cancer patients (controls) included all new cases treated in the Department of Gastrointestinal-Tract Surgery during the same period. Observed survival was estimated using the Kaplan-Meier method. Cumulative survival probability was estimated at 5 years within each group and stratified by various clinical and pathological variables. The age distribution at diagnosis of sporadic patients was significantly higher than that of FAP and HNPCC patients (median 60 years vs. 43 and 49 years; p < 0.0001). In the HNPCC group, 40% had a right cancer location, vs. 14% in the FAP group and 13% in the sporadic-cancer group. In the sporadic group, 51% were early-stage cancers (Dukes A or B) vs. 48.4% and 52.1% in the FAP and HNPCC groups respectively. In the HNPCC, FAP and sporadic-cancer groups, the 5-year cumulative survival rate was 56.9%, 54.4% and 50.6% respectively. Survival analysis by the Cox proportional-hazards method revealed no substantial survival advantage for HNPCC and FAP patients compared with the sporadic group, after adjustment for age, gender, stage and tumor location. The hazard ratio for HNPCC was 1.01 (95% CI 0.72-1.39) and 1.27 (95% CI 0.95-1.7) for FAP patients compared with the sporadic-colorectal-cancer group.

Adenomatous Polyposis Coli↗