Publications by authors named "Gianluca Tedaldi"

18 Publications

  • Page 1 of 1

Poorly Cohesive Carcinoma of the Nonampullary Small Intestine: A Distinct Histologic Subtype With Prognostic Significance.

Am J Surg Pathol 2021 Oct 11. Epub 2021 Oct 11.

Anatomic Pathology Unit, Department of Molecular Medicine, University of Pavia Anatomic Pathology, Fondazione IRCCS San Matteo Hospital Clinical Epidemiology & Biometry Unit, Fondazione IRCCS San Matteo Hospital Department of Internal Medicine, University of Pavia and Fondazione IRCCS San Matteo Hospital Medical Oncology Unit, ICS Maugeri-IRCCS SpA SB, Pavia Pathology Unit, Department of Surgical and Diagnostic Sciences (DISC), University of Genoa and Ospedale Policlinico San Martino IRCCS, Genoa Surgical Pathology Unit, Department of Medicine (DIMED), University of Padua Veneto Institute of Oncology, IOV-IRCCS, Padua Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori," Meldola Pathology Unit, Department of Medicine and Surgery, University of Insubria, Varese Gatroenterology Unit, ASST Fatebenefratelli-Sacco, L. Sacco University Hospital Department of Biochemical and Clinical Sciences, University of Milan, Milan Division of General and HPB Surgery, ASST Rhodense, Rho Gatroenterology Unit, Department of Systems Medicine, University of Rome "Tor Vergata," Rome, Italy Department of Pathology, Koç University Hospital and Koç University Research Center for Translational Medicine (KUTTAM), Istanbul, Turkey.

Poorly cohesive carcinomas (PCCs) are neoplasms characterized by a dyshesive cell invasion pattern featuring single-cell or cord-like stromal infiltration. Although they have been extensively studied in the stomach and other digestive system organs, limited data regarding nonampullary small bowel poorly cohesive carcinomas (SB-PCCs) are hitherto available. The aims of our study were to analyze the clinicopathologic and immunophenotypical features of SB-PCCs (PCC pattern accounting for >50% of the neoplasm) and to compare them with small bowel adenocarcinomas (SBAs), not otherwise specified (SBAs-NOS) and with cancers with a histologically distinct PCC component accounting for 10% to 50% of the neoplasm (mixed-poorly-cohesive-glandular-SBAs). Fifteen SB-PCCs were identified and compared with 95 SBAs-NOS and 27 mixed-poorly-cohesive-glandular-SBAs. Most SB-PCCs (67%) were composed of <10% of signet-ring cells, and all but 1 SB-PCCs exhibited loss of membranous expression of E-cadherin. Compared with SBAs-NOS, SB-PCCs showed a significantly younger patient age at diagnosis, and a stronger association with Crohn disease, and both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs featured a higher rate of lymphovascular and perineural invasion and a lower percentage of mismatch repair-deficient cases. Importantly, the cancer-specific survival of SB-PCC (hazard ratio: 3.81; 95% confidence interval: 1.90-7.64; P<0.001) and mixed-poorly-cohesive-glandular-SBA (4.12; 2.20-7.71; P<0.001) patients was significantly worse compared with SBAs-NOS cases. This study provides objective evidence to the World Health Organization (WHO) 2019 introduction of SB-PCC as a distinctive subtype of nonampullary SBA, by virtue of its unique clinical and histologic features, and suggests that both SB-PCCs and mixed-poorly-cohesive-glandular-SBAs should be separated from SBAs-NOS.
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http://dx.doi.org/10.1097/PAS.0000000000001821DOI Listing
October 2021

Moving beyond PARP Inhibition: Current State and Future Perspectives in Breast Cancer.

Int J Mol Sci 2021 Jul 23;22(15). Epub 2021 Jul 23.

Department of Medical Oncology, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy.

Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms "PARP inhibitors" and "breast cancer", was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.
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http://dx.doi.org/10.3390/ijms22157884DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8346118PMC
July 2021

Genetic and Epigenetic Alterations of Regulatory Regions in Hereditary and Sporadic Gastric Cancer.

Pharmaceuticals (Basel) 2021 May 12;14(5). Epub 2021 May 12.

Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) "Dino Amadori", 47014 Meldola, Italy.

E-cadherin is a key player in gastric cancer (GC) and germline alterations of , its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC -negative patients and 6 healthy controls. The NGS analysis on coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with expression levels and have a role in its regulation.
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http://dx.doi.org/10.3390/ph14050457DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151134PMC
May 2021

Early Gastric Cancer: identification of molecular markers able to distinguish submucosa-penetrating lesions with different prognosis.

Gastric Cancer 2021 Mar 6;24(2):392-401. Epub 2020 Nov 6.

Pathology Unit, Morgagni-Pierantoni Hospital, Forlì, Italy.

Background: Early Gastric Cancer (EGC) reaches 25% of the gastric cancers surgically treated in some areas of Northeastern Italy and is usually characterized by a good prognosis. However, among EGCs classified according to Kodama's criteria, Pen A subgroup is characterized by extensive submucosal invasion, lymph node metastases and worse prognosis, whereas Pen B subgroup by better prognosis. The aim of the study was to characterize the differences between Pen A, Pen B and locally advanced gastric cancer (T3N0) in order to identify biomarkers involved in aggressiveness and clinical outcome.

Methods: We selected 33 Pen A, 34 Pen B and 20 T3N0 tumors and performed immunohistochemistry of mucins, copy number variation analysis of a gene panel, microsatellite instability (MSI), TP53 mutation and loss of heterozygosity (LOH) analyses.

Results: Pen A subgroup was characterized by MUC6 overexpression (p = 0.021). Otherwise, the Pen B subgroup was significantly associated with the amplification of GATA6 gene (p = 0.002). The higher percentage of MSI tumors was observed in T3N0 group (p = 0.002), but no significant differences between EGC types were found. Finally, TP53 gene analysis showed that 32.8% of Pen tumors have a mutation in exons 5-8 and 50.0% presented LOH. Co-occurrence of TP53 mutation and LOH mainly characterized Pen A tumors (p = 0.022).

Conclusions: Our analyses revealed that clinico-pathological parameters, microsatellite status and frequency of TP53 mutations do not seem to distinguish Pen subgroups. Conversely, the amplification of GATA6 was associated with Pen B, as well as the overexpression of MUC6 and the TP53 significantly characterized Pen A.
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http://dx.doi.org/10.1007/s10120-020-01135-8DOI Listing
March 2021

Instability of Non-Standard Microsatellites in Relation to Prognosis in Metastatic Colorectal Cancer Patients.

Int J Mol Sci 2020 May 16;21(10). Epub 2020 May 16.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Very few data are reported in the literature on the association between elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) and prognosis in advanced colorectal cancer. Moreover, there is no information available in relation to the response to antiangiogenic treatment. We analyzed EMAST and vascular endothelial growth factor-B (VEGF-B) microsatellite status, together with standard microsatellite instability (MSI), in relation to prognosis in 141 patients with metastatic colorectal cancer (mCRC) treated with chemotherapy (CT) alone ( = 51) or chemotherapy with bevacizumab (B) (CT + B; = 90). High MSI (MSI-H) was detected in 3% of patients and was associated with progression-free survival (PFS; = 0.005) and overall survival (OS; < 0.0001). A total of 8% of cases showed EMAST instability, which was associated with worse PFS ( = 0.0006) and OS ( < 0.0001) in patients treated with CT + B. A total of 24.2% of patients showed VEGF-B instability associated with poorer outcome in ( = 0.005) in the CT arm. In conclusion, our analysis indicated that EMAST instability is associated with worse prognosis, particularly evident in patients receiving CT + B.
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http://dx.doi.org/10.3390/ijms21103532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7279028PMC
May 2020

Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients.

Diagnostics (Basel) 2020 Apr 30;10(5). Epub 2020 Apr 30.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than and . We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the gene and six in the gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in , , , , and genes. From our study, and emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development.
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http://dx.doi.org/10.3390/diagnostics10050269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7277207PMC
April 2020

Genetic Predisposition to Breast and Ovarian Cancers: How Many and Which Genes to Test?

Int J Mol Sci 2020 Feb 8;21(3). Epub 2020 Feb 8.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

Breast and ovarian cancers are some of the most common tumors in females, and the genetic predisposition is emerging as one of the key risk factors in the development of these two malignancies. and are the best-known genes associated with hereditary breast and ovarian cancer. However, recent advances in molecular techniques, Next-Generation Sequencing in particular, have led to the identification of many new genes involved in the predisposition to breast and/or ovarian cancer, with different penetrance estimates. , , , and have been identified as high penetrance genes for the risk of breast/ovarian cancers. Besides them, , , , , , , , , and mismatch repair genes have been recognized as moderate and low penetrance genes, along with other genes encoding proteins involved in the same pathways, possibly associated with breast/ovarian cancer risk. In this review, we summarize the past and more recent findings in the field of cancer predisposition genes, with insights into the role of the encoded proteins and the associated genetic disorders. Furthermore, we discuss the possible clinical utility of genetic testing in terms of prevention protocols and therapeutic approaches.
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http://dx.doi.org/10.3390/ijms21031128DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038038PMC
February 2020

Identification of a novel large EPCAM-MSH2 duplication, concurrently with LOHs in chromosome 20 and X, in a family with Lynch syndrome.

Int J Colorectal Dis 2019 Nov 26;34(11):1999-2002. Epub 2019 Oct 26.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Via Piero Maroncelli 40, 47014, Meldola, FC, Italy.

Background: Lynch syndrome (LS) is associated with germline mutations in one of the mismatch repair genes or EPCAM. The majority of the causative alterations are point mutations. Large genomic rearrangements represent only 5-20%. Hypothetically, the allelic imbalance, like the loss of heterozygosity, may be another high penetrance risk factor.

Case Presentation: We describe the case of a patient who developed 5 tumors during her lifetime and with a family history characterized by a high frequency of tumors associated with LS. The proband was tested for mutations and copy number alterations with a panel of hereditary cancer genes and by SNP array. She showed a 187 Kb duplication including EPCAM and the first 7 exons of MSH2, plus two loss of heterozygosity (LOHs) in chromosome 20 and one in chromosome X which include many tumor suppressor genes.

Conclusion: We found a novel large EPCAM-MSH2 duplication associated with LS and the presence of LOHs in regions containing numerous tumor suppressors, raising the hypothesis that these alterations could contribute to cancer susceptibility. Our results underline the importance to deepen the knowledge of molecular mechanisms in order to determine the role in cancer predisposition of novel genetic alterations.
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http://dx.doi.org/10.1007/s00384-019-03414-yDOI Listing
November 2019

Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition.

Cancers (Basel) 2019 Sep 11;11(9). Epub 2019 Sep 11.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

The main gene involved in gastric cancer (GC) predisposition is , the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). only explains a fraction (10-50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in , , , and breast/ovarian cancer susceptibility genes, as well as in , , , , and genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides , our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.
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http://dx.doi.org/10.3390/cancers11091340DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769562PMC
September 2019

E-cadherin Downregulation and microRNAs in Sporadic Intestinal-Type Gastric Cancer.

Int J Mol Sci 2019 Sep 10;20(18). Epub 2019 Sep 10.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, 47014 Meldola, Italy.

gene, encoding E-cadherin, is a tumor suppressor gene frequently altered in gastric cancers (GCs) of both diffuse (DGC) and intestinal (IGC) histotypes, albeit through different mechanisms. The study aimed to characterize expression in sporadic IGC and to investigate whether microRNAs (miRs) are involved in its transcriptional control. We evaluated expression by quantitative real-time PCR (RT-qPCR) in 33 IGC patients and found a significant downregulation in tumor tissues compared to normal counterparts (-value = 0.025). Moreover, 14 miRs, predicted to be involved in regulation in both a direct and indirect manner, were selected and analyzed by RT-qPCR in an independent case series of 17 IGCs and matched normal tissues. miR-101, miR-26b, and miR-200c emerged as significantly downregulated and were confirmed in the case series of 33 patients (-value < 0.001). Finally, we evaluated expression, a target of both miR-101 and miR-26b, which showed significant upregulation in IGCs (-value = 0.005). A significant inverse correlation was observed between overexpression and , miR-101, and miR-26b levels (-value < 0.001). Our results reinforce the link between and IGC, highlighting the role of miRs in its transcriptional control and improving our understanding of GC subtypes and biomarkers.
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http://dx.doi.org/10.3390/ijms20184452DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6769612PMC
September 2019

Evaluation of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk.

Endocr Connect 2019 Aug;8(8):1224-1229

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

Breast cancer in men is a rare and still poorly characterized disease. Inherited mutations in BRCA1, BRCA2 and PALB2 genes, as well as common polymorphisms, play a role in male breast cancer genetic predisposition. Male breast cancer is considered a hormone-dependent tumor specifically related to hyperestrogenism. Polymorphisms in genes involved in estrogen biosynthesis and metabolism pathways, such as CYP17A1 and CYP1B1, have been associated with breast cancer risk. Here, we aimed to investigate the role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer risk. A series of 597 male breast cancer cases and 1022 male controls, recruited within the Italian Multicenter Study on male breast cancer, was genotyped for CYP17A1 rs743572, CYP1B1 rs1056836 and rs1800440 polymorphisms by allelic discrimination real-time PCR with TaqMan probes. Associations with male breast cancer risk were estimated using logistic regression. No statistically significant associations between male breast cancer risk and the three analyzed polymorphisms emerged. Similar results were obtained also when BRCA1/2 mutational status was considered. No significant differences in the distribution of the genotypes according to estrogen receptor status emerged. In conclusion, our study, based on a large series of male breast cancer cases, is likely to exclude a relevant role of CYP17A1 and CYP1B1 polymorphisms in male breast cancer predisposition. Overall, these results add new data to the increasing evidence that polymorphisms in these genes may not be associated with breast cancer risk.
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http://dx.doi.org/10.1530/EC-19-0225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6733362PMC
August 2019

Genetic Testing and Clinical Management Practices for Variants in Non-BRCA1/2 Breast (and Breast/Ovarian) Cancer Susceptibility Genes: An International Survey by the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) Clinical Working Group.

JCO Precis Oncol 2018 26;2. Epub 2018 Oct 26.

Catalan Institute of Oncology and CIBERONC, Barcelona.

Purpose: To describe a snapshot of international genetic testing practices, specifically regarding the use of multigene panels, for hereditary breast/ovarian cancers. We conducted a survey through the Evidence-Based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium, covering questions about 16 non-/ genes.

Methods: Data were collected via in-person and paper/electronic surveys. ENIGMA members from around the world were invited to participate. Additional information was collected via country networks in the United Kingdom and in Italy.

Results: Responses from 61 cancer genetics practices across 20 countries showed that 16 genes were tested by > 50% of the centers, but only six (, , , , , and ) were tested regularly. US centers tested the genes most often, whereas United Kingdom and Italian centers with no direct ENIGMA affiliation at the time of the survey were the least likely to regularly test them. Most centers tested the 16 genes through multigene panels; some centers tested , , and other cancer syndrome-associated genes individually. Most centers reported (likely) pathogenic variants to patients and would test family members for such variants. Gene-specific guidelines for breast and ovarian cancer risk management were limited and differed among countries, especially with regard to starting age and type of imaging and risk-reducing surgery recommendations.

Conclusion: Currently, a small number of genes beyond / are routinely analyzed worldwide, and management guidelines are limited and largely based on expert opinion. To attain clinical implementation of multigene panel testing through evidence-based management practices, it is paramount that clinicians (and patients) participate in international initiatives that share panel testing data, interpret sequence variants, and collect prospective data to underpin risk estimates and evaluate the outcome of risk intervention strategies.
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http://dx.doi.org/10.1200/PO.18.00091DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6742430PMC
October 2018

Multiple-gene panel analysis in a case series of 255 women with hereditary breast and ovarian cancer.

Oncotarget 2017 Jul;8(29):47064-47075

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

As new genes predisposing to breast (BC) and ovarian cancer (OC) are constantly emerging, the use of panels of genes analyzed by Next-Generation Sequencing (NGS) is increasing in clinical diagnostics. The identification of a large number of new germline mutations allows for deeper knowledge of cancer predisposition, although raising many questions about patient management.BC and OC patients recruited by our counseling service between 2012-2015 were included in this study. DNA was extracted from peripheral blood and a panel of 94 genes involved in hereditary tumors was analyzed by NGS. Patient clinical features of BC and OC and cancer family history were collected and compared to the patient genetic profile.A total of 255 women were analyzed, 57 of whom had a pathogenic mutation in BRCA1/2 genes, and 17 carried pathogenic mutations in other genes, such as PALB2, ATM, BRIP1, RAD51D, MSH6, PPM1D, RECQL4, ERCC3, TSC2, SLX4 and other Fanconi anemia genes.Patients with a pathogenic mutation in genes other than BRCA1 and BRCA2 showed no significant difference from the BRCA1/2-mutated carriers with respect to age at diagnosis and clinical features, suggesting that mutations in other genes could pose a high risk of cancer development.These patients had a much higher percentage of bilateral breast cancer (BBC) and a lower rate of OC than BRCA-mutated patients and patients with no pathogenic mutations: as a consequence, the surveillance protocol should be customized to the patient genetic characteristics.
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http://dx.doi.org/10.18632/oncotarget.16791DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5564544PMC
July 2017

Cell-free DNA as a diagnostic marker for cancer: current insights.

Onco Targets Ther 2016 25;9:6549-6559. Epub 2016 Oct 25.

Biosciences Laboratory.

The increasing knowledge of the molecular pathogenesis of cancer and the rapid development of new molecular techniques are promoting the study of early molecular alterations involved in cancer development in body fluids. Specific genetic and epigenetic alterations could be found in plasma, serum, and urine cell-free DNA (cfDNA) and could potentially be used as diagnostic biomarkers for several types of cancers. This review focuses on the role of cfDNA in diagnosis: a PubMed search was performed by selecting papers according to journal impact factor and robustness of statistical analysis. A comprehensive evaluation of "liquid biopsy", including cfDNA analysis, will be one of the critical challenges to better understand the early mechanisms of cancer development.
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http://dx.doi.org/10.2147/OTT.S100901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5087772PMC
October 2016

Multiple primary tumors in a family with Li-Fraumeni syndrome with a TP53 germline mutation identified by next-generation sequencing.

Int J Biol Markers 2016 Dec 23;31(4):e461-e465. Epub 2016 Dec 23.

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola (Forlì-Cesena) - Italy.

Li-Fraumeni syndrome (LFS) is an autosomal dominant disorder occurring at a young age that predisposes individuals to multiple forms of cancer and to a heterogeneous spectrum of malignancies. We describe the clinical history of a patient who had 5 primary malignant cancers and a familiar history consistent with LFS. We analyzed the genomic DNA of the proband and her relatives by next-generation sequencing (NGS) technology using an enrichment protocol for the simultaneous sequencing of 94 genes involved in hereditary cancers. Genetic analysis of the proband revealed a TP53 germline mutation in exon 5 determining a nucleotide alteration at codon 175 (R175H), a hot spot mutation site related to LFS and a reported pathogenic mutation. The proband daughter's and brother's DNA did not carry the TP53 mutation but they had some rare variants in common with the proband, in addition to other variants with a still unclear role. In conclusion, we identified a TP53 mutation in a patient with multiple primary tumors and a family history characterized by a severe susceptibility to cancer. The genetic analysis by targeted NGS led to the identification of the genetic background and to the exclusion of a cancer risk for the family members. Targeted NGS represents an efficient approach for the identification of mutations in families with a heterogeneous phenotype.
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http://dx.doi.org/10.5301/jbm.5000227DOI Listing
December 2016

Morphological and genetic heterogeneity in multifocal lung adenocarcinoma: The case of a never-smoker woman.

Lung Cancer 2016 06 25;96:52-5. Epub 2016 Mar 25.

Immunology and Molecular Oncology Unit, Istituto Oncologico Veneto IRCCS, via Gattamelata 64, 35128 Padova, Italy. Electronic address:

Discrimination of multifocal primary lung cancers from lung metastases is crucial to allow for an appropriate clinical management. We report here a case of multifocal lung adenocarcinomas with different morphological and molecular patterns. Radical surgery of one lung nodule was performed at the time of diagnosis, and subsequently on two other lung nodules. At the time of distant relapse, biopsy was repeated for molecular characterization. The patient was treated with EGFR tyrosine kinase inhibitor according to the detection of EGFR exon 21 mutation in metastatic sample and in one of the three lung tumors, characterized by lower mutated allele frequency. The progression free survival was three months according to radiological criteria and the treatment was provided for six months, until clinical progression. Following the assessment of EGFR mutations by pyrosequencing, tumor samples were analyzed by a 30-gene next generation sequencing (NGS) panel, allowing to study intra- and inter-tumor heterogeneity and to confirm the three lung tumors as independent. Different molecular profiles of synchronous tumors and identical EGFR, PIK3CA and TP53 mutations in one of three primary lung tumors and the metachronous metastasis were identified. In conclusion, morphological and molecular characterization of multiple lung nodules by NGS may help to define synchronous and metachronous adenocarcinomas, thus affecting surgical indication and systemic treatment. Intratumor heterogeneity may be associated with differential sensitivity to targeted treatment.
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http://dx.doi.org/10.1016/j.lungcan.2016.03.009DOI Listing
June 2016

Preclinical evidence of multiple mechanisms underlying trastuzumab resistance in gastric cancer.

Oncotarget 2016 Apr;7(14):18424-39

Biosciences Laboratory, Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

HER2-positive advanced gastric cancer patients frequently develop resistance to trastuzumab through mechanisms still poorly understood. In breast cancer, other members of the HER-family are known to be involved in trastuzumab-resistance, as is overexpression of the scaffold protein IQGAP1. In the present work, we investigated acquired resistance to trastuzumab in gastric cancer experimental models. Trastuzumab-resistant (HR) subclones derived from 3 HER2-overexpressing gastric cancer cells were generated and characterized for alterations in HER2-signaling mechanisms by next-generation sequencing, immunohistochemical, western blot and qRT-PCR techniques, and molecular modeling analysis. All subclones showed a reduced growth rate with respect to parental cell lines but each had a different resistance mechanism. In NCI N87 HR cells, characterized by a marked increase in HER2-signaling pathways with respect to the parental cell line, trastuzumab sensitivity was restored when IQGAP1 expression was silenced. AKG HR subclone showed higher HER3 protein expression than the parental line. High nuclear HER4 levels were observed in KKP HR cells. In conclusion, our study revealed that high IQGAP1 expression leads to resistance to trastuzumab in gastric cancer. Furthermore, 2 new mutations of the HER2 gene that may be involved in acquired resistance were identified in AKG HR and KKP HR subclones.
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http://dx.doi.org/10.18632/oncotarget.7575DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4951299PMC
April 2016

First evidence of a large CHEK2 duplication involved in cancer predisposition in an Italian family with hereditary breast cancer.

BMC Cancer 2014 Jul 1;14:478. Epub 2014 Jul 1.

Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS, Meldola, Italy.

Background: CHEK2 is a multi-cancer susceptibility gene whose common germline mutations are known to contribute to the risk of developing breast and prostate cancer.

Case Presentation: Here, we describe an Italian family with a high number of cases of breast cancer and other types of tumour subjected to the MLPA test to verify the presence of BRCA1, BRCA2 and CHEK2 deletions and duplications. We identified a new 23-kb duplication in the CHEK2 gene extending from intron 5 to 13 that was associated with breast cancer in the family. The presence and localisation of the alteration was confirmed by a second analysis by Next-Generation Sequencing.

Conclusions: This finding suggests that CHEK2 mutations are heterogeneous and that techniques other than sequencing, such as MLPA, are needed to identify CHEK2 mutations. It also indicates that CHEK2 rare variants, such as duplications, can confer a high susceptibility to cancer development and should thus be studied in depth as most of our knowledge of CHEK2 concerns common mutations.
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http://dx.doi.org/10.1186/1471-2407-14-478DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4091954PMC
July 2014
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