Abstract #4331: Mutational analysis of FANCL, FANCM and FANCI fanconi anemia genes in high-risk non-BRCA1/BRCA2 breast cancer families
Authors: Maria Garcia, Victoria Fernandez, Ana Osorio, Alicia Barroso, Miguel Urioste, Javier Benitez
Journal: Cancer Research (2009)

Fanconi anemia (FA) is a genetic syndrome characterized by the presence of congenital anomalies, bone marrow failure in childhood and predisposition to hematological malignancies and solid tumors. To date 13 FA genes have been described. FA pathway is involved in DNA interstrand crosslink repair, resolution of stalled replication forks and general maintenance of genomic stability. In 2002 it was discovered that FANCD1 was the high-risk breast cancer susceptibility gene BRCA2. Since then other FA genes became candidate breast cancer-predisposing genes. In this regard FANCA, FANCC, FANCD2, FANCE, FANCF and FANCG were screened for mutations in familial breast cancer patients but pathogenic sequence variants were not found. However, recent findings have shown thatgerminal mutations in FANCJ/BRIP1 and FANCN/PALB2 confer moderate breast cancer risk, emphasizing the link between the FA pathway and breast cancer. We recently reported a novel FANCN/PALB2 mutation in Spanish familial breast cancer population and ruled out the involvement of FANCB as major breast cancer susceptibility gene. Nevertheless contribution of FANCM, FANCL and the newly cloned FANCI remained to be evaluated. In order to determine their potential role in breast cancer susceptibility we analyzed the entire coding sequence and intron-exon boundaries of FANCM, FANCL and FANCI. Index cases from 95 high-risk non-BRCA1/2 Spanish breast and ovarian cancer families were screened for mutations. PCR fragments covering exons and splicing sites were analyzed by denaturing high-performance liquid chromatography (DHPLC) and scrutinized for aberrant profiles pinpointing sequence variants. Samples representative of each DHPLC pattern were sequenced and non-described sequence variants were confirmed by sequencing a fresh aliquot of the stock DNA. We did not find any pathogenic mutation either at coding regions or splicing sites of any of the three genes. However, our comprehensive analysis led to the detection of 24, 14 and 36 sequence variants in FANCM,FANCL and FANCI, respectively. Fourteen FANCM variants were novel, 8 non-coding and 6 coding. We identified 7 not previously reported non-coding FANCL sequence variants and 13 novel FANCI variants, 1 corresponding to a non-synonymous coding change and 12 intronic or within regulatory regions. We present results of \#8220;in silico\#8221; analysis performed to assess the pathogenic potential of all novel coding changes and extended analysis of a control population for variants predicted to be damaging. Our analysis of FANCL, FANCM and FANCI completes the evaluation of all known FA genes in regard to their implication with breast cancer susceptibility. Although larger-scale studies are required in order to rule out the existence of rare pathogenic alleles that might confer modest effects our data rule out a major a major implication of FANCL, FANCM and FANCI as high-risk breast cancer genes.  Citation Information: In: Proc Am Assoc Cancer Res; 2009 Apr 18-22; Denver, CO. Philadelphia (PA): AACR; 2009. Abstract nr 4331.