Correspondence re: M. S. van der Heijden et al., Fanconi Anemia Gene Mutations in Young-onset Pancreatic Cancer. Cancer Res.,63: 2585–2588, 2003.
Authors: Quinten Waisfisz, Gerard Pals, Hans Joenje, Michiel S. Van Der Heijden, Ralph H. Hruban, Scott E. Kern
Journal: Cancer Research (2003)

is a rare chromosomal instability syndrome with autosomalrecessive inheritance. FA patients have a reduced life expectancy, themain causes of death being bone marrow failure, AML, and solidtumors, in particular, squamous cell carcinomas. The disease is ge-netically heterogeneous, with seven distinct disease genes currentlybeing known: FANCA, -C, -D1(identical to BRCA2), -D2, -E, -F,and-G, the products of which are thought to function in an integratedgenome protection pathway (1, 2). Cells from FA patients exhibitincreased spontaneous chromosomal breakage with gross rearrange-ments and are hyperresponsive (5–100-fold) to the clastogenic andcytostatic effects of bifunctional alkylating agents such as mitomycinC and cisplatinum. That FA genes (other than BRCA2) might play arole in the causation of sporadic cancer has been proposed forFANCF, which appeared inactivated through epigenetic silencing in aproportion of cisplatin-sensitive ovarian tumor cell lines (3). Alterna-tive inactivating mechanisms may include somatic mutations, in com-bination with loss of heterozygosity or inherited mutations. However,such mechanisms have not been convincingly documented thus far,whereas obligatory mutation carriers (parents of FA patients) are notknown to be at increased risk for any type of malignancy.In a recent issue of Cancer Research, van der Heijden et al. (4)conclude that a significant proportion of young-onset pancreatic can-cers is associated with mutations in the FA genes FANCC or FANCG,in some cases associated with loss of the other allele by loss ofheterozygosity. The authors suggest that patients with this subset ofpancreatic cancers may benefit from treatment with mitomycin C orother cross-linking cytostatic agents, in that way exploiting the intrin-sic hypersensitivity of FA cells. However, we think their conclusionsare not necessarily supported by the data, the main problem being thestatus of the sequence variations reported.A total of six genetic variants were found (two were mentioned asa “Note added in Proof”), four in FANCC and two in FANCG. Onlyone of these (E105X in FANCG) has been known as a pathogenicmutation in FA complementation group-G patients (5), but the others(four missense and one frameshift alteration) are at least questionable.The first missense alteration (D195V in FANCC), observed in tumorPX19, is a known polymorphism. This was shown by Lo Ten Foe etal. (6), who demonstrated correction of the cellular phenotype ofFA-C lymphoblasts transfected with FANCC cDNA, which containedthis variant. Even though it cannot be excluded for the D195V-containing FANCC protein to have a somewhat reduced activity, theloss of the other allele observed by van der Heijden et al. would seemto be insufficient for assuming a FA genotype for this tumor. Themissense alteration S7F in FANCG found in the CAPAN1 cell line,although not functionally tested, has been described as a polymorphicvariant (5). Another missense alteration, found in the CAPAN2 cellline, was E521K in FANCC. This alteration has not been foundpreviously, so that without a functional test, its status is questionable.Moreover, because the second allele had no mutations and was ap-parently expressed, the missense mutation in the first allele, even ifpathogenic, should be without a biological effect. Likewise, M350Vin FANCC has not been reported before and awaits confirmation by afunctional test.The remaining mutation was a somatic deletion of 5 bp (CCT-TAAA to CA) in FANCC resulting in a frameshift. Although frame-shifts are often deleterious, this specific frameshift may result in afunctional product. The alteration is situated close to the 3 end of theopen reading frame, which results in replacement of the last 8 aminoacids by 45 new amino acids. It is not self-evident that this protein isunable to function, because tags such as HA or GFP added to theFANCC COOH terminus are known to be without effect for theprotein’s function. Therefore, the status of this mutation should beevaluated by a complementation test.Thus, we are left with only one convincing pathogenic mutation,E105X in FANCG, present in the Hs766T cell line. Without results ofadditional studies to test the status of the other alterations, the sug-gestion that FA gene mutations play a significant role in the etiologyof pancreatic cancer would seem premature.Quinten WaisfiszGerard PalsHans JoenjeDepartment of Clinical Genetics and Human GeneticsVU University Medical CenterVan der boechorststraat 7NL-1081 BT Amsterdam, the NetherlandsReferences