TY  - JOUR
AU  - Försti, Asta
AU  - Ambrozkiewicz, Filip
AU  - Marciniak, Magdalena
AU  - Lubinski, Jan
AU  - Hemminki, Kari
TI  - Search for germline gene variants in colorectal cancer families presenting with multiple primary colorectal cancers.
JO  - International journal of cancer
VL  - 156
IS  - 7
SN  - 0020-7136
CY  - Bognor Regis
PB  - Wiley-Liss
M1  - DKFZ-2024-02609
SP  - 1393-1403
PY  - 2025
N1  - #EA:B062# / 2025 Apr 1;156(7):1393-1403
AB  - A double primary colorectal cancer (CRC) in a familial setting signals a high risk of CRC. In order to identify novel CRC susceptibility genes, we whole-exome sequenced germline DNA from nine persons with a double primary CRC and a family history of CRC. The detected variants were processed by bioinformatics filtering and prioritization, including STRING protein-protein interaction and pathway analysis. A total of 150 missense, 19 stop-gain, 22 frameshift and 13 canonical splice site variants fulfilled our filtering criteria. The STRING analysis identified 20 DNA repair/cell cycle proteins as the main cluster, related to genes CHEK2, EXO1, FAAP24, FANCI, MCPH1, POLL, PRC1, RECQL, RECQL5, RRM2, SHCBP1, SMC2, XRCC1, in addition to CDK18, ENDOV, ZW10 and the known mismatch repair genes. Another STRING network included extracellular matrix genes and TGFβ signaling genes. In the nine whole-exome sequenced patients, eight harbored at least two candidate DNA repair/cell cycle/TGFβ signaling gene variants. The number of families is too small to provide evidence for individual variants but, considering the known role of DNA repair/cell cycle genes in CRC, the clustering of multiple deleterious variants in the present families suggests that these, perhaps jointly, contributed to CRC development in these families.
KW  - familial colorectal cancer (Other)
KW  - germline variant (Other)
KW  - multiple primaries (Other)
KW  - whole‐exome sequencing (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:39654522
DO  - DOI:doi:10.1002/ijc.35283
UR  - https://inrepo02.dkfz.de/record/294899
ER  -