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Hereditary breast cancer accounts for 5-10% of all cases, with pathogenic variants in BRCA1/2 and other susceptibility genes playing a crucial role. This study elucidates the prevalence and spectrum of germline variants in 13 cancer predisposition genes among high-risk hereditary breast cancer patients from Southern Italy. We employed next-generation sequencing (NGS) to analyze 254 individuals selected through genetic counseling. Pathogenic or likely pathogenic variants were identified in 13% (34/254) of patients, with 54% of these variants occurring in non- BRCA1/2 genes. Notably, we observed a recurrent BRCA1 c.4964_4982del founder mutation, underscoring the importance of population-specific genetic screening. The spectrum of variants extended beyond BRCA1/2 to include PALB2 , ATM , TP53 , CHEK2 , and RAD51C , highlighting the genetic heterogeneity of breast cancer susceptibility. Variants of uncertain significance were detected in 20% of patients, emphasizing the ongoing challenge of variant interpretation in the era of multi-gene panel testing. These findings not only enhance our understanding of the genetic landscape of breast cancer in Southern Italy but also provide a foundation for developing more targeted, population-specific approaches to genetic testing and counseling, ultimately contributing to the advancement of precision medicine in oncology.

Alendronate (ALN) is a second-generation bisphosphonate widely used for osteoporosis and cancer-induced bone lesions. Many studies have confirmed a strong relationship between osteonecrosis of the jaws (ONJ) development and oral bisphosphonates, especially ALN, although the molecular mechanisms underlying this pathology have not yet been elucidated. The reduction in bone turnover and vascularization usually observed in ONJ are the result of ALN action on different cell types harboured in oral microenvironment, such as osteoclasts, endothelial cells, and periodontal ligament stem cells (PDLSCs). In this perspective, the present study aims to investigate the effects of different ALN concentrations (2 μM, 5 μM, 10 μM, 25 μM, 50 μM) on the phenotype and functional properties of human PDLSCs (hPDLSCs). hPDLSCs showed a decrease in cell viability (MTT assay) only when treated with ALN concentration of 10 μM or larger for 48 h and 72 h. Cell cycle analysis revealed a moderate increase in proportion of S-phase cells after exposure to low ALN concentration (2-5 μM), an effect that was reverted after exposure to 10-50 μM ALN. Conversely, cell death was evidenced via Annexin V/PI assay at very high concentration of ALN (50 μM) after 4 days of treatment. In addition, we explored whether the effects of ALN on hPDLSCs growth and survival can be mediated by its ability to modulate oxidative stress. To this, we quantified the intracellular ROS amount and lipid peroxidation by using DCF probe and Bodipy staining, respectively. Flow cytometry analysis showed that ALN induced a dose-dependent reduction of intracellular oxidative stress and lipid peroxidation upon treatment with low concentrations at both 48 h and 72 h. Increased levels of oxidative stress was reported at 50 μM ALN and was also confirmed via TEM analysis. Despite the stability of the cellular immunophenotype, hPDLSCs showed impaired mobility after ALN exposure. Chronic exposure (7-14 days) to ALN in the range of 2-10 μM significantly decreased the expression of the differentiation-related factors ALP, RUNX2, COLI, and OPN as well as the osteogenic ability of hPDLSCs compared with untreated cells. Conversely, higher doses were found to be neutral. Our findings indicated that the effects of ALN on hPDLSCs behavior are dose-dependent and suggest a role for oxidative stress in ALN-induced cell death that may lead to novel therapeutic approaches for ONJ., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Germline pathogenic variants (PVs) in oncogenes and tumour suppressor genes are responsible for 5 to 10% of all diagnosed cancers, which are commonly known as hereditary cancer predisposition syndromes (HCPS). A total of 104 individuals at high risk of HCPS were selected by genetic counselling for genetic testing in the past 2 years. Most of them were subjects having a personal and family history of breast cancer (BC) selected according to current established criteria. Genes analysis involved in HCPS was assessed by next-generation sequencing (NGS) using a custom cancer panel with high- and moderate-risk susceptibility genes. Germline PVs were identified in 17 of 104 individuals (16.3%) analysed, while variants of uncertain significance (VUS) were identified in 21/104 (20.2%) cases. Concerning the germline PVs distribution among the 13 BC individuals with positive findings, 8/13 (61.5%) were in the BRCA1/2 genes, whereas 5/13 (38.4%) were in other high- or moderate-risk genes including PALB2 , TP53 , ATM and CHEK2 . NGS genetic testing showed that 6/13 (46.1%) of the PVs observed in BC patients were detected in triple-negative BC. Interestingly, the likelihood of carrying the PVs in the moderate-to-high-risk genes calculated by the cancer risk model BOADICEA was significantly higher in pathogenic variant carriers than in negative subjects. Collectively, this study shows that multigene panel testing can offer an effective diagnostic approach for patients at high risk of hereditary cancers.

The optimal duration of lenalidomide maintenance post-autologous stem cell transplant (ASCT) in Multiple Myeloma (MM), and choice of therapy at relapse post-maintenance, need further evaluation. This retrospective study assessed outcomes of patients with MM (n = 213) seen at Mayo Clinic, Rochester between 1/1/2005-12/31/2016 who received lenalidomide maintenance post-ASCT. The median PFS was 4 (95% CI: 3.4, 4.5) years from diagnosis of MM; median OS was not reached (5-year OS: 77%). Excluding patients who stopped lenalidomide maintenance within 3 years due to progression on maintenance, ≥3 years of maintenance had a superior 5-year OS of 100% vs. 85% in <3 years (p = 0.011). Median PFS was 7.2 (95% CI: 6, 8.5) years in ≥3 years vs. 4.4 (95% CI: 4.3, 4.5) years in <3 years (p < 0.0001). Lenalidomide refractoriness at first relapse was associated with inferior PFS2 [8.1 (95% CI: 6.4, 9.9) months vs. 19.9 (95% CI: 9.7, 30.2; p = 0.002) months in nonrefractory patients]. At first relapse post-maintenance, median PFS2 was superior with daratumumab-based regimens [18.4 (95% CI: 10.9, 25.9) months] versus regimens without daratumumab [8.9 (95% CI: 5.5, 12.3) months; p = 0.006]. Daratumumab + immunomodulatory drugs had superior median PFS2 compared to daratumumab + bortezomib [NR vs 1 yr (95% CI: 0.5, 1.5); p = 0.004]., (© 2021. The Author(s).)

Bisphosphonates-related osteonecrosis of the jaw (BRONJ) was firstly reported by Marx in 2003. Since 2014, the term medication-related osteonecrosis of the jaw (MRONJ) is recommended by the American Association of Oral and Maxillofacial Surgeons (AAOMS). Development of MRONJ has been associated to the assumption of bisphosphonates but many MRONJ-promoting factors have been identified. A strong involvement of immunity components has been suggested. Therapeutic intervention includes surgical and non-surgical treatments, as well as regenerative medicine procedures for the replacement of the lost tissues. The literature confirms that the combination of mesenchymal stem cells (MSCs), biomaterials and local biomolecules can support the regeneration/repair of different structures. In this review, we report the major open topics in the pathogenesis of MRONJ. Then, we introduce the oral tissues recognized as sources of MSCs, summing up in functional terms what is known about the exosomes release in physiological and pathological conditions.

Systemic Bartonella henselae infections are unusual in immunocompetent adults. However, here we report one such case of bartonellosis in a 34-year-old patient, who presented with fever and multinodular splenomegaly. We also describe a novel method of identifying Bartonella henselae by real-time quantitative polymerase chain reaction and sequencing of amplified products. This could prevent splenic bartonellosis being mistaken for lymphoma and thereby avert unnecessary splenectomy.

Single nucleotide polymorphisms (SNPs) are germline variations interspersed in the human genome. These subtle changes of DNA sequence can influence the susceptibility to various pathologies including cancer. The functional meaning of SNPs is not always clear, being, the majority of them, localized in noncoding regions. The discovery of microRNAs, tiny noncoding RNAs able to bind the 3' untranslated region (UTR) of target genes and to consequently downregulate their expression, has provided a functional explanation of how some SNPs positioned in noncoding regions contribute to cancer susceptibility. In this paper we summarize the current knowledge of the effect on cancer susceptibility of SNPs included in regions related with miRNA-dependent pathways. Hereditary cancer comes up from mutations that occur in high-penetrant predisposing tumor genes. However, a considerable part of inherited cancers arises from multiple low-penetrant predisposing gene variants that influence the behavior of cancer insurgence. Despite the established significance of such polymorphic variants in cancer predisposition, sometimes their functional role remains unknown. The discovery of a new group of genes called microRNAs (miRNAs) opened an avenue for the functional interpretation of polymorphisms involved in cancer predisposition.

The metabolic syndrome (MetS) is a common disorder, where systemic insulin-resistance is associated with increased risk for type 2 diabetes (T2D) and cardiovascular disease. Identifying genetic traits influencing risk and progression of MetS is important. We and others previously reported a functional HMGA1 gene variant, rs146052672, predisposing to T2D. Here we investigated the association of rs146052672 variant with MetS and related components. In a case-control study from Italy and Turkey, increased risk of MetS was seen among carriers of the HMGA1 variant. In the larger Italian cohort, this variant positively correlated with BMI, hyperglycemia and insulin-resistance, and negatively correlated with serum HDL-cholesterol. Association between rs146052672 variant and MetS occurred independently of T2D, indicating that HMGA1 gene defects play a pathogenetic role in MetS and other insulin-resistance-related conditions. Overall, our results indicate that the rs146052672 variant represents an early predictive marker of MetS, as well as a predictive tool for therapy.

We describe a SYBR Green I-based real-time PCR targeting Bartonella quintana transcriptional regulatory protein (bqtR) gene, recently found as invariant gene among different B. quintana strains. Melting curve analysis allowed us to discriminate between B. quintana and Bartonella henselae amplified products. We also show its usefulness in the management of a blood culture-negative patient affected by enlarged cervical lymphonodes and long-lasting fever. B. quintana DNA detection in patient whole blood samples and blood culture bottles was confirmed by sequencing and analyzing amplified products., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Mutations in the gene HR coding for the hairless protein are associated with atrichia with papular lesions (APL), an autosomal recessive form of alopecia universalis that is characterized by generalized scalp and body atrichia with papular lesions. We here describe a South Italian family of ancient Albanian heritage. The full phenotype with complete atrichia was expressed in 2 siblings, whereas the parents and one sister were unaffected. Direct sequencing of the gene coding for the hairless protein allowed the identification of a new mutation in exon 17. Consistent with the recessive inheritance of the disease, both the siblings were homozygous for the mutation, whereas the parents and the unaffected sister where heterozygous. A relevant discrepancy with a haplotype linkage study is reported, stressing the importance of gene sequencing in genetic diagnosis and counseling because linkage studies can be biased by recombination events.

Ovarian epithelial tumors are an hallmark of hereditary cancer syndromes which are related to the germ-line inheritance of cancer predisposing mutations in BRCA1 and BRCA2 genes. Although these genes have been associated with multiple different physiologic functions, they share an important role in DNA repair mechanisms and therefore in the whole genomic integrity control. These findings have risen a variety of issues in terms of treatment and prevention of breast and ovarian tumors arising in this context. Enhanced sensitivity to platinum-based anticancer drugs has been related to BRCA1/2 functional loss. Retrospective studies disclosed differential chemosensitivity profiles of BRCA1/2-related as compared to "sporadic" ovarian cancer and led to the identification of a "BRCA-ness" phenotype of ovarian cancer, which includes inherited BRCA1/2 germ-line mutations, a serous high grade histology highly sensitive to platinum derivatives. Molecularly-based tailored treatments of human tumors are an emerging issue in the "era" of molecular targeted drugs and molecular profiling technologies. We will critically discuss if the genetic background of ovarian cancer can indeed represent a determinant issue for decision making in the treatment selection and how the provocative preclinical findings might be translated in the therapeutic scenario. The presently available preclinical and clinical evidence clearly indicates that genetic background has an emerging role in treatment individualization for ovarian cancer patients.

Second primary tumours represent one of the major causes of failure in the treatment of head and neck cancer. Advances in early diagnosis and treatment have improved the patient's disease-specific survival. However, the increase in the occurrence of second primary tumours negatively influences the patient's chance of long-term survival. To understand the molecular events underlying the appearance of head and neck multiple tumours, the clinical history has been evaluated in 2 patients both of whom developed 3 primary tumours of the head and neck. To establish the genetic relationship between the different head and neck cancers which had developed in these 2 patients, loss of heterozygosity was investigated using microsatellite markers located on chromosomes 3p, 9p, 11q, 13q, and 17p. These markers were selected as they frequently demonstrate loss of heterozygosity in head and neck cancer. The following markers were used: D3S1234, D3S1300, D9S170, D11S490, and D17S158. Primer sequences were obtained from the genome database for all of these markers. The third tumour that developed in the first patient, 13 years after the primary, showed loss of heterozygosity on chromosome 17p (in the locus for the gene TP53), which was not present in the previous tumours. All tumours in the second patient showed heterozygosity of chromosome 11 at the locus D11S490. These 2 cases show that multiple tumours can be derived from a genetic alteration of a subclone from previous tumours or from an independent preneoplastic cell clone present in the head and neck mucosa.

Familial adenomatous polyposis (FAP) is one of the most important clinical hereditary forms of inherited susceptibility to colorectal cancer and is characterized by a high degree of phenotypic heterogeneity. We used a mass spectrometry driven-proteomic strategy to identify serum molecules differently expressed in FAP patients. The data obtained were subsequently processed by bioinformatic analysis and confirmed by Western blotting. Significant differences were highlighted in the expression of serum proteins of FAP patients. In particular, two proteins (alpha-2-HS-glycoprotein and apoliprotein D) were down-regulated (about 0.5- and 0.7-fold, respectively) in carpeting versus diffuse FAP patients and healthy donors, while alpha-2-antiplasmin was up-regulated (about 1.4-fold). Moreover, mass spectrometry approach enabled us to identify serum biomarkers specific for two distinct clinical form of FAP, i.e. carpeting and diffuse FAP. In particular, vitronectin was up-regulated (more than 1.4-fold) in diffuse FAP patients versus carpeting FAP and versus healthy donors, and two additional proteins (Haptoglobin and alpha-1-acid glycoprotein 1) were up-regulated in 2 out of 3 carpeting FAP patients. Our study suggests that mass spectrometry combined to a strong bioinformatics analysis is a valuable tool for the identification of quali/quantitative differences in the serum proteome of otherwise indistinguishable FAP phenotypes. Moreover, the definition of a proteomic profile, supported by the supervised classification, is a powerful and highly sensitive approach for the identification molecular signatures that are able to outperform the traditional disease markers and can therefore be efficiently applied for the diagnosis and clinical management of FAP patients.

Purpose: The aim of this study was to explore the gene expression pattern produced by the cancer-associated BRCA1 5083del19 founder mutation by using a microarray analysis. Such a mutation, identified in a subset of familial breast cancer patients, involves a deletion at the 3' end of the BRCA1 messenger leading, in the mature protein, to the ablation of the BRCT tandem domain., Experimental Design: We generated HeLa cells stably expressing both exogenous wild-type (HeLa/(wt)BRCA1), used as a control, and 5083del19 BRCA1 (HeLa/(5083del19)BRCA1) alleles; gene chips were then used to investigate any changes in the transcription profile induced by the 5083del19 BRCA1 mutant compared with controls., Results: Among the genes showing perturbation of their expression, periostin was found to be up-regulated in HeLa/(5083del19)BRCA1 cells to an extent of 72-fold versus HeLa/(pcDNA3.1/empty) and 76-fold versus HeLa/(wt)BRCA1 cells. This finding was validated both in vitro in breast cancer cell lines harboring mutations of BRCA1 and in vivo by immunohistochemistry of breast cancer specimens bearing the 5083del19 BRCA1 mutation as well as by Western blot analysis of sera obtained from patients and healthy carriers of the same mutation., Conclusions: Our results suggest that periostin overexpression, whose product is released from cells in the extracellular fluids, might be a potential marker for early cancer detection in a specific subset of hereditary breast carcinomas triggered by cancer-associated BRCA1 mutations that affect the BRCT tandem domain.

The tumor suppressor protein p53 triggers many of the cellular responses to DNA damage by regulating the transcription of a series of downstream target genes. p53 acts on the promoter of the target genes by interacting with the trimeric transcription factor NF-Y. H ferritin promoter activity is tightly dependent on a multiprotein complex called Bbf; on this complex NF-Y plays a major role. The aim of this work was to study the modulation of H ferritin expression levels by p53. CAT reporter assays indicate that: (i) p53 overexpression strongly downregulates the transcriptional efficiency driven by an H ferritin promoter construct containing only the NF-Y recognition sequence and that the phenomenon is reverted by p53 siRNA; (ii) the p53 C-terminal region is sufficient to elicitate this regulation and that a correct C-terminal acetylation is also required. The H ferritin promoter displays no p53-binding sites; chromatin immunoprecipitation assays indicate that p53 is recruited on this promoter by NF-Y. The p53-NF-Y interaction does not alter the NF-Y DNA-binding ability as indicated by electrophoretic mobility shift assay (EMSA) analysis. These results demonstrate that the gene coding for the H ferritin protein belongs to the family of p53-regulated genes, therefore adding a new level of complexity to the regulation of the H ferritin transcription and delineate a role for this protein in a series of cellular events triggered by p53 activation.

BRCA1 is a nuclear phosphoprotein that plays a key role in many cell functions, including DNA repair, control of transcription, recombination and cell cycle homeostasis. Inherited missense mutations in the BRCA1 gene may predispose to breast and ovarian cancer, but the molecular mechanisms underlying BRCA1-induced tumorigenesis are still to be elucidated. Functional studies performed so far have contributed to the characterization of several single-nucleotide variants, mostly located at the BRCT domain, but very little is known about modifications in the protein pattern occurring in cells carrying these mutations. To shed more light in the molecular events triggered by missense mutations affecting breast cancer susceptibility genes, we have analyzed the whole cell proteome of stably transfected HeLa cell lines bearing three distinct single aminoacid changes in the BRCA1 protein (Ser1841Asn, Met1775Arg and Trp1837Arg) by means of liquid chromatography coupled to tandem-mass spectrometry. The results show that the Met1775Arg and the Trp1837Arg do not produce significant changes in the proteomic pattern compared to cells transfected with the wild-type BRCA1 cDNA. On the other hand, a different profile is detected in the BRCA1 Ser1841Asn-bearing cell line. In this particular subset, our attention has been focused on two proteins--the tumor protein D52 (TD52) and the folate receptor alpha (FOL1)--whose expression has been already reported to be upregulated in breast cancer, as well as in other tumors. Our findings indicate that Ser1841Asn BRCA1 mutation is able to activate specific protein pathways that are not triggered by other single aminoacid changes and pinpoint to the role TD52 and FOL1 as potential markers in breast cancer patients carrying this particular BRCA1 gene alteration.

Women with BRCA1 gene mutations have an increased risk for breast and ovarian cancer (BOC). Classification of missense variants as neutral or disease causing is still a challenge and has major implications for genetic counseling. BRCA1 is organized in an N-terminal ring-finger domain and two BRCT (breast cancer C-terminus) domains, involved in protein-protein interaction. The integrity of the C-terminal, BRCT repeat region is also critical for BRCA1 tumor suppressor function. Several molecular partners of BRCA1 have so far been identified; among them, the tumor suppressor protein p53 seems to play a major role. This study was aimed at evaluating the impact of two missense mutations, namely the W1837R and the S1841N, previously identified in BOC patients and located in the BRCT domain of the BRCA1 gene, on the binding capacity of this protein to p53. Co-immunoprecipitation assays of E. coli-expressed wild-type and mutated BRCTs challenged with a HeLa cell extract revealed, for the S1841N variant a significant reduction in the binding activity to p53, while the W1837R mutant showed an inverse effect. Furthermore, a clonogenic soft agar growth assay performed on HeLa cells stably transfected with either wild-type or mutant BRCA1 showed a marked decrease of the growth in wild-type BRCA1-overexpressing cells and in BRCA1S1841N-transfected cells, while no significant changes were detected in the BRCA1W1837R-transfected cells. These results demonstrate that: i) distinct single nucleotide changes in the BRCT domain of BRCA1 affect binding of this protein to the tumor suppressor p53, and ii) the two missense mutations here described are likely to play a role in breast tumorigenesis. We suggest that in vitro/in vivo experiments testing the effects of unclassified BRCA1 gene variants should therefore be taken in to consideration and that increased surveillance should be adopted in individuals bearing these two BRCA1 missense alterations.

The H ferritin promoter spans approximately 150 bp, upstream of the transcription start and is composed by two cis-elements in position -132 (A box) and -62 (B-box), respectively. The A box is recognized by the transcription factor Sp1, and the B-box by a protein complex called Bbf, which includes the CAAT binding factor NF-Y. In this study we performed a functional analysis of an H ferritin promoter allele carrying a G to T substitution adjacent to the Bbf binding site, in position -69. In vitro studies with reporter constructs revealed a significantly reduced transcriptional activity of this allele compared to that of the w.t. promoter that was mirrored by a decrease in Bbf binding. In vivo, this variant genotype is accompanied by a reduced amount of the H mRNA in peripheral blood lymphocytes.

The BRCA1 tumor suppressor gene encodes a phosphoprotein involved in many cellular key functions including DNA repair, transcription regulation, cell-cycle control and apoptosis. Most of these functions are strictly related to the ability of BRCA1 to interact with the other partners of a multimeric complex called BASC. Among these components, an important role is played by the human homolog of the bacterial MutL, MLH1. In this study, we have identified the BRCA1 binding domains to MLH1 and demonstrated that three distinct mutations in one of these interaction domains can produce, in vitro, a microsatellite instability phenotype, one of the hallmarks of an imbalance in the mismatch DNA repair machinery. These data support a model in which a structural modification in a critical domain of the BRCA1 gene product secondary to single amino acid mutations, may be able, per se, to impair the DNA damage response pathway, inducing genomic instability and eventually leading to breast carcinogenesis., (Copyright 2006 Wiley-Liss, Inc.)

Germline mutations within the mismatch repair (MMR) genes are generally found in colorectal cancer (CRC) patients with a positive family history for the presence of the neoplasia. Clinical standard criteria have been established to define hereditary-non-polyposis-colorectal cancer (HNPCC)-prone families. Interestingly, the number of MMR gene mutations found in kindreds not fulfilling these criteria is still increasing. In this work we report the identification of a novel germline mutation of the hMSH2 gene, in two CRC-bearing subjects. The two probands belong to a large kindred from South Italy with no history suggestive for cancer aggregation. On the other hand, the early-onset of the neoplasia as well as the presence of a high number of tumor infiltrating lymphocytes (TILs) in the histological specimens of both patients, prompted us to perform a comprehensive genetic analysis. This analysis included the evaluation of the microsatellite instability (MSI) status with five markers according to the National Cancer Institute recommendations, followed by direct sequencing of the hMLH1 and hMSH2 genes. Both probands were found to carry a germline missense (277 C>T) mutation leading to the change (L93F) of an amino acid residue in a highly conserved domain of the MSH2 protein. This mutation is accompanied by the loss of expression of the hMSH2 gene in the tumor tissue. Our findings suggest that in the presence of the above-mentioned criteria it may be useful to perform a molecular analysis of the MMR genes, even if the pedigree does not show marked aggregation of cancers.

We recently isolated the r-PTPeta gene, which encodes a receptor-type tyrosine phosphatase protein that suppresses the neoplastic phenotype of retrovirally transformed rat thyroid cells. The human homologue gene PTPRJ/DEP-1 is deleted in various tumors. Moreover, the Gln276Pro polymorphism, located in the extracellular region of the gene, seems to play a critical role in susceptibility to some human neoplasias. Here we report the loss of heterozygosity (LOH) of PTPRJ in 11/76 (14.5%) informative thyroid tumors (including adenomas and carcinomas). We also looked for the Gln276Pro, Arg326Gln and Asp872Glu polymorphisms in exons 5, 6 and 13 of PTPRJ in 88 patients with thyroid tumors and in 54 healthy individuals. We found that the PTPRJ genotypes homozygous for the Gln276Pro and Arg326Gln polymorphisms, and the Asp872 allele were more frequent in thyroid carcinoma patients than in healthy individuals (P=0.032). In addition, PTPRJ LOH was more frequent in thyroid carcinomas of heterozygotes for Gln276Pro and Arg326Gln compared with homozygotes (P=0.006). This suggests that the presence of hemizygosity for these polymorphisms in the tumor facilitates tumor progression. These results indicate that the genotypic profile of PTPRJ affects susceptibility to thyroid carcinomas, and that allelic loss of this gene is involved in thyroid carcinogenesis.

Germline mutations of BRCA1 and BRCA2 genes confer susceptibility to breast and ovarian cancer. It has been recently reported that BRCA1/2 mutations may also predispose to fallopian tube cancer. We report the presence of germline BRCA2 gene mutations in three out of four subjects with fallopian tube cancer diagnosed in a two-year time span at our clinic. The mothers of two of these women suffered from breast or ovarian carcinoma. These results suggest on one hand that in patients with a history suggestive for a heredofamilial breast/ovarian cancer syndrome fallopian tube carcinoma is associated with high risk of BRCA2 mutation, and on the other hand that in patients/individuals with germline BRCA2 gene mutations in whom a prophylactic oophorectomy is performed, removal of fallopian tubes may be considered.

Fallopian tube cancer (FTC) accounts for 0.1-0.5% of all gynaecological malignancies, so that very few studies have demonstrated a significant linkage between this cancer type and BRCA1/BRCA2 mutations. We report the identification of a novel germline mutation (Q3034R) in BRCA2 gene in a 41-year-old patient. The nucleotide change (CAG > CGG) abolishes a DdeI restriction site, making genotype identification rapid and inexpensive. Our findings support the hypothesis that the primary FTC should be considered, at least in a subset of patients, as a BRCA2-associated tumor. Genetic counselling could result, in these cases, in early diagnosis of genetically predisposed individuals., (Copyright 2002 Elsevier Science Ireland Ltd.)

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., (Copyright 2001 Wiley-Liss, Inc.)

Hereditary nonpolyposis colon cancer results from heritable defects in the MLH1, MSH2, PMS1 and PMS2 genes, which encode proteins involved in the mismatch repair process. In this work we report the identification of two novel germline mutations in the MLH1 gene from two unrelated HNPCC families. The two affected families do not fulfill the Amsterdam criteria. In family 1 we found a missense S93G mutation, which lies in a MLH1 domain critical for its MMR functions. In family 2 we found a two nucleotide insertion (AG) in position 523 from the AUG which determines an early stop codon at position 606 (codon 203). In both families the mutant alleles cosegregate with the cancer phenotype.