title: Germ-line variants identified by next generation sequencing in a panel of estrogen and cancer associated genes correlate with poor clinical outcome in Lynch syndrome patients.
abstract: BACKGROUND
  The risk to develop colorectal and endometrial cancers among subjects testing positive for a pathogenic Lynch syndrome mutation varies, making the risk prediction difficult. Genetic risk modifiers alter the risk conferred by inherited Lynch syndrome mutations, and their identification can improve genetic counseling. We aimed at identifying rare genetic modifiers of the risk of Lynch syndrome endometrial cancer.
  
  
  METHODS
  A family based approach was used to assess the presence of genetic risk modifiers among 35 Lynch syndrome mutation carriers having either a poor clinical phenotype (early age of endometrial cancer diagnosis or multiple cancers) or a neutral clinical phenotype. Putative genetic risk modifiers were identified by Next Generation Sequencing among a panel of 154 genes involved in endometrial physiology and carcinogenesis.
  
  
  RESULTS
  A simple pipeline, based on an allele frequency lower than 0.001 and on predicted non-conservative amino-acid substitutions returned 54 variants that were considered putative risk modifiers. The presence of two or more risk modifying variants in women carrying a pathogenic Lynch syndrome mutation was associated with a poor clinical phenotype.
  
  
  CONCLUSIONS
  A gene-panel is proposed that comprehends genes that can carry variants with putative modifying effects on the risk of Lynch syndrome endometrial cancer. Validation in further studies is warranted before considering the possible use of this tool in genetic counseling.
authors.affiliation: Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.|Department of Clinical Genetics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Balazs
authors.initials: B
authors.lastname: Jóri
authors.affiliation: Department of Clinical Genetics, Genomics & Bioinformatics, CARIM - School for Cardiovascular Diseases, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Rick
authors.initials: R
authors.lastname: Kamps
authors.affiliation: Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Sofia
authors.initials: S
authors.lastname: Xanthoulea
authors.affiliation: Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Bert
authors.initials: B
authors.lastname: Delvoux
authors.affiliation: Department of Clinical Genetics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Marinus J
authors.initials: MJ
authors.lastname: Blok
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.|Current address: Divisions of Diagnostic Oncology & Molecular Pathology, Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, The Netherlands.
authors.forename: Koen K
authors.initials: KK
authors.lastname: Van de Vijver
authors.affiliation: Department of Clinical Genetics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Bart
authors.initials: B
authors.lastname: de Koning
authors.affiliation: Department of Clinical Genetics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Felicia Trups
authors.initials: FT
authors.lastname: Oei
authors.affiliation: Department of Clinical Genetics, Leiden University Medical Centre, Leiden, The Netherlands.
authors.forename: Carli M
authors.initials: CM
authors.lastname: Tops
authors.affiliation: Department of Pathology, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Ernst Jm
authors.initials: EJ
authors.lastname: Speel
authors.affiliation: Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Roy F
authors.initials: RF
authors.lastname: Kruitwagen
authors.affiliation: Department of Clinical Genetics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Encarna B
authors.initials: EB
authors.lastname: Gomez-Garcia
authors.affiliation: Department of Gynecology and Obstetrics, GROW - School for Oncology & Developmental Biology, Maastricht University Medical Centre, Maastricht, The Netherlands.
authors.forename: Andrea
authors.initials: A
authors.lastname: Romano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics* / Q000378:metabolism; D016889:Endometrial Neoplasms / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing / Q000379:methods*; D006801:Humans; D007150:Immunohistochemistry / Q000706:statistics & numerical data; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D012307:Risk Factors
chemical_list: D004967:Estrogens
keywords: Lynch syndrome; endometrial cancer; estrogens; genetic risk modifier; next generation sequencing