title: Characterization of a novel POLD1 missense founder mutation in a Spanish population.
abstract: BACKGROUND
  We identified a new and a recurrent POLD1 mutation associated with predisposition to colorectal cancer (CRC). We characterized the molecular and clinical nature of the potential POLD1 founder mutation in families from Valencia (Spain).
  
  
  METHODS
  Clinical and molecular data were collected from four independent families known to have a POLD1 Leu474Pro mutation. To establish its founder effect, haplotype construction was performed using 14 flanking POLD1 polymorphic markers. We calculated penetrance estimates and clinical expressivity, globally and stratified by age and sex.
  
  
  RESULTS
  We included 32 individuals from the four families: 20 carriers and 12 noncarriers. A common haplotype was identified in these families in a region comprising 2,995 Mb, confirming L474P as the first founder POLD1 mutation identified. Thirteen tumors diagnosed in 10 POLD1 carriers: eight CRC, three endometrial and two other tumors were considered. The median age of cancer onset for POLD1 mutation carriers was 48 years. The observed penetrance was 50% and the cumulative risk at age of 50 years was 30%.
  
  
  CONCLUSIONS
  The findings of the present study contribute to a better understanding of CRC genetics in the Spanish population. The clinical phenotype for this mutation is similar to that in Lynch syndrome. Future studies using next generation sequencing with large gene panels for any hereditary cancer condition will offer the possibility of detecting POLE/POLD1 mutations in unsuspected clinical situations, demonstrating a more real and unbiased picture of the associated phenotype.
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Ferrer-Avargues
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.
authors.forename: Virginia
authors.initials: V
authors.lastname: Díez-Obrero
authors.affiliation: Análisis Clínicos, Hospital Universitario Elche, Elche, Spain.
authors.forename: Ester
authors.initials: E
authors.lastname: Martín-Tomás
authors.affiliation: Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL), Alicante, Spain.|Unidad Investigación, Hospital Universitario Alicante, Alicante, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Hernández-Illán
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.
authors.forename: María-Isabel
authors.initials: MI
authors.lastname: Castillejo
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.
authors.forename: Alan
authors.initials: A
authors.lastname: Codoñer-Alejos
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.|Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL), Alicante, Spain.
authors.forename: Víctor-Manuel
authors.initials: VM
authors.lastname: Barberá
authors.affiliation: Consejo Genético en Cáncer, Hospital Universitario Elche, Elche, Spain.
authors.forename: Ana-Beatriz
authors.initials: AB
authors.lastname: Sánchez-Heras
authors.affiliation: Consejo Genético en Cáncer, Hospital Universitario La Fe, Valencia, Spain.
authors.forename: Ángel
authors.initials: Á
authors.lastname: Segura
authors.affiliation: Consejo Genético en Cáncer, Fundación Instituto Valenciano Oncología, Valencia, Spain.
authors.forename: María-José
authors.initials: MJ
authors.lastname: Juan
authors.affiliation: Consejo Genético en Cáncer, Hospital Provincial Castellón, Castellón, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Tena
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.
authors.forename: Adela
authors.initials: A
authors.lastname: Castillejo
authors.affiliation: Unidad Genética Molecular, Hospital Universitario Elche, Elche, Spain.|Instituto Investigación Sanitaria y Biomédica Alicante (ISABIAL), Alicante, Spain.
authors.forename: José-Luis
authors.initials: JL
authors.lastname: Soto
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis / Q000453:epidemiology / Q000235:genetics; D004258:DNA Polymerase III / Q000235:genetics*; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease; D005828:Genetics, Population; D018095:Germ-Line Mutation; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D020125:Mutation, Missense; D019683:Penetrance; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011159:Population Surveillance; D013030:Spain; D044465:White People / Q000235:genetics*; D055815:Young Adult
chemical_list: C434055:POLD1 protein, human; D004258:DNA Polymerase III
keywords: colon/rectal cancer; molecular genetics