No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast‐cancer families linked to 17q22
Open accessAbstract
At least 10% of all breast cancer is estimated to result from an inherited predisposition.1 Mutations in 2 genes, BRCA1 and BRCA2, have been shown to confer a very high risk for breast and ovarian cancer.2 A significant proportion of familial cases, however, cannot be attributed to BRCA1 or BRCA2 mutations,3, 4 and additional breast cancer susceptibility gene(s) may account for a fraction of high-risk families. Recently, it was suggested that a novel protein, BACH1, a member of the DEAH helicase family could be one such gene.5 BACH1 maps to 17q22 and consists of 20 exons, spanning over 180 kb of genomic sequence. It encodes a 130 kDa polypeptide that binds directly to BRCT repeats of BRCA1 and interferes with normal double-strand break repair in a manner that was dependent on the BRCA1 binding.5 Furthermore, 2 germ-line missense mutations were detected in 65 individuals with breast cancer (1 in familial and 1 with early-onset breast cancer) lacking mutations in both BRCA1 and BRCA2. None of them occurred in any of 200 normal controls. We have evaluated a putative contribution of this locus to breast cancer susceptibility by analyzing 197 breast cancer families in which we did not detect BRCA1 and BRCA2 mutations (Table I). The exon 11 of BRCA1 was screened on genomic DNA using PTT and the remaining exons were analyzed using SSCP, CDGE or direct sequencing.4, 6 The BRCA2 gene was screened by PTT using genomic DNA for exon 10 and 11 and using RNA for all other exons, or the entire gene was screened using direct sequencing of genomic DNA.4, 7 High-risk breast cancer families were identified and collected through the Cancer Counseling Clinic at the Karolinska Hospital. The families were selected if 2 or more close relatives were affected with breast cancer, and if the proband was counseled a 2–4 times increased risk for the disease compared to the normal population. Blood samples were obtained from the affected and unaffected family members with informed consent. Linkage analysis involved 285 members of 102 breast cancer families, including 245 breast cancer patients. The average age at diagnosis in the patients was 54.7 years old, ranging between 30–72. Nine of the families were breast-ovarian cancer families. Additional 95 patients with a family history of breast cancer, negative for BRCA1 and BRCA2 mutations, were selected to be screened for mutations in the BACH1 gene. Control females were mothers of Swedish patients with IgA deficiency ascertained as described previously8 and apparently unrelated blood donors drawn from the Swedish population. Genotyping was carried out using 19 fluorescent-labeled microsatellite markers on chromosome 17 (D17S1308; D17S1845; D17S1810; D17S1298; D17S1832; D17S974; D17S1303; D17S969; D17S921; D17S122; D17S1294; D17S1293; D17S1299; D17S809;D17S1290; D17S31B11; D17S1301; D17S784; D17S928), including 3 markers flanking the BACH1 gene (underlined). The amplified fragments were analyzed on an ABI377 automated sequencer (Applera, USA), together with internal size standard. The gels were analyzed with GENESCAN (v.3.1) and GENOTYPER (v.2.0) software packages (Applera). The average heterozygosity of markers was 0.76 with an average intermarker genetic distance of 7.8 cM. Nonparametric and multipoint linkage analysis was performed by using Genehunter (v.2.0) program.9 The genetic linkage analysis showed negative multipoint nonparametric LOD scores (NPL) for markers around BRCA1 and BRCA2 in 73 of 102 breast cancer and breast-ovarian cancer families. Only 29 families, including 3 early onset breast-ovarian cancer families, showed a positive NPL for markers flanking the BACH1 locus. A positive NPL indicates that the affected individuals in the pedigree share alleles at the analyzed loci in excess, which makes this region more likely to harbor a predisposing gene. Thus, the 29 families were selected and screened for germline mutations in the BACH1 gene, together with additional 95 familial breast cancer cases without detectable BRCA1 and BRCA2 mutations (Table I). Twenty-four segments of BACH1 coding exons and flanking intronic sequences were amplified from genomic DNA. The average size of PCR products was 247 bp, with a range of 164–331 bp. Oligonucleotide primers and PCR conditions are shown at http://www.biosci.ki.se/fam/res/BACH1.htm. The PCR-SSCP analysis and nucleotide sequencing was carried out as described.10 The PCR-SSCP analysis showed 4 different alterations. Three alterations turned out to be known polymorphisms (Table II), 5 whereas 1 alteration was a 517C-T transition not previously reported (Table II). This rare variant, which results in Arg173Cys substitution in the putative nuclear localization signal of BACH1, as predicted by PSORTII,11 was found in a family where 5 women were diagnosed with breast cancer. The variant was identified in 1 woman with breast cancer at age 51 but was not shared by her daughter who had breast cancer at age 45. Although this alteration did no
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Tumor suppression likely requires both the helicase domain and nuclear co-localization with BRCA1, because variants in the nuclear localization sequence (A173C) or BRCA1-binding domain were detected in patients with a strong family history of breast cancer.
“Tumor suppression likely requires not only the helicase domain, but also nuclear co-localization with BRCA1, given that variants with a sequence change in the nuclear localization sequence (A173C) [60] or BRCA1-binding domain were detected in patients with a strong family history of breast cancer [43,53].”
From Hereditary Breast Cancer and the BRCA1-Associated FANCJ/BACH1/BRIP1 (2011) · cites this paper as [60]
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- Authors
- Luo, L., Lei, H., Du, Q., von Wachenfeldt, A., Kockum, I., Luthman, H., Vorechovsky, I., & Lindblom, A.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Lindblom, Annika
- Venue
- International Journal of Cancer
- Publisher
- Wiley
- Published
- 2002-01-15
- Volume
- 98
- Issue
- 4
- Pages
- 638-639
- ISSN
- 0020-7136 (ISSN-L)
- 1097-0215
- OpenAlex
- W2087009778
- Cited by
- 28
- References
- 13
- Citations by year
- 2019: 1 · 2017: 2 · 2015: 1 · 2014: 1 · 2013: 3
- FWCI
- 0.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- International Journal of Cancer (publishedVersion)
- PubMed (publishedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Funders
- Cancerfonden
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › BRCA gene mutations in cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Pathology and Forensic Medicine › Genetic factors in colorectal cancer
- Keywords
- BACH1, BRCA1, BRCA2, breast cancer susceptibility, hereditary breast cancer, BRCT domain, germline mutations, linkage analysis, genetic susceptibility, early-onset breast cancer, DNA double-strand break repair
- MeSH terms
- Breast Neoplasms, Chromosomes, Human, Pair 17, DNA Mutational Analysis, DNA-Binding Proteins, DNA, Neoplasm, Family Health, Female, Gene Frequency, Genotype, Humans, Genetic Linkage, Lod Score, Middle Aged, Mutation, Polymorphism, Single-Stranded Conformational, Microsatellite Repeats, BRCA1 Protein, Amino Acid Substitution, RNA Helicases, BRCA2 Protein, Fanconi Anemia Complementation Group Proteins
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