Germline Mutations in FAN1 Cause Hereditary Colorectal Cancer by Impairing DNA Repair

Nuria Seguí, Leonardo B. Mina, Conxi Lázaro, Rebeca Sanz-Pamplona, Tirso Pons, Matilde Navarro, Fernando Bellido, Adriana López-Doriga, Rafael Valdés-Mas, Marta Pineda, Elisabet Guinó, August Vidal, José Luís Soto, Trinidad Caldés, Mercedes Durán, Miguel Urioste, Daniel Rueda, Joan Brunet, Milagros Balbín, Pilar BlaySilvia Iglesias, Pilar Garré, Enrique Lastra, Ana Beatriz Sánchez-Heras, Alfonso Valencia, Victor Moreno, Miguel Ángel Pujana, Alberto Villanueva, Ignacio Blanco, Gabriel Capellá, Jordi Surrallés, Xose S. Puente, Laura Valle

Research output: Contribution to journalArticlepeer-review

87 Scopus citations


Identification of genes associated with hereditary cancers facilitates management of patients with family histories of cancer. We performed exome sequencing of DNA from 3 individuals from a family with colorectal cancer who met the Amsterdam criteria for risk of hereditary nonpolyposis colorectal cancer. These individuals had mismatch repair-proficient tumors and each carried nonsense variant in the FANCD2/FANCI-associated nuclease 1 gene (FAN1), which encodes a nuclease involved in DNA inter-strand cross-link repair. We sequenced FAN1 in 176 additional families with histories of colorectal cancer and performed in vitro functional analyses of the mutant forms of FAN1 identified. We detected FAN1 mutations in approximately 3% of families who met the Amsterdam criteria and had mismatch repair-proficient cancers with no previously associated mutations. These findings link colorectal cancer predisposition to the Fanconi anemia DNA repair pathway, supporting the connection between genome integrity and cancer risk.

Original languageEnglish
Pages (from-to)563-566
Number of pages4
Issue number3
StatePublished - 1 Sep 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2015 AGA Institute.


  • DNA Mismatch Repair
  • Genetic Risk Factor
  • Lynch Syndrome
  • Susceptibility


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