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

被引：78

作者：

Segui, Nuria ^{[1
]}

Mina, Leonardo B. ^{[2
,3
]}

Lazaro, Conxi ^{[1
]}

Sanz-Pamplona, Rebeca ^{[4
,5
]}

Pons, Tirso ^{[6
]}

Navarro, Matilde ^{[1
]}

Bellido, Fernando ^{[1
]}

Lopez-Doriga, Adriana ^{[4
,5
]}

Valdes-Mas, Rafael ^{[7
]}

Pineda, Marta ^{[1
]}

Guino, Elisabet ^{[4
,5
]}

Vidal, August ^{[8
]}

Luis Soto, Jose ^{[9
]}

Caldes, Trinidad ^{[10
]}

Duran, Mercedes ^{[11
]}

Urioste, Miguel ^{[12
,13
]}

Rueda, Daniel ^{[14
]}

Brunet, Joan ^{[15
]}

Balbin, Milagros ^{[16
]}

Blay, Pilar ^{[17
]}

Iglesias, Silvia ^{[1
]}

Garre, Pilar ^{[10
]}

Lastra, Enrique ^{[18
]}

Beatriz Sanchez-Heras, Ana ^{[19
]}

Valencia, Alfonso ^{[6
]}

Moreno, Victor ^{[4
,5
,20
]}

Angel Pujana, Miguel ^{[21
]}

Villanueva, Alberto ^{[21
]}

Blanco, Ignacio ^{[1
]}

Capella, Gabriel ^{[1
]}

Surralles, Jordi ^{[2
,3
]}

Puente, Xose S. ^{[7
]}

Valle, Laura ^{[1
]}

机构：

[1] IDIBELL, Catalan Inst Oncol, Hereditary Canc Program, Lhospitalet De Llobregat 08908, Spain

[2] Univ Autonoma Barcelona, Dept Genet & Microbiol, Genome Instabil & DNA Repair Grp, E-08193 Barcelona, Spain

[3] Ctr Biomed Network Res Rare Dis CIBERER, Barcelona, Spain

[4] IDIBELL, Catalan Inst Oncol, Unit Biomarkers & Susceptibil, Lhospitalet De Llobregat, Spain

[5] CIBERESP, Lhospitalet De Llobregat, Spain

[6] Spanish Natl Canc Res Ctr CNIO, Struct Biol & Biocomp Program, Madrid, Spain

[7] Univ Oviedo, Inst Univ Oncol Principado Asturias, Dept Bioquim & Biol Mol, Oviedo, Spain

[8] Bellvitge Univ Hosp, Dept Pathol, IDIBELL, Lhospitalet De Llobregat, Spain

[9] Elche Univ Hosp, Mol Genet Lab, Elche, Spain

[10] Hosp Clin San Carlos, Serv Oncol Med, Lab Oncol Mol, Madrid, Spain

[11] UVA, CSIC, IBGM, Valladolid, Spain

[12] Spanish Natl Canc Ctr, Human Canc Genet Program, Familial Canc Clin Unit, Madrid, Spain

[13] Ctr Biomed Network Res Rare Dis, Madrid, Spain

[14] 12 Octubre Univ Hosp, Mol Biol Lab, Madrid, Spain

[15] Catalan Inst Oncol, Hereditary Canc Program, IDIBGi, Girona, Spain

[16] Lab Oncol Mol, Oviedo, Spain

[17] Hosp Univ Cent Asturias, Inst Univ Oncol Principado Asturias, Dept Med Oncol, Familial Canc Unit, Oviedo, Spain

[18] Hosp Gen Yague, Dept Oncol, Burgos, Spain

[19] Elche Univ Hosp, Unit Genet Counseling Canc, Elche, Spain

[20] Univ Barcelona, Fac Med, Dept Clin Sci, Barcelona 7, Spain

[21] IDIBELL, Catalan Inst Oncol, Translat Res Lab, Lhospitalet De Llobregat 08908, Spain

来源：

GASTROENTEROLOGY | 2015年 / 149卷 / 03期

关键词：

Lynch Syndrome; Genetic Risk Factor; Susceptibility; DNA Mismatch Repair; KARYOMEGALIC INTERSTITIAL NEPHRITIS; CROSS-LINK REPAIR; FANCONI-ANEMIA; NUCLEASE; KIAA1018/FAN1; DAMAGE;

D O I：

10.1053/j.gastro.2015.05.056

中图分类号：

R57 [消化系及腹部疾病];

学科分类号：

摘要：

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.

引用

页码：563 / 566

页数：4

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