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. Fanconi Anemia (FA) is a genetically heterogeneous rare autosomal recessive disorder characterized by developmental abnormalities, bone marrow failure, and childhood cancers. 2 Somehow unexpectedly, a common genetic basis for breast/ovarian cancer susceptibility and FA emerged when biallelic BRCA2 loss-of-function mutations were identified in FA type D1 patients. 3 Later, mutations in FANCJ/BRIP1, FANCN/PALB2, FANCO/RAD51C, and XRCC2 have been found to lead both to FA (when biallelic) and to increased breast cancer risk (when monoallelic). [4][5][6][7] Recently, two studies have demonstrated that SLX4 loss-offunction biallelic mutations explain a novel FA subgroup (FANCP). 8,9 Not surprisingly, both reports suggest that SLX4 might be a breast and/or ovarian cancer predisposing gene. So far, this hypothesis has been tested by analyzing SLX4 in 52 German/ Byelorussian, 94 Spanish and 526 Italian non-BRCA1/2 families, but obvious loss-of-function germ-line mutations (or any other evidence supporting a causative role) have not been reported. [10][11][12] To further investigate the role of SLX4 in breast/ovarian cancer susceptibility, we have performed a comprehensive scanning of germ-line mutations in a cohort of 486 index cases from Spanish non-BRCA1/2 families.

Physical interaction between SLX4 (FANCP) and XPF (FANCQ) proteins and biological consequences of interaction-defective missense mutations

“…We found that L530A amino acid change (#7, Table 2) abolished the interaction, but Y546A (#6) or L550A (#3), as well as E532A (#2), did not affect appreciably the interaction. Interestingly, Y546C (rs150547487) was detected in the SLX4 mutation screening of non-BRCA1/2-mutated breast cancer families [23] and is recorded as a global minor allele with a frequency of 0.0038 (dbSNP, NCBI Resources). The Y546C mutation (#5) did not significantly impair the interaction.…”

PALB2 sequencing in Italian familial breast cancer cases reveals a high-risk mutation recurrent in the province of Bergamo

“…2 Mutations in the RAD51C/FANCO gene were originally found in breast/ovarian cancer families. 8 [10][11][12][13] However, subsequent analyses allowed the identification of (i) three unique SLX4-truncating mutations, [14][15][16] indicating these mutations are very rare in familial cases, and (ii) a nonsense mutation in FANCM, whose frequency in cases was, however, not significantly higher than that in controls. 17 Finally, deleterious mutations in the FA gene XRCC2 were detected in families with breast cancer ascertained mainly in Australia.…”

A low‐frequency haplotype spanning SLX4/FANCP constitutes a new risk locus for early‐onset breast cancer (<60 years) and is associated with reduced DNA repair capacity

“…A dominant negative mutation has not been observed in the >2500 index cases from hereditary breast cancer families which have been analyzed for deleterious mutations in the coding sequences of the SLX4 gene in eight studies . In one of these studies, the LD structure of the region was detected and two selected variants were tested for association in larger cohorts.…”