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.
Fanconi Anemia (FA) is a genetically heterogeneous, rare autosomal recessive disorder characterized by development abnormalities, bone marrow failure, and childhood cancers. Over the past few years, a common genetic basis for FA and breast and/or ovarian cancer susceptibility has been uncovered. In particular, BRCA2 (FANCD1), BRIP1 (also known as BACH1 and FANCJ), PALB2 (FANCN), and RAD51C germ-line mutations have been found to lead both to FA (when biallelic) and to increased breast and/or ovarian cancer risk (when monoallelic). Recently, two studies demonstrated that biallelic germ-line mutations in SLX4, which encodes an endonuclease, cause a previously unknown FA subtype (FA-P). Therefore, SLX4 should be considered a bona fide candidate gene for breast cancer susceptibility, as suggested in both studies. We have screened 347 non-BRCA1/BRCA2 index cases from multiple case breast and/or ovarian cancer families for point mutations in the SLX4 gene. The whole coding sequence and flanking intronic regions were analyzed using High Resolution Melting (HRM) analysis followed by direct sequencing of abnormal melting curve samples. An SLX4 missense change in c.1114C>T (p.Arg372Trp) was detected in a family with four cases of breast cancer in two generations. This mutation segregates with disease within the family and is not present in the dbSNP (build 34). Polyphen-2 and SIFT in silico analysis tools predict a deleterious effect on protein structure and multiple alignment within orthologous proteins suggests a high degree of conservation. Previous studies in FA patients have identified two different splicing mutations (c.1163+2T>A and c.1163+3dupT) that cause in frame exon 5 skipping. The resulting protein (p.Arg317_Phe387del) lacks two repeated UBZ4 domains known to interact with other endonucleases, mismatch repair proteins, and ubiquitin. It has been suggested that UBZ4 may be involved in targeting SLX4 to sites of DNA damage by binding to ubiquitinated proteins. The missense change we have found introduces a highly hydrophobic amino acid within the same region, which could affect the folding of the UBZ4 domain or disrupt a specific protein-protein interaction. Our study supports a role for SLX4 in breast cancer susceptibility. Further studies performed in larger cohorts will be necessary to determine the prevalence of SLX4 mutations among breast cancer risk factors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-441. doi:1538-7445.AM2012-LB-441
e14147 Background: In patients with metastatic colorectal cancer (mCRC), activating mutations within KRAS, which result in EGFR-independent intracellular signal transduction activation, are found in approximately 35-40% of patients with mCRC have been significantly associated with lack of response to cetuximab or panitumumab therapy. Although current guidelines recommend testing for frequent KRAS codons 12/13 mutations, emerging data indicate that additional KRAS and BRAF mutations are also predictive of non-responsiveness to anti-EGFR antibodies in mCRC. This study is aimed to analyze the prevalence of low-penetrance KRAS and BRAF V600 mutations in caucasian mCRC population. Methods: A two-institution retrospective cohort of 1,238 consecutive KRAS wild type mCRC patients previously studied for 7 mutations in codons 12/13 (G12D, G12A, G12V, G12S, G12R, G12C and G13D) by the CE-IVD marked ARMS-scorpion real-time polymerase chain reaction PCR (Therascreen, Qiagen) was assayed by the diagnostic TaqMelt PCR assay cobas KRAS mutation and cobas BRAF V600 mutation tests (Roche), which are designed to detect 19 mutations in KRAS codons 12, 13 and 61 (including G12F, G13C, G13R, G13S, G13A, G13V, G13I, Q61H, Q61K, Q61R, Q61L, Q61E and Q61P) and BRAF V600 (V600E, V600K and V600D) mutations. An additional cohort of 146 KRAS mutated patients by ARMS-scorpion PCR was studied. DNA was obtained by cobas DNA preparation kit from one single 5µm formalin-fixed paraffin-embedded tissue section. Results: In all samples, sufficient DNA was obtained for KRAS and BRAF mutational studies. Among 1238 KRAS codons 12/13 wild-type patients by ARMS-scorpion PCR,166 (13.4%) showed KRAS mutations, 117 (9.5%) in codons 12/13, and 49 (4%) in codon 61. BRAF V600 mutations were detected in 9% cases. In ARMS-scorpion PCR KRAS mutated patients, mutations were confirmed by cobas in all cases. Conclusions: The cobas mutation tests are robust and reproducible assays that, 1) detects a higher incidence (13.4%) of mutations in codons 12, 13, and 61 of the KRAS gene in wild-type mCRC population, 2) a relevant rate of BRAF mutations is present in the same population, and 3) requires a very small amount of tissue.
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