title: A comprehensive custom panel design for routine hereditary cancer testing: preserving control, improving diagnostics and revealing a complex variation landscape.
abstract: We wanted to implement an NGS strategy to globally analyze hereditary cancer with diagnostic quality while retaining the same degree of understanding and control we had in pre-NGS strategies. To do this, we developed the I2HCP panel, a custom bait library covering 122 hereditary cancer genes. We improved bait design, tested different NGS platforms and created a clinically driven custom data analysis pipeline. The I2HCP panel was developed using a training set of hereditary colorectal cancer, hereditary breast and ovarian cancer and neurofibromatosis patients and reached an accuracy, analytical sensitivity and specificity greater than 99%, which was maintained in a validation set. I2HCP changed our diagnostic approach, involving clinicians and a genetic diagnostics team from panel design to reporting. The new strategy improved diagnostic sensitivity, solved uncertain clinical diagnoses and identified mutations in new genes. We assessed the genetic variation in the complete set of hereditary cancer genes, revealing a complex variation landscape that coexists with the disease-causing mutation. We developed, validated and implemented a custom NGS-based strategy for hereditary cancer diagnostics that improved our previous workflows. Additionally, the existence of a rich genetic variation in hereditary cancer genes favors the use of this panel to investigate their role in cancer risk.
authors.affiliation: Hereditary Cancer Group, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Castellanos
authors.affiliation: Hereditary Cancer Group, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Bernat
authors.initials: B
authors.lastname: Gel
authors.affiliation: Hereditary Cancer Group, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Inma
authors.initials: I
authors.lastname: Rosas
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Tornero
authors.affiliation: Genomics and Bioinformatics Unit, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Sheila
authors.initials: S
authors.lastname: Santín
authors.affiliation: Genomics and Bioinformatics Unit, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Raquel
authors.initials: R
authors.lastname: Pluvinet
authors.affiliation: Genomics and Bioinformatics Unit, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Velasco
authors.affiliation: Genomics and Bioinformatics Unit, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Lauro
authors.initials: L
authors.lastname: Sumoy
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Jesús
authors.initials: J
authors.lastname: Del Valle
authors.affiliation: Hereditary Cancer Group, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Manuel
authors.initials: M
authors.lastname: Perucho
authors.affiliation: Clinical Genetics and Genetic Counseling Program, Germans Trias i Pujol Hospital, Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Ignacio
authors.initials: I
authors.lastname: Blanco
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Matilde
authors.initials: M
authors.lastname: Navarro
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IdibGi in Girona, Catalonia, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Brunet
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Pineda
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Feliubadaló
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Gabi
authors.initials: G
authors.lastname: Capellá
authors.affiliation: Hereditary Cancer Program, Joint Program on Hereditary Cancer, Catalan Institute of Oncology, IDIBELL campus in Hospitalet de Llobregat, Catalonia, Spain.
authors.forename: Conxi
authors.initials: C
authors.lastname: Lázaro
authors.affiliation: Hereditary Cancer Group, Program on Predictive and Personalized Medicine of Cancer (PMPPC), Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, Badalona, Barcelona, Spain.
authors.forename: Eduard
authors.initials: E
authors.lastname: Serra
mesh_terms: D055088:Early Detection of Cancer / Q000379:methods*; D005820:Genetic Testing / Q000379:methods*; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods; D006801:Humans; D025202:Molecular Diagnostic Techniques / Q000379:methods*; D009386:Neoplastic Syndromes, Hereditary / Q000175:diagnosis* / Q000235:genetics*; D012680:Sensitivity and Specificity