• What Gene Mutations Cause Familial Colorectal Cancers?

What Gene Mutations Cause Familial Colorectal Cancers?

Mutations in the DNA repair gene, FAN1, cause some inherited forms of colorectal cancer (CRC), researchers report in the September issue of Gastroenterology. Identification of another gene associated with this hereditary cancer will facilitate management of patients with family histories of cancer.

 (A) Pedigrees of families with germline FAN1 mutations. Filled symbol, cancer; +, mutation carrier; (+), obliged mutation carrier; –, no mutation; arrow, index case. Ages at information gathering or at death are given on the top-left corner of each individual’s symbol. (B) MMC sensitivity assay. The FAN1-knockout HEK293T cell line was stably transfected with a pUltra empty vector (EV), the vector with full length FAN1 (WT), and the vector with c.418G>T (p.D140Y) mutation in FAN1.

(A) Pedigrees of families with germline FAN1 mutations. Filled symbol, cancer; +, mutation carrier; (+), obliged mutation carrier; –, no mutation; arrow, index case. Ages at information gathering or at death are given on the top-left corner of each individual’s symbol. (B) MMC sensitivity assay. The FAN1-knockout HEK293T cell line was stably transfected with a pUltra empty vector (EV), the vector with full length FAN1 (WT), and the vector with c.418G>T (p.D140Y) mutation in FAN1.

Germline mutations in EPCAM, APC, MUTYH, POLE, POLD1, GREM1, SMAD4, BMPR1A, STK11, and PTENamong others, have been found to cause hereditary forms of CRC. However, there are still many families in whom a cancer-causing gene has not been found.

Nuria Seguí et al 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 (Lynch syndrome). These people had mismatch repair-proficient tumors and each carried nonsense variant in FAN1, which encodes a nuclease involved in DNA inter-strand cross-link repair.

In sequencing FAN1 in 176 additional families with histories of colorectal cancer, the authors 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.

Seguí et al write that an analysis of larger familial CRC series will provide information about the prevalence of FAN1 mutations and allow the estimation of lifetime cancer risks for mutation carriers. Analysis of genetic and genomic alterations found in tumors with FAN1 mutations will provide important information about mechanisms of colorectal carcinogenesis.

The findings support the relationship between defects in DNA repair and cancer predisposition, and link the Fanconi anemia pathway to DNA mismatch repair and CRC.

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