Low prevalence of SLX4 loss-of-function mutations in non-BRCA1/2 breast and/or ovarian cancer families

Abstract

Fanconi anemia is a genetically heterogeneous autosomal recessive disorder characterized by development abnormalities, bone marrow failure, and childhood cancers. Compelling evidence indicates a common genetic basis for FA and breast/ovarian cancer susceptibility. Recently, biallelic germ-line mutations in SLX4 have been demonstrated to cause a previously unknown FA subtype (FA-P). We address the role of SLX4/FANCP in breast/ovarian cancer susceptibility by conducting a comprehensive mutation scanning in 486 index cases from non-BRCA1/BRCA2 multiple-case breast and/or ovarian cancer families (non-BRCA1/2 families) from Spain. We detected one unequivocal loss-of-function mutation (p.Glu1517X). In addition, one missense change (p.Arg372Trp) predicted to be pathogenic by in silico analysis co-segregates with disease in one family. Overall, the study indicates that SLX4 mutation screening will have a very low impact (if any) in the genetic counseling of non-BRCA1/2 families.

Figure 1

Left panel displays a representative electropherogram demonstrating the SLX4 germ-line mutation c.4549G>T (p.Glu1517X). This truncating mutation was identified in a pedigree (right panel) with multiple cases of breast cancer, but not ovarian cancer. The mutation was identified in the index case (arrow). Unfortunately, it was not possible to perform co-segregation analysis. BC, breast cancer. dx, age at diagnosis.

Figure 2

The SLX4 variants p.Arg372Trp and p.Gly141Trp are predicted to be pathogenic by in silico analysis. In the case of p.Arg372Trp, co-segregation analysis is compatible with a pathogenic role (family ID_452). In the case of p.Gly141Trp, co-segregation analysis is complicated by the fact that CHEK2*1100delC is also detected in this family (family ID_1035). Index cases are indicated with arrows. BC, breast cancer. GC, gastric cancer. dx, age at diagnosis.