New insights into POLE and POLD1 germline mutations in familial colorectal cancer and polyposis.
Por:
Valle, L, Hernandez-Illan, E, Bellido, F, Aiza, G, Castillejo, A, Castillejo, M, Navarro, M, Segui, N, Vargas, G, Guarinos, C, Juarez, M, Sanjuan, X, Iglesias, S, Alenda, C, Egoavil, C, Segura, A, Juan, M, Rodriguez-Soler, M, Brunet, J, Gonzalez, S, Jover, R, Lazaro, C, Capella, G, Pineda, M, Luis Soto, J and Blanco, I
Publicada:
1 jul 2014
Resumen:
Germline mutations in DNA polymerase ? (POLE) and d (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-onset CRC 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 a mismatch 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.
Filiaciones:
Valle, L:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
:
Alicante Univ Hosp, Res Lab, Alicante, Spain
Bellido, F:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
Aiza, G:
IDIBELL, Catalan Inst Oncol, Translat Res Lab, Lhospitalet De Llobregat, Spain
:
Elche Univ Hosp, Mol Genet Lab, Elche, Spain
Castillejo, M:
Elche Univ Hosp, Mol Genet Lab, Elche, Spain
Navarro, M:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
Segui, N:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
Vargas, G:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
:
Alicante Univ Hosp, Res Lab, Alicante, Spain
:
Alicante Univ Hosp, Res Lab, Alicante, Spain
Sanjuan, X:
IDIBELL, Bellvitge Univ Hosp, Dept Pathol, Lhospitalet De Llobregat, Spain
Iglesias, S:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
:
Alicante Univ Hosp, Dept Pathol, Alicante, Spain
:
Alicante Univ Hosp, Dept Pathol, Alicante, Spain
Segura, A:
La Fe Univ Hosp, Hereditary Canc Unit, Valencia, Spain
Juan, M:
Valencian Inst Oncol, Hereditary Canc Unit, Valencia, Spain
:
Alicante Univ Hosp, Dept Gastroenterol, Alicante, Spain
Brunet, J:
IDIBGI, Catalan Inst Oncol, Hereditary Canc Program, Girona, Spain
Gonzalez, S:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
:
Alicante Univ Hosp, Dept Gastroenterol, Alicante, Spain
Lazaro, C:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
Capella, G:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
Pineda, M:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
:
Elche Univ Hosp, Mol Genet Lab, Elche, Spain
Blanco, I:
IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat, Spain
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