Functional defects in the Fanconi anemia pathway in pancreatic cancer cells

Michiel S. Van Der Heijden, Jonathan R. Brody, Eike Gallmeier, Steven C. Cunningham, David A. Dezentje, Dong Shen, Ralph H. Hruban, Scott E. Kern

Research output: Contribution to journalArticlepeer-review

104 Scopus citations


Biallelic BRCA2-mutations can cause Fanconi anemia and are found in ∼7% of pancreatic cancers. Recently, several sequence changes in FANCC and FANCG were reported in pancreatic cancer. Functional defects in the Fanconi pathway can result in a marked hypersensitivity to interstrand crosslinking agents, such as mitomycin C. The functional implications of mutations in the Fanconi pathway in cancer have not been fully studied yet; these studies are needed to pave the way for clinical trials of treatment with crosslinking agents of Fanconi-defective cancers. The competence of the proximal Fanconi pathway was screened in 21 pancreatic cancer cell lines by an assay of Fancd2 monoubiquitination using a Fancd2 immunoblot. The pancreatic cancer cell lines Hs766T and PL11 were defective in Fancd2 monoubiquitination. In PL11, this defect led to the identification of a large homozygous deletion in FANCC, the first cancer cell line found to be FANCC-null. The Fanconidefective cell lines Hs766T, PL11, and CAPAN1 were hypersensitive to the crosslinking agent mitomycin C and some to cis-platin, as measured by cell survival assays and G 2/M cell-cycle arrest. These results support the practical exploration of crosslinking agents for non-Fanconi anemia patients that have tumors defective in the Fanconi pathway.

Original languageEnglish (US)
Pages (from-to)651-657
Number of pages7
JournalAmerican Journal of Pathology
Issue number2
StatePublished - Aug 2004
Externally publishedYes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine


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