TY - JOUR
T1 - New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis
AU - Valle, Laura
AU - Hernández-Illán, Eva
AU - Bellido, Fernando
AU - Aiza, Gemma
AU - Castillejo, Adela
AU - Castillejo, María Isabel
AU - Navarro, Matilde
AU - Seguí, Nuria
AU - Vargas, Gardenia
AU - Guarinos, Carla
AU - Juarez, Miriam
AU - Sanjuán, Xavier
AU - Iglesias, Silvia
AU - Alenda, Cristina
AU - Egoavil, Cecilia
AU - Segura, Ángel
AU - Juan, María José
AU - Rodriguez-Soler, María
AU - Brunet, Joan
AU - González, Sara
AU - Jover, Rodrigo
AU - Lázaro, Conxi
AU - Capellá, Gabriel
AU - Pineda, Marta
AU - Soto, José Luís
AU - Blanco, Ignacio
N1 - Funding Information:
This work was supported by the Spanish Ministry of Economy and Competitiveness (State Secretariat for Research, Development and Innovation) (SAF2012-38885 to L.V.); the Spanish Ministry of Health and the Carlos III Health Institute (FIS PI08/0726 to R.J.); L’Oréal-UNESCO ‘For Women in Science’; the Scientific Foundation Asociación Española Contra el Cáncer; and the Government of Catalonia (2009SGR290). L.V. is a recipient of a Ramón y Cajal contract and F.B. of a fellowship both from the Spanish Ministry of Economy and Competitiveness. E.H.-I. and N.S. hold fellowships from the Carlos III Health Institute and C.G. from the Con-selleria d’Educació of the Valencian Autonomous Community.
PY - 2014/7
Y1 - 2014/7
N2 - Germline mutations in DNA polymerase ε (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onsetCRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in amismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays.POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.
AB - Germline mutations in DNA polymerase ε (POLE) and δ (POLD1) have been recently identified in families with multiple colorectal adenomas and colorectal cancer (CRC). All reported cases carried POLE c.1270C>G (p.Leu424Val) or POLD1 c.1433G>A (p.Ser478Asn) mutations. Due to the scarcity of cases reported so far, an accurate clinical phenotype has not been defined. We aimed to assess the prevalence of these recurrent mutations in unexplained familial and early-onsetCRC and polyposis, and to add additional information to define the clinical characteristics of mutated cases. A total of 858 familial/early onset CRC and polyposis patients were studied: 581 familial and early-onset CRC cases without mismatch repair (MMR) deficiency, 86 cases with MMR deficiency and 191 polyposis cases. Mutation screening was performed by KASPar genotyping assays and/or Sanger sequencing of the involved exons. POLE p.L424V was identified in a 28-year-old polyposis and CRC patient, as a de novo mutation. None of the 858 cases studied carried POLD1 p.S478N. A new mutation, POLD1 c.1421T>C (p.Leu474Pro), was identified in amismatch repair proficient Amsterdam II family. Its pathogenicity was supported by cosegregation in the family, in silico predictions, and previously published yeast assays.POLE and POLD1 mutations explain a fraction of familial CRC and polyposis. Sequencing the proofreading domains of POLE and POLD1 should be considered in routine genetic diagnostics. Until additional evidence is gathered, POLE and POLD1 genetic testing should not be restricted to polyposis cases, and the presence of de novo mutations, considered.
UR - http://www.scopus.com/inward/record.url?scp=84902330508&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddu058
DO - 10.1093/hmg/ddu058
M3 - Artículo
C2 - 24501277
AN - SCOPUS:84902330508
SN - 0964-6906
VL - 23
SP - 3506
EP - 3512
JO - Human Molecular Genetics
JF - Human Molecular Genetics
IS - 13
M1 - ddu058
ER -