[show abstract][hide abstract] ABSTRACT: SULT1A1, a member of sulfotransferase superfamily, is a drug and hormone metabolizing enzyme involved in the metabolism of a variety of potential mammary carcinogens of endogenous and exogenous origin. Interestingly, the metabolic activity of SULT1A1 can be affected by variations in gene copy number. Male Breast Cancer (MBC) is a rare disease and less investigated disease compared to female BC (FBC). As in FBC, the concurrent effects of genetic risk factors, particularly BRCA2 mutations, increased exposure to estrogens and environmental carcinogens play a relevant role in MBC. By quantitative real-time PCR with TaqMan probes, we investigated the presence of SULT1A1 gene copy number variations (CNVs) in a series of 72 MBCs. SULT1A1 gene deletion was observed in 10 of the 72 MBCs (13.9%). In a multivariate analysis association between BRCA2 mutation and SULT1A1 gene deletion emerged (p = 0.0005). Based on the evidence that the level of SULT1A1 enzyme activity is correlated with CNV, our data suggest that in male breast tumors SULT1A1 activity may be decreased. Thus, it can be hypothesized that in a proportion of MBCs, particularly in BRCA2-associated MBCs, the level of estrogens and environmental carcinogens exposure might be increased suggesting a link between gene and environmental exposure in the pathogenesis of MBC.
Journal of Cellular and Molecular Medicine 05/2013; 17(5):605-607. · 4.75 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, the number of studies on male breast cancer (MBC) has been increasing. However, as MBC is a rare disease there are difficulties to undertake studies to identify specific MBC subgroups. At present, it is still largely unknown whether BRCA-related breast cancer (BC) in men may display specific characteristics as it is for BRCA-related BC in women. To investigate the clinical-pathologic features of MBC in association with BRCA mutations we established a collaborative Italian Multicenter Study on MBC with the aim to recruit a large series of MBCs. A total of 382 MBCs, including 50 BRCA carriers, were collected from ten Italian Investigation Centres covering the whole country. In MBC patients, BRCA2 mutations were associated with family history of breast/ovarian cancer (p<0.0001), personal history of other cancers (p=0.044) and contralateral BC (p=0.001). BRCA2-associated MBCs presented with high tumor grade (p=0.001), PR-(p=0.026) and HER2+ (p=0.001) status. In a multivariate logistic model BRCA2 mutations showed positive association with personal history of other cancers (OR 11.42, 95% CI 1.79-73.08) and high tumor grade (OR 4.93, 95% CI 1.02-23.88) and inverse association with PR+ status (OR 0.19, 95% CI 0.04-0.92). Based on immunohistochemical (IHC) profile, four molecular subtypes of MBC were identified. Luminal A was the most common subtype (67.7%), luminal B was observed in 26.5% of the cases and HER2 positive and triple negative were represented by 2.1% and 3.7% of tumors, respectively. Intriguingly, we found that both luminal B and HER2 positive subtypes were associated with high tumor grade (p=0.003 and 0.006, respectively) and with BRCA2 mutations (p=0.016 and 0.001, respectively). In conclusion, our findings indicate that BRCA2-related MBCs represent a subgroup of tumors with a peculiar phenotype characterized by aggressive behavior. The identification of a BRCA2-associated phenotype might define a subset of MBC patients eligible for personalized clinical management.
Breast Cancer Research and Treatment 04/2012; 134(1):411-8. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: We read with great interest the paper by Akbari and colleagues  in a recent issue of Breast Cancer Research. Th e authors reported on the absence of RAD51C mutations in 454 patients with BRCA1/2-negative familial breast cancer/ovarian cancer (BC/OC). In the initial report by Meindl and colleagues , RAD51C mutations were identifi ed in 6 out of 480 patients with BRCA1/2negative familial BC/OC. Interestingly, on the basis of histopathologic features, including intermediate grade (G2), estrogen receptor-positive (ER + ), progesterone receptor-positive (PR + ), and HER2-negative (HER2 − ) expression, RAD51C-associated BCs were found to be similar to BRCA2-associated BCs . BRCA2 is known to play a signifi cant role in male BC (MBC); however, no occur rence of MBC was observed in the six RAD51C families described . To investigate the role of RAD51C in MBC, we screened for RAD51C mutations in 97 MBC patients selected from our population-based series of 126 cases because they were previously found negative for BRCA1/2, CHEK2, PALB2, and BRIP1 mutations [3,4]. Notably, 25.8% of cases showed a positive fi rst-degree family history of BC or OC or both. Th e majority of MBCs were invasive ductal carcinomas (74.5%), G2 (53.5%), ER + (90.7%), PR + (82.6%), or HER2 − (85.4%). Overall, 66% of the MBCs showed an ER + /PR + /HER2 − phenotype. All patients provided informed consent to the study. We carried out mutation screening of the nine exons and intron/exon boundaries of RAD51C by high resolution melting (HRM) analysis, a rapid closed-tube mutation scanning method with high sensitivity and speci fi city. Cases displaying abnormal profi les were evaluated by direct sequencing. Primers are available upon request. We found no truncating RAD51C mutations. We identi fi ed a novel intronic variant, IVS3 c.738-16G>T, in
Breast cancer research: BCR 02/2011; 13(1):404. · 5.87 Impact Factor
[show abstract][hide abstract] ABSTRACT: Breast cancer (BC) in men is rare compared with BC in women, but its incidence is increasing along with attention toward this uncommon disease. Although with some differences, male and female BC share similar genetic predisposition factors, including BRCA1/2, CHEK2, and PALB2 mutations. As other BRCA1/2 functionally related DNA repair genes, such as CHEK2 and PALB2, BRIP1 is considered a moderate-penetrance BC susceptibility gene. At present, the role of BRIP1 on BC susceptibility in men is unknown. In this study, we aimed to assess whether BRIP1 variants may contribute to male BC (MBC) risk, by screening 97 MBC cases, all negative for BRCA1/2, CHEK2, and PALB2 mutations, selected from a population-based series of 126 MBCs from Central Italy. A total of five BRIP1 germ-line sequence alterations, three coding, and two non-coding variants, were detected in our series. The two non-coding variants IVS4-28G > A and 3'UTR 4049C > T were classified as neutral by in silico analysis. Of the three coding variants, one was a silent variant (E879E) and two resulted in amino acid substitution (R264W and P919S) showing a putative pathogenic role by in silico analysis. However, further analysis of tumor-associated loss of heterozygosity and the frequency of variant alleles, tested in 203 male population controls, suggested a neutral effect for both of these variants. Overall, our results indicate that BRIP1 variants may not play a relevant role in MBC predisposition.
Breast Cancer Research and Treatment 12/2010; 126(2):539-43. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Risk factors for gastric cancer (GC) include inter-individual variability in the inflammatory response to Helicobacter pylori infection, in the ability of detoxifying DNA reactive species and repairing DNA damage generated by oxidative stress and dietary carcinogens. To evaluate the association between polymorphic DNA repair genes and GC risk, a case-control study including 314 histologically confirmed GC patients and 548 healthy controls was conducted in a GC high-risk area in Tuscany, Italy. Polymorphic variants of base excision repair (APE1-D148E, XRCC1-R194W, XRCC1-R399Q and OGG1-S326C), nucleotide excision repair (XPC-PAT, XPA-23G>A, ERCC1-19007T>C and XPD-L751Q), recombination (XRCC3-T241M) and alkylation damage reversal (MGMT-L84F) were tested for their potential role in the development of GC by using logistic regression models. The same population was also characterised for GSTT1 and GSTM1 variant alleles to search for possible functional interactions between metabolic and DNA repair genotypes by two-way interactions using multivariate logistic models. No significant association between any single DNA repair genotype and GC risk was detected with a borderline association with the XPC-PAT homozygous genotype [odds ratio (OR) =1.42; 95% confidence interval (CI) 0.94-2.17]. Gene-gene interaction analysis revealed combinations of unfavourable genotypes involving either multiple DNA repair polymorphisms or DNA repair and GST-specific genotypes. The combination of the XPC-PAT and the XPA variant alleles significantly increased GC risk (OR=2.15; 95% CI 1.17-3.93, P=0.0092). A significant interaction was also found between the APE1 wild-type genotype and either the single GSTT1 (OR=4.90; 95% CI 2.38-10.11, P=0.0079) or double GSTM1-GSTT1 null (OR=7.84; 95% CI 3.19-19.22, P=0.0169) genotypes or the XPA-mutant allele (OR=3.56; 95% CI 1.53-8.25, P=0.0012). These findings indicate that a complex interaction between host factors such as oxidative stress, antioxidant capacity and efficiency of multiple DNA repair pathways underlies the inter-individual variability in GC risk.
[show abstract][hide abstract] ABSTRACT: No study has evaluated the performance of BRCA1/2 mutations prediction models in male breast cancer (MBC) series. Although rare, MBC deserves attention because male and female breast cancers share many characteristics, including the involvement of genetic predisposition factors such as BRCA1/BRCA2 mutations. Indeed, the occurrence of MBC is a commonly used criterion to select families for BRCA mutation testing. We evaluated the performance and clinical effectiveness of four different predictive models in a population-based series of 102 Italian MBC patients characterized for BRCA1/2 mutations. Sensitivity, specificity, and positive and negative predictive values (PPV, NPV) were calculated for each risk model at the 10% threshold. The area under the ROC (AUC) curves and its corresponding asymptotic 95% CIs were calculated as a measure of the accuracy. In our study, the BRCAPRO version 5.0 had the highest combination of sensitivity, specificity, NPV and PPV for the combined probability and for the discrimination of BRCA2 mutations. In individuals with negative breast-ovarian cancer family history, BRCAPRO 5.0 reached a high discriminatory capacity (AUC=0.92) in predicting BRCA2 mutations and showed values of sensitivity, specificity, NPV and PPV of 0.5, 0.98, 0.97 and 0.67, respectively, for the combined probability. BRCAPRO version 5.0 can be particularly useful in dealing with non-familial MBC, a circumstance that often represents a challenging situation in genetic counseling.
European journal of human genetics: EJHG 03/2010; 18(7):856-8. · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: The simultaneous occurrence of mutations in two different tumor suppressor genes in the same individual is a very rare event. Here we report the case of a woman in whom germline mutations in both MEN1 and BRCA1 were identified. The severity of MEN1-related biochemical and clinical findings did not significantly differ from that for other affected family members lacking the BRCA1 mutation, except for the development of an extremely large visceral lipoma; the proband has not developed any BRCA1-related malignancies. We explore genetic and molecular rationales for an association between these neoplastic processes.
Cancer genetics and cytogenetics 11/2009; 195(1):75-9. · 1.54 Impact Factor
[show abstract][hide abstract] ABSTRACT: Recently, it has been demonstrated that monoallelic PALB2 mutations predispose to familial breast cancer. We investigated the contribution of PALB2 mutations in a set of 132 Italian BRCA1/BRCA2-negative breast cancer families; one truncating PALB2 mutation, c.2257C>T, resulting in p.Arg753X, was identified in a woman and her daughter, with breast cancer diagnosed at 60 and 31 years old, respectively. This study supports the recent observation that PALB2 mutation are present, although infrequently, in familial BRCA1/BRCA2-negative breast cancer cases; moreover, it sustains latest evidences that some PALB2 mutations are associated with a substantially increased risk of breast cancer.
Familial Cancer 09/2009; 9(2):181-5. · 1.94 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background Male breast cancer (MBC) is a rare and scarcely investigated disease. The strongest genetic risk factor for MBC is represented
by inherited BRCA2 mutations, whereas the association between MBC and BRCA1 mutations is less clear. MBC appears to be biologically similar to breast cancer in females, however the phenotypic characteristics
of BRCA1/2-related MBCs are not yet well elucidated. Objective To investigate the genetic and phenotypic characteristics of MBC in a large and well-characterized population-based series
of 108 MBCs from Tuscany (Central Italy) and to evaluate associations between BRCA1/BRCA2 mutation status and clinical-pathological features including breast/ovarian cancer first-degree family history, tumor histology
and grade, proliferative activity, estrogen/progesterone receptors (ER/PR) and epidermal growth factor receptor 2 (HER2) expression.
BRCA1/BRCA2 mutations were identified in ten MBCs, in particular, two cases (1.9%) carried BRCA1 and eight cases (7.4%) carried BRCA2 mutations. The same BRCA1 mutation (3347delAG) was detected in two unrelated MBC cases. Three novel BRCA2 pathogenic mutations were found. Statistically significant associations emerged between BRCA2-related tumors and absence of PR expression (P = 0.008), HER2 over-expression (P = 0.002) and high tumor grade (P = 0.005). Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior. Overall, our results may have important implications on clinical management
for this rare disease.
Breast Cancer Research and Treatment 01/2009; 116(3):577-586. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Germline mutations in the BRCA1 and BRCA2 tumour-suppressor genes predispose to early-onset breast and ovarian cancer. Although both genes display a highly heterogeneous mutation spectrum, a number of alterations recur in some populations. Only a limited number of founder mutations have been identified in the Italian population so far.
To investigate the spectrum of BRCA1/BRCA2 mutations in a set of families originary from the Central-Eastern part of Tuscany and to ascertain the presence of founder effects. We also wanted to approximate the age of the most frequent BRCA1 founder mutation.
Overall, four distinct BRCA1 mutations accounted for a large fraction (72.7%) of BRCA1-attributable hereditary breast/ovarian cancer in families originary from this area. We identified common haplotypes for two newly recognised recurrent BRCA1 mutations, c.3228_3229delAG and c.3285delA. The c.3228_3229delAG mutation was estimated to have originated about 129 generations ago. Interestingly, male breast cancer cases were present in 3 out of 11 families with the c.3228_3229delAG mutation.
The observation that a high proportion of families with BRCA1 alterations from Central-Eastern Tuscany harbours a limited number of founder mutations can have significant impact on clinical management of at risk subjects from this area. In addition, the identification of a large set of families carrying an identical mutation that predisposes to breast and ovarian cancer provides unique opportunities to study the effect of other genetic and environmental factors on penetrance and disease phenotype.
Breast Cancer Research and Treatment 10/2008; 117(3):497-504. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Air pollution and particulate matter in urban areas have been associated with increased mortality from cardiovascular and respiratory diseases and increased cancer risk. Carcinogenic effects of particulate matter have been related to the contents of specific compounds, such as polycyclic aromatic hydrocarbons. The latter may form bulky DNA adducts, that may be considered as candidate markers of cancer risk. We have recently shown that traffic-exposed workers and the general population in Florence have divergent levels of DNA adducts, possibly related to different levels of exposure to genotoxic agents from vehicle emissions. In the current study, in a series of 214 Florence City healthy adults enrolled in a prospective study in the period 1993-1998 (152 residents / 62 traffic-exposed workers), we investigated the correlation between individual levels of DNA bulky adducts and PM(10) exposure scores based on daily environmental measures provided by the local Environmental Protection Agency for the whole study period, by two types of urban monitoring stations (high- and low-traffic). We found that PM(10) cumulative scores from high-traffic stations over the last 1-2 weeks prior to blood drawing significantly correlated (r=0.58, p=0.02) with DNA adduct levels among non-smoking traffic-exposed workers (but not among residents with no occupational exposure to vehicle emissions). A multivariate regression analysis adjusted for possible confounders confirmed these findings. PM(10) scores from low-traffic stations did not show any correlation. These results show that DNA adduct levels in non-smoking workers reflect the average levels of exposure to PM(10) in high-traffic urban areas experienced over a time period of 1-2 weeks. Since DNA adduct levels have been found predictive of lung cancer risk, our findings provide clues relevant to the reduction of genotoxic damage and possibly cancer risk among traffic-exposed urban workers.
Science of The Total Environment 08/2008; 403(1-3):105-12. · 3.26 Impact Factor
[show abstract][hide abstract] ABSTRACT: Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G>A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate cancer. Here, we investigated the contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family history and all negative for BRCA1/BRCA2 germ-line mutations. A total of 102 unrelated Italian MBC cases were screened for deletions/duplications of BRCA1, BRCA2 and CHEK2 by multiplex ligation-dependent probe amplification. No BRCA1, BRCA2 and CHEK2 genomic rearrangements, including the CHEK2 del9-10, were found in the series analysed. Furthermore, none of the MBC cases and 263 male population controls, also included in this study, carried the CHEK2 1100delC, IVS2+1G>A and I157T common mutations. Overall, our data suggest that screening of BRCA1/2 rearrangements is not advantageous in MBC cases not belonging to high-risk breast cancer families and that common CHEK2 mutations play an irrelevant role in MBC predisposition in Italy.
Breast Cancer Research and Treatment 07/2008; 110(1):161-7. · 4.47 Impact Factor
[show abstract][hide abstract] ABSTRACT: Gastric cancer is one of the leading causes of cancer death worldwide, and although the incidence has decreased in Western countries, specific high-risk areas are present in Italy. Gastric cancer with high-level microsatellite instability (MSI-H) represents a well-defined subset of carcinomas showing distinctive clinicopathologic features. We examined clinicopathologic associations and long-term survival in a series of 159 gastric cancer cases from a high-risk population in Tuscany (central Italy). MSI-H was associated with antral location of the tumor (P = .001), intestinal type according to Lauren classification (P = .002), expanding type according to Ming classification (P = .0001), and mucinous histologic type according to the Japanese Research Society for Gastric Cancer classification (P = .002). In addition, MSI-H was strongly associated with a higher survival at 15 years (P = .01) and with loss of hMLH1 expression, evaluated by immunohistochemistry (P = .001). Multivariate analyses showed a significant association between the absence of hMLH1 reactivity and the expanding tumor type (P = .002). We also investigated the MSI-H-related genetic changes by analyzing coding repeats within target genes involved in pathways that control cell growth (TGFbetaRII, IGFIIR, RIZ, TCF4, DP2), apoptosis (BAX, BCL10, FAS, CASPASE5, APAF1), and DNA repair genes (hMSH6, hMSH3, MED1, RAD50, BLM, ATR, BRCA2, MRE11). Gastric cancer cases with MSI-H were found to accumulate heterozygous mutations affecting multiple molecular pathways and multiple genes within each pathway. Intriguingly, in this subset, TGFbetaRII mutations appeared to be inversely related to BLM mutations (P = .006), whereas RAD50 mutation carriers showed significantly reduced survival (P = .03).
Human pathology 07/2008; 39(6):925-32. · 3.03 Impact Factor
[show abstract][hide abstract] ABSTRACT: Male breast cancer (MBC) is a rare and poorly known disease. Germ-line mutations of BRCA2 and, to lesser extent, BRCA1 genes are the highest risk factors associated with MBC. Interestingly, BRCA2 germ-line rearrangements have been described in high-risk breast/ovarian cancer families which included at least one MBC
case. Germ-line mutations of CHEK2 gene have been also implicated in inherited MBC predisposition. The CHEK2 1100delC mutation has been shown to increase the risk of breast cancer in men lacking BRCA1/BRCA2 mutations. Intriguingly, two other CHEK2 mutations (IVS2+1G>A and I157T) and a CHEK2 large genomic deletion (del9-10) have been associated with an elevated risk for prostate cancer. Here, we investigated the
contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family
history and all negative for BRCA1/BRCA2 germ-line mutations. A total of 102 unrelated Italian MBC cases were screened for deletions/duplications of BRCA1, BRCA2 and CHEK2 by multiplex ligation-dependent probe amplification. No BRCA1, BRCA2 and CHEK2 genomic rearrangements, including the CHEK2 del9-10, were found in the series analysed. Furthermore, none of the MBC cases and 263 male population controls, also included
in this study, carried the CHEK2 1100delC, IVS2+1G>A and I157T common mutations. Overall, our data suggest that screening of BRCA1/2 rearrangements is not advantageous in MBC cases not belonging to high-risk breast cancer families and that common CHEK2 mutations play an irrelevant role in MBC predisposition in Italy.
Breast Cancer Research and Treatment - BREAST CANCER RES TREAT. 01/2008; 110(1):161-167.
[show abstract][hide abstract] ABSTRACT: Male breast cancer (MBC) is a rare disease and little is known about its aetiology. Germ-line mutations of BRCA2 and, at lower frequency, of BRCA1 are implicated in a relatively small proportion of MBC cases. Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level. Considering the relevant role of BRCA2 in MBC, we investigated whether the BRCA2 N372H variant, representing the only common non-synonymous polymorphism in BRCA2, might modulate the risk of BC in male populations.
A case-control study was performed comparing a population-based series of 99 MBC cases, characterized for BRCA1 and BRCA2 mutations, with 261 male population controls, all residing in Tuscany, Central Italy. All MBC cases and controls were genotyped for the BRCA2 N372H allele by TaqMan allelic discrimination assays. To evaluate the genotype specific risk of the BRCA2 N372H variant, MBC carriers of germ-line BRCA1/2 mutations were excluded from the analyses.
No association emerged in univariate and age-adjusted analyses. Age-specific analyses suggested an increased risk for the HH homozygous genotype in subjects younger than 60 years. A statistically significant interaction emerged between this genotype and age (p = 0.032). When analyses were restricted to MBC cases enrolled in the first 4 years following diagnosis, a recessive model showed a significantly increased risk of MBC in HH subjects younger than 60 years (OR = 5.63; 95% CI = 1.70;18.61).
Overall, our findings, although based on a relatively small series, suggest that the BRCA2 HH homozygous genotype might be positively associated with an increased risk of MBC in men younger than 60 years.
[show abstract][hide abstract] ABSTRACT: Glutathione S-Transferases (GSTs) are a family of phase II enzymes involved in the detoxification of potential carcinogens and provided of a strong antioxidant function by neutralizing electrophiles and free radicals. The GSTM1 and GSTT1 isoenzymes exhibit deletion polymorphisms, resulting in a lack of activity, and the null genotypes have been associated with increased cancer risk at several sites, including the stomach, although with contrasting results. We carried out a case-control study to evaluate whether these polymorphisms modulate the risk of developing gastric cancer (GC). Genotypes for GSTM1 and GSTT1 were obtained from a series of 175 histologically confirmed GC patients and a large series of 546 healthy controls randomly sampled from the general population of Tuscany, an area at high GC risk. No difference in the frequency of GSTM1 null genotype was observed between cases and controls, whereas the GSTT1 null genotype was more frequent among cases (p = 0.04). Multivariate single-gene analyses adjusted for possible confounders showed that the GSTT1 null genotype, but not the GSTM1 null genotype, was associated with an increased GC risk. Combined-genotype analyses showed a significantly increased GC risk only for the double null (GSTM1-GSTT1) genotype (OR = 2.27; 95% CI: 1.14-4.53). A statistically significant positive interaction between the 2 null genotypes was observed (p = 0.02). Our findings suggest that only subjects lacking both GSTM1 and GSTT1 activity are at increased GC risk. This study provides further support to the hypothesis that the risk of developing GC is influenced by inter-individual variation in both carcinogen detoxification and antioxidant capacity. (c) 2005 Wiley-Liss, Inc.
International Journal of Cancer 07/2005; 115(2):284-9. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: The association of male breast cancer (MBC) with a positive breast cancer (BC) family history and with BRCA1/2 germ-line mutations points to a genetic component; a relationship with occupation has also been reported. Recently, we identified pathogenetic BRCA1/2 mutations in a population-based series of Italian MBC patients: here in, we investigated interactions between a carrier status for BRCA1/2 mutations and occupation using a case-case design and estimating case-only odds ratios (CORs). Truck-driving was the most frequent occupation (3/4 BRCA-related cases and 2/19 unrelated cases). An interaction between carrier status and working as a truck-driver emerged, when we classified MBC cases as "ever/never-held" this job title (COR 25.5; 95% Confidence Limits (CL): 1.1-1,412.5) or according to truck-driving as the "longest-held" work (COR 54.0; 95% CL: 1.6-2,997.5). The possible modifying effect on MBC risk in subjects carrying BRCA1/2 germ-line mutations of an occupation characterised by exposure to chemicals such as polycyclic aromatic hydrocarbons (PAH) that are capable of inducing DNA damage, may provide clues to the role of environmental exposures in modifying BC risk in mutation carriers in both genders.
European Journal of Cancer 12/2004; 40(16):2474-9. · 5.06 Impact Factor
[show abstract][hide abstract] ABSTRACT: Gastric carcinomas (GCs) with high-level microsatellite instability (MSI-H) are characterized by widespread mutations at coding and non-coding mononucleotide repeats. Deletions at coding mononucleotide tracts are predicted to cause frameshift mutations and alter normal protein functions. Mutations affecting non-coding mononucleotide repeats may lead to functional consequences if they occur in gene regulatory regions. To investigate whether mutations in non-coding polypyrimidine tracts within cancer-related genes may contribute to the phenotype of MSI-H GCs, we analysed the poly(T)11 tract constituting an accessory splicing signal within the intron 4 of the MRE11 gene. Mutations at the intronic MRE11 poly(T)11 were evaluated by PCR-based assay in 27 MSI-H, 22 MSI-low and 29 MSI-negative GCs derived from a well-characterized series of GCs identified in a high-risk area in Tuscany, Central Italy. Deletion of 2 and 1 bp at the MRE11poly(T)11 were identified in 33 and 48% MSI-H GCs, respectively. Biallelic mutations were frequently observed (77%) in GCs harbouring 2 bp deletions. The presence of MRE11poly(T)11 2 bp deletion was associated with a totally absent or strongly reduced MRE11 immunostaining (P < 0.001) and with a positive GC family history (P = 0.046). Immunoblotting assays confirmed the absence of MRE11 expression in GCs with a 2 bp deletion. The relatively high frequency of the MRE11poly(T)11 mutations, the occurrence of biallelic mutations and the evidence of loss of protein expression indicate MRE11 as novel mutational target in MSI-H GC. Overall, our results indicate that MSI-associated mutations occurring in non-coding repeats may affect protein expression in MSI-H GC.