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Dive into the research topics where Franco Roviello is active.

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Featured researches published by Franco Roviello.


PLOS ONE | 2009

Profiling Critical Cancer Gene Mutations in Clinical Tumor Samples

Laura E. MacConaill; Catarina D. Campbell; Sarah M. Kehoe; Adam J. Bass; Charles Hatton; Lili Niu; Matthew M. Davis; Keluo Yao; Megan Hanna; Chandrani Mondal; Lauren Luongo; Caroline Emery; Alissa C. Baker; Juliet Philips; Deborah J. Goff; Michelangelo Fiorentino; Mark A. Rubin; Kornelia Polyak; Jennifer Chan; Yuexiang Wang; Jonathan A. Fletcher; Sandro Santagata; Gianni Corso; Franco Roviello; Ramesh A. Shivdasani; Mark W. Kieran; Keith L. Ligon; Charles D. Stiles; William C. Hahn; Matthew Meyerson

Background Detection of critical cancer gene mutations in clinical tumor specimens may predict patient outcomes and inform treatment options; however, high-throughput mutation profiling remains underdeveloped as a diagnostic approach. We report the implementation of a genotyping and validation algorithm that enables robust tumor mutation profiling in the clinical setting. Methodology We developed and implemented an optimized mutation profiling platform (“OncoMap”) to interrogate ∼400 mutations in 33 known oncogenes and tumor suppressors, many of which are known to predict response or resistance to targeted therapies. The performance of OncoMap was analyzed using DNA derived from both frozen and FFPE clinical material in a diverse set of cancer types. A subsequent in-depth analysis was conducted on histologically and clinically annotated pediatric gliomas. The sensitivity and specificity of OncoMap were 93.8% and 100% in fresh frozen tissue; and 89.3% and 99.4% in FFPE-derived DNA. We detected known mutations at the expected frequencies in common cancers, as well as novel mutations in adult and pediatric cancers that are likely to predict heightened response or resistance to existing or developmental cancer therapies. OncoMap profiles also support a new molecular stratification of pediatric low-grade gliomas based on BRAF mutations that may have immediate clinical impact. Conclusions Our results demonstrate the clinical feasibility of high-throughput mutation profiling to query a large panel of “actionable” cancer gene mutations. In the future, this type of approach may be incorporated into both cancer epidemiologic studies and clinical decision making to specify the use of many targeted anticancer agents.


Journal of Medical Genetics | 1999

Familial gastric cancer: overview and guidelines for management*

Carlos Caldas; Fátima Carneiro; Henry T. Lynch; Jun Yokota; Georgia L. Wiesner; Steven M. Powell; Frank R. Lewis; David Huntsman; Paul Pharoah; Janusz Jankowski; Patrick MacLeod; Holger Vogelsang; Gisela Keller; Ken G M Park; Frances M. Richards; Eamonn R. Maher; Simon A. Gayther; Carla Oliveira; Nicola Grehan; Derek Wight; Raquel Seruca; Franco Roviello; Bruce A.J. Ponder; Charles E. Jackson

Families with autosomal dominant inherited predisposition to gastric cancer have been described. More recently, germlineE-cadherin/CDH1mutations have been identified in hereditary diffuse gastric cancer kindred. The need to have protocols to manage and counsel these families in the clinic led a group of geneticists, gastroenterologists, surgeons, oncologists, pathologists, and molecular biologists to convene a workshop to produce consensus statements and guidelines for familial gastric cancer. Review of the available cancer pathology from people belonging to families with documented germlineE-cadherin/CDH1mutations confirmed that the gastric cancers were all of the diffuse type. Criteria to define the different types of familial gastric cancer syndromes were agreed. Foremost among these criteria was that review of histopathology should be part of the evaluation of any family with aggregation of gastric cancer cases. Guidelines for genetic testing and counselling in hereditary diffuse gastric cancer were produced. Finally, a proposed strategy for clinical management in families with high penetrance autosomal dominant predisposition to gastric cancer was defined.


Annals of Surgery | 2007

The ratio between metastatic and examined lymph nodes (N ratio) is an independent prognostic factor in gastric cancer regardless of the type of lymphadenectomy: results from an Italian multicentric study in 1853 patients.

Alberto Marchet; Simone Mocellin; Alessandro Ambrosi; Paolo Morgagni; Domenico Garcea; Daniele Marrelli; Franco Roviello; Giovanni de Manzoni; Anna Maria Minicozzi; Giovanni Natalini; Francesco De Santis; Luca Baiocchi; Arianna Coniglio; Donato Nitti

Purpose:To investigate whether the ratio between metastatic and examined lymph nodes (N ratio) is a better prognostic factor as compared with traditional staging systems in patients with gastric cancer regardless of the extension of lymph node dissection. Patients & Methods:We retrospectively reviewed the data of 1853 patients who underwent radical resection for gastric carcinoma at 6 Italian centers. Patients with >15 (group 1, n = 1421) and those with ≤15 (group 2, n = 432) lymph nodes examined were separately analyzed. N ratio categories (N ratio 0, 0%; N ratio 1, 1%–9%; N ratio 2, 10%–25%; N ratio 3, >25%) were determined by the best cut-off approach. Results:After a median follow-up of 45.5 months (range, 4–182 months), the 5-year overall survival of N0, N1, and N2 patients of group 1 versus group 2 was 83.4% versus 74.2% (P = 0.0026), 54.3% versus 44.3% (P = 0.018), and 32.7% versus 14.7% (P = 0.004), respectively, suggesting that a low number of excised lymph nodes can lead to the understaging of patients. N ratio identified subsets of patients with significantly different survival rates within N1 and N2 stages in both groups. At multivariate analysis, the N ratio (but not N stage) was retained as an independent prognostic factor both in group 1 and group 2 (HR for N ratio 1, N ratio 2, and N ratio 3 = 1.67, 2.96, and 6.59, and 1.56, 2.68, and 4.28, respectively). In our series, the implementation of N ratio led to the identification of subgroups of patients prognostically more homogeneous than those classified by the TNM system. Conclusion:N ratio is a simple and reproducible prognostic tool that can stratify patients with gastric cancer also in case of limited lymph node dissection. These data may represent the rational for improving the prognostic power of current UICC TNM staging system and ultimately the selection of patients who may most benefit from adjuvant treatments.


Cancer Research | 2012

Gastrointestinal Adenocarcinomas of the Esophagus, Stomach, and Colon Exhibit Distinct Patterns of Genome Instability and Oncogenesis

Austin M. Dulak; Steven E. Schumacher; Jasper Van Lieshout; Yu Imamura; Cameron Fox; Byoungyong Shim; Alex H. Ramos; Gordon Saksena; Sylvan C. Baca; José Baselga; Josep Tabernero; Jordi Barretina; Peter C. Enzinger; Giovanni Corso; Franco Roviello; Lin Lin; Santhoshi Bandla; James D. Luketich; Arjun Pennathur; Matthew Meyerson; Shuji Ogino; Ramesh A. Shivdasani; David G. Beer; Tony E. Godfrey; Rameen Beroukhim; Adam J. Bass

A more detailed understanding of the somatic genetic events that drive gastrointestinal adenocarcinomas is necessary to improve diagnosis and therapy. Using data from high-density genomic profiling arrays, we conducted an analysis of somatic copy-number aberrations in 486 gastrointestinal adenocarcinomas including 296 esophageal and gastric cancers. Focal amplifications were substantially more prevalent in gastric/esophageal adenocarcinomas than colorectal tumors. We identified 64 regions of significant recurrent amplification and deletion, some shared and others unique to the adenocarcinoma types examined. Amplified genes were noted in 37% of gastric/esophageal tumors, including in therapeutically targetable kinases such as ERBB2, FGFR1, FGFR2, EGFR, and MET, suggesting the potential use of genomic amplifications as biomarkers to guide therapy of gastric and esophageal cancers where targeted therapeutics have been less developed compared with colorectal cancers. Amplified loci implicated genes with known involvement in carcinogenesis but also pointed to regions harboring potentially novel cancer genes, including a recurrent deletion found in 15% of esophageal tumors where the Runt transcription factor subunit RUNX1 was implicated, including by functional experiments in tissue culture. Together, our results defined genomic features that were common and distinct to various gut-derived adenocarcinomas, potentially informing novel opportunities for targeted therapeutic interventions.


Journal of Medical Genetics | 2015

Hereditary diffuse gastric cancer: updated clinical guidelines with an emphasis on germline CDH1 mutation carriers

Rachel S. van der Post; Ingrid P. Vogelaar; Fátima Carneiro; Parry Guilford; David Huntsman; Nicoline Hoogerbrugge; Carlos Caldas; Karen E Chelcun Schreiber; Richard H. Hardwick; Margreet G. E. M. Ausems; Linda Bardram; Patrick R. Benusiglio; Tanya M. Bisseling; Vanessa Blair; Eveline M. A. Bleiker; Alex Boussioutas; Annemieke Cats; Daniel G. Coit; Lynn DeGregorio; Joana Figueiredo; James M. Ford; Esther Heijkoop; Rosella Hermens; Bostjan Humar; Pardeep Kaurah; G. Keller; Jennifer Lai; Marjolijn J. L. Ligtenberg; Maria O'Donovan; Carla Oliveira

Germline CDH1 mutations confer a high lifetime risk of developing diffuse gastric (DGC) and lobular breast cancer (LBC). A multidisciplinary workshop was organised to discuss genetic testing, surgery, surveillance strategies, pathology reporting and the patients perspective on multiple aspects, including diet post gastrectomy. The updated guidelines include revised CDH1 testing criteria (taking into account first-degree and second-degree relatives): (1) families with two or more patients with gastric cancer at any age, one confirmed DGC; (2) individuals with DGC before the age of 40 and (3) families with diagnoses of both DGC and LBC (one diagnosis before the age of 50). Additionally, CDH1 testing could be considered in patients with bilateral or familial LBC before the age of 50, patients with DGC and cleft lip/palate, and those with precursor lesions for signet ring cell carcinoma. Given the high mortality associated with invasive disease, prophylactic total gastrectomy at a centre of expertise is advised for individuals with pathogenic CDH1 mutations. Breast cancer surveillance with annual breast MRI starting at age 30 for women with a CDH1 mutation is recommended. Standardised endoscopic surveillance in experienced centres is recommended for those opting not to have gastrectomy at the current time, those with CDH1 variants of uncertain significance and those that fulfil hereditary DGC criteria without germline CDH1 mutations. Expert histopathological confirmation of (early) signet ring cell carcinoma is recommended. The impact of gastrectomy and mastectomy should not be underestimated; these can have severe consequences on a psychological, physiological and metabolic level. Nutritional problems should be carefully monitored.


JAMA Oncology | 2015

Hereditary Diffuse Gastric Cancer Syndrome: CDH1 Mutations and Beyond

Samantha Hansford; Pardeep Kaurah; Hector Li-Chang; Michelle Woo; Janine Senz; Hugo Pinheiro; Kasmintan A. Schrader; David F. Schaeffer; Karey Shumansky; George Zogopoulos; Teresa Almeida Santos; Isabel Claro; Joana Carvalho; Cydney Nielsen; Sarah Padilla; Amy Lum; Aline Talhouk; Katie Baker-Lange; Sue Richardson; Ivy Lewis; Noralane M. Lindor; Erin Pennell; Andree MacMillan; Bridget A. Fernandez; G. Keller; Henry T. Lynch; Sohrab P. Shah; Parry Guilford; Steven Gallinger; Giovanni Corso

IMPORTANCE E-cadherin (CDH1) is a cancer predisposition gene mutated in families meeting clinically defined hereditary diffuse gastric cancer (HDGC). Reliable estimates of cancer risk and spectrum in germline mutation carriers are essential for management. For families without CDH1 mutations, genetic-based risk stratification has not been possible, resulting in limited clinical options. OBJECTIVES To derive accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and determine if germline mutations in other genes are associated with HDGC. DESIGN, SETTING, AND PARTICIPANTS Testing for CDH1 germline mutations was performed on 183 index cases meeting clinical criteria for HDGC. Penetrance was derived from 75 mutation-positive families from within this and other cohorts, comprising 3858 probands (353 with gastric cancer and 89 with breast cancer). Germline DNA from 144 HDGC probands lacking CDH1 mutations was screened using multiplexed targeted sequencing for 55 cancer-associated genes. MAIN OUTCOMES AND MEASURES Accurate estimates of gastric and breast cancer risks in CDH1 mutation carriers and the relative contribution of other cancer predisposition genes in familial gastric cancers. RESULTS Thirty-one distinct pathogenic CDH1 mutations (14 novel) were identified in 34 of 183 index cases (19%). By the age of 80 years, the cumulative incidence of gastric cancer was 70% (95% CI, 59%-80%) for males and 56% (95% CI, 44%-69%) for females, and the risk of breast cancer for females was 42% (95% CI, 23%-68%). In CDH1 mutation-negative index cases, candidate mutations were identified in 16 of 144 probands (11%), including mutations within genes of high and moderate penetrance: CTNNA1, BRCA2, STK11, SDHB, PRSS1, ATM, MSR1, and PALB2. CONCLUSIONS AND RELEVANCE This is the largest reported series of CDH1 mutation carriers, providing more precise estimates of age-associated risks of gastric and breast cancer that will improve counseling of unaffected carriers. In HDGC families lacking CDH1 mutations, testing of CTNNA1 and other tumor suppressor genes should be considered. Clinically defined HDGC families can harbor mutations in genes (ie, BRCA2) with different clinical ramifications from CDH1. Therefore, we propose that HDGC syndrome may be best defined by mutations in CDH1 and closely related genes, rather than through clinical criteria that capture families with heterogeneous susceptibility profiles.


Human Molecular Genetics | 2009

Germline CDH1 deletions in hereditary diffuse gastric cancer families

Carla Oliveira; Janine Senz; Pardeep Kaurah; Hugo Pinheiro; Remo Sanges; Anne Haegert; Giovanni Corso; Jan Schouten; Rebecca C. Fitzgerald; Holger Vogelsang; Gisela Keller; Sarah Dwerryhouse; Donna Grimmer; Suet Feung Chin; Han Kwang Yang; Charles E. Jackson; Raquel Seruca; Franco Roviello; Elia Stupka; Carlos Caldas; David Huntsman

Germline CDH1 point or small frameshift mutations can be identified in 30–50% of hereditary diffuse gastric cancer (HDGC) families. We hypothesized that CDH1 genomic rearrangements would be found in HDGC and identified 160 families with either two gastric cancers in first-degree relatives and with at least one diffuse gastric cancer (DGC) diagnosed before age 50, or three or more DGC in close relatives diagnosed at any age. Sixty-seven carried germline CDH1 point or small frameshift mutations. We screened germline DNA from the 93 mutation negative probands for large genomic rearrangements by Multiplex Ligation-Dependent Probe Amplification. Potential deletions were validated by RT–PCR and breakpoints cloned using a combination of oligo-CGH-arrays and long-range-PCR. In-silico analysis of the CDH1 locus was used to determine a potential mechanism for these rearrangements. Six of 93 (6.5%) previously described mutation negative HDGC probands, from low GC incidence populations (UK and North America), carried genomic deletions (UK and North America). Two families carried an identical deletion spanning 193 593 bp, encompassing the full CDH3 sequence and CDH1 exons 1 and 2. Other deletions affecting exons 1, 2, 15 and/or 16 were identified. The statistically significant over-representation of Alus around breakpoints indicates it as a likely mechanism for these deletions. When all mutations and deletions are considered, the overall frequency of CDH1 alterations in HDGC is ∼46% (73/160). CDH1 large deletions occur in 4% of HDGC families by mechanisms involving mainly non-allelic homologous recombination in Alu repeat sequences. As the finding of pathogenic CDH1 mutations is useful for management of HDGC families, screening for deletions should be offered to at-risk families.


American Journal of Pathology | 1999

Origin of Microsatellite Instability in Gastric Cancer

Kevin C. Halling; Jeffrey F. Harper; Christopher A. Moskaluk; Stephen N. Thibodeau; Gina R. Petroni; Aron S. Yustein; Piero Tosi; Chiara Minacci; Franco Roviello; Paolo Piva; Stanley R. Hamilton; Charles E. Jackson; Steven M. Powell

Microsatellite instability (MSI) is observed in 13-44% of gastric carcinoma. The etiology of MSI in gastric carcinoma has not been clearly defined. To assess the role of mismatch repair in the development of MSI in gastric cancer, expression of hMSH2 and hMLH1 was explored. We examined 117 gastric carcinomas for MSI and observed instability at one or more loci in 19 (16%) of these tumors. Of the 19 tumors with MSI, nine exhibited low-rate MSI (MSI-L) with instability at <17% of loci, whereas the remaining 10 exhibited high-rate MSI (MSI-H) with instability at >33% of loci examined. Immunohistochemical staining for hMLH1 and hMSH2 was performed on eight of the tumors with MSI-H, five with MSI-L, and 15 tumors without MSI. All eight tumors with MSI-H showed loss of staining for either hMLH1 (n = 5) or hMSH2 (n = 3). In contrast, tumors with MSI-L or without MSI all showed normal hMSH2 and hMLH1 protein expression patterns. Moreover, all eight of the tumors with MSI-H also showed instability at BAT-26, whereas none of the MSI-L tumors or tumors without instability showed instability at BAT-26. These findings suggest that the majority of high-level MSI in gastric cancer is associated with defects of the mismatch repair pathway. Although larger studies are needed, BAT-26 appears to be a sensitive and specific marker for the MSI-H phenotype in gastric carcinoma.


Oncology | 1999

Prognostic significance of CEA, CA 19-9 and CA 72-4 preoperative serum levels in gastric carcinoma.

Daniele Marrelli; Franco Roviello; Alfonso De Stefano; Maurizio Farnetani; Lorenzo Garosi; Angelo Messano; Enrico Pinto

The prognostic value of preoperative serum levels of CEA, CA 19-9 and CA 72-4 tumor markers was investigated in 153 patients resected for gastric cancer. The positivity rates for CEA, CA 19-9 and CA 72-4 were 20.9, 34.6 and 28.1%, respectively. Multiple logistic regression analysis for positive levels of tumor markers indicates that CEA positivity is significantly related to the depth of invasion (p < 0.005) and the presence of distant metastasis (p < 0.05), CA 19-9 positivity is related to nodal involvement (p < 0.05) and the depth of invasion (p < 0.05), whereas CA 72-4 positivity is influenced by tumor size (p < 0.005) and noncurative surgery (p < 0.05). Positive levels of each tumor marker were associated with a worse prognosis if compared with negative cases using univariate analysis. Multivariate analysis of curatively resected cases identified depth in gastric wall (p < 0.0001), nodal status (p < 0.0005), and tumor location in the upper third (p < 0.05) as significant prognostic variables; CEA, CA 19-9 and CA 72-4 serum positivity did not reach statistical significance. However, when the positivity of the three markers was associated, a p value < 0.05 was observed. The analysis of survival curves stratified by tumor stage revealed that marker positivity significantly affects survival in stages I, II and IV (p < 0.05). The combined assay of CEA, CA 19-9 and CA 72-4 preoperative serum levels provides additional prognostic information in patients resected for gastric cancer; patients with preoperative positivity for one of these tumor markers should be considered at high risk of recurrence even in early stages of gastric carcinoma.


Annals of Surgery | 2005

Prediction of Recurrence After Radical Surgery for Gastric Cancer: A Scoring System Obtained From a Prospective Multicenter Study

Daniele Marrelli; Alfonso De Stefano; Giovanni de Manzoni; Paolo Morgagni; Alberto Di Leo; Franco Roviello

Objective:The aim of this prospective multicenter study was to define a scoring system for the prediction of tumor recurrence after potentially curative surgery for gastric cancer. Summary Background Data:The estimation of the risk of recurrence in individual patient may be relevant in clinical practice, to apply adjuvant therapies after surgery, and plan an adequate follow-up program. Only a few studies, most of which were retrospective or performed on a limited number of patients, have developed a prognostic score in patients with gastric cancer. Methods:A total of 536 patients who underwent UICC R0 resection between 1988 and 1998 at 3 surgical departments in Italy were considered. All patients were followed up using a standard protocol after discharge from the hospital. The mean follow-up period was 56 ± 44 months, and 94 ± 29 months for surviving patients. The scoring system was calculated on the basis of a logistic regression model, where the presence of the recurrence was the dependent variable, and clinicopathologic variables were the covariates. Results:Recurrence occurred in 272 of 536 patients (50.7%). The scoring system for the prediction of the risk in individual cases gave values ranging from 1.4 to 99.9; the model distributed most cases in the extremes of the range. The risk of recurrence increased remarkably with score values; it was only 5% in patients with a score below 10, up to 95.4% in patients with a score of 91 to 100. No recurrence was observed in 43 patients with a score below 4, whereas all of the 56 patients with a score over 97 presented a recurrence. The model correctly predicted recurrence in 227 of 272 patients (sensitivity, 83.5%), whereas the absence of recurrence was correctly predicted in 214 of 264 patients (specificity, 81.1%); the overall accuracy was 82.2%. Prognostic score was clearly superior to UICC tumor stage in predicting recurrence. The high effectiveness of the score was confirmed in preliminary data of a validation study. Conclusions:The scoring system obtained with a regression model on the basis of our follow-up data is useful for defining subgroups of patients at a very low or very high risk of tumor recurrence after radical surgery for gastric cancer. Final results of the validation study are essential for a clinical application of the model.

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Giovanni Corso

European Institute of Oncology

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