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Novel Inherited Mutations and Variable Expressivity of BRCAI Alleles, Including the Founder Mutation 185Delag in Ashkenazi Jewis

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Novel Inherited Mutations and Variable Expressivity of BRCAI Alleles, Including the Founder Mutation 185Delag in Ashkenazi Jewis Am. J. Hum. Genet. 57:1284-1297, 1995 Novel Inherited Mutations and Variable Expressivity of BRCA I Alleles, Including the Founder Mutation 185delAG in Ashkenazi Jewish Families Lori S. Friedman,* Csilla 1. Szabo,* Elizabeth A. Ostermeyer,* Patrick Dowd,t Lesley Butler,* Tari Park,t Ming K. Lee,* Ellen L. Goode,* Sarah E. RowelI,§ and Mary-Claire King* Department of Molecular and Cell Biology and School of Public Health, University of California, Berkeley Summary Introduction Thirty-seven families with four or more cases ofbreast can- Breast cancer is the most common malignancy among cer or breast and ovarian cancer were analyzed for muta- women, with a cumulative risk by age 85 years of one tions in BRCA1. Twelve different germ-line mutations, four in eight for a female born in 1990 (American Cancer novel and eight previously observed, were detected in 16 Society 1994). The strongest epidemiological risk fac- families. Five families of Ashkenazi Jewish descent carried tor for the disease is a positive family history (Petrakis the 185deIAG mutation and shared the same haplotype at et al. 1982; Kelsey and Gammon 1991). Complex seg- eight polymorphic markers spanning -850 kb at BRCA1. regation analysis of families with high incidence of Expressivity of 185delAG in these families varied, from breast cancer indicated the existence of one or more early-onset bilateral breast cancer and ovarian cancer to autosomal dominant susceptibility genes contributing late-onset breast cancer without ovarian cancer. Mutation to 5%-10% of all breast cancer (Newman et al. 1988; 4184delTCAA occurred independently in two families. In Claus et al. 1991). Approximately 1 of every 200 one family, penetrance was complete, with females devel- women in the general population may carry a predis- oping early-onset breast cancer or ovarian cancer and the posing mutation in one of these genes (Newman et al. male carrier developing prostatic cancer, whereas, in the 1988; King et al. 1993). other family, penetrance was incomplete and only breast In 1990, a breast-ovarian cancer susceptibility gene, cancer occurred, diagnosed at ages 38-81 years. Two novel BRCA1, was mapped to chromosome 17q21 (Hall et al. nonsense mutations led to the loss of mutant BRCA1 tran- 1990). Subsequent studies verified linkage to this region, script in families with 10 and 6 cases of early-onset breast with odds >1026:1 (Narod et al. 1991; Easton et al. cancer and ovarian cancer. A 665-nt segment ofthe BRCA1 1993). Women who inherit a BRCA1 mutation have an 3'-UTR and 1.3 kb ofgenomic sequence induding the puta- 80% lifetime risk of breast cancer and are also at an tive promoter region were invariant by single-strand confor- elevated risk for ovarian cancer (Newman et al. 1988; mation analysis in 13 families without coding-sequence mu- Easton et al. 1993; Ford et al. 1994). BRCA1 was re- tations. Overall in our series, BRCA1 mutations have been cently isolated by positional cloning (Futreal et al. 1994; detected in 26 families: 16 with positive BRCA1 lod scores, Miki et al. 1994) and inherited BRCA1 mutations rap- 7 with negative lod scores (reflecting multiple sporadic idly identified, confirming the identity of this gene (Cas- breast cancers), and 3 not tested for linkage. Three other tilla et al. 1994; Friedman et al. 1994; Futreal et al. families have positive lod scores for linkage to BRCA2, 1994; Miki et al. 1994; Simard et al. 1994). but 13 families without detected BRCA1 mutations have The BRCA1 gene encodes a 7.8-kb transcript com- negative lod scores for both BRCA1 and BRCA2. posed of 22 coding exons that span >80 kb of genomic DNA (gDNA) (Miki et al. 1994). Except for a single C3HC4 RING finger motif (Lovering et al. 1993) located near the amino terminus, the predicted 1,863-amino acid Received June 29, 1995; accepted for publication September 13, protein contains no significant homologies to known 1995. genes. Thus, little insight has been gained into the possible Address for correspondence and reprints: Dr. Mary-Claire King, function of BRCA1. Although 102 germ-line BRCA1 mu- University of Washington, Box 357720, Seattle, WA 98195-7720. E-mail: [email protected] tations have been published to date, the nearly ubiquitous *Present address: Departments of Medicine and Genetics, University distribution of these mutations in the gene (Boyd et al. of Washington, Seattle. 1995; Hogervorst et al. 1995; Shattuck-Eidens et al. tPresent address: Genentech, San Francisco. 1995; Struewing et al. 1995; Takahashi et al. 1995) has tPresent address: Tufts University Medical School, Boston. frustrated not only mutation searching efforts but hopes 5Present address: Kaiser Permanente, Oakland. © 1995 by The American Society of Human Genetics. All rights reserved. that important functional domains would be identified. 0002-9297/95/5706-0005$02.00 The significance of the RING finger motif, however, has 1284 Friedman et al.: Expressivity of Germ-Line BRCA1 Mutations 1285 been underscored by the occurrence of both germ-line probands of breast cancer families. Amplified samples (Castilla et al. 1994; Friedman et al. 1994) and somatic were diluted 1:10 in formamide buffer (98% for- (Merajver et al. 1995) missense mutations resulting in the mamide, 10 mM EDTA pH 8, 0.05% Bromophenol loss of conserved cysteine residues. blue, 0.05% Xylene cyanol), held at 95°C for 5 min, The majority of the 52 distinct BRCA1 mutations pub- then cooled rapidly to 40C and held for 5 min. For each lished so far lead to truncation of the mutant protein sample, S ,l is loaded onto an SSCP gel and run at 6 W (Hogervorst et al. 1995; Shattuck-Eidens et al. 1995; (constant power) for 16 h in 0.6 x Tris-borate EDTA Struewing et al. 1995; Takahashi et al. 1995). These (TBE). (An 80-ml gel solution contains 0.5 x mutation frameshift, nonsense, and splice mutations likely reflect detection enhancement (AT Biochem), 0.6 x TBE, 160 loss of function characteristic of a tumor-suppressor gene. ul 25% ammonium persulfate, and 38 ,l NNN'N' tetra- However, most families in these studies were selected for methylethylenediamine.) Gels are dried on a vacuum gel multiple cases of early-onset breast and ovarian cancer dryer and exposed to film for 12-24 h with an intensi- and may not represent the full spectrum of mutations in fying screen. Variant bands were cut from the gel, rehy- the general population. Further characterization of drated in 100 ,l of water, amplified with appropriate BRCA1 mutations by using several different screening SSCP PCR primers, and directly sequenced with the USB approaches should reveal additional predisposing alleles. PCR product sequencing kit, according to manufactur- Despite the number of BRCA1 mutations identified, er's instructions. Mutations were confirmed in multiple very little information of predictive value can be gleaned members of each family by amplifying gDNA and di- from the existing data, because genotype does not ap- rectly sequencing. SSCP primers for the BRCA1 pro- pear strongly correlated with phenotype (Shattuck- moter region (P-1 through P-8) are given in table 1. Eidens et al. 1995). Evaluation of population-based se- ries of breast cancer patients unselected for family his- Allele-Specific Oligonucleotide (ASO) Hybridization to Dot Blots tory will be necessary to determine accurately the gDNA of breast cancer patients was amplified by nonra- frequency and penetrance of specific BRCA1 mutations dioactive PCR using published primers (Friedman et al. in the general population. Nevertheless, the question of 1994). Five microliters of DNA product from each PCR whether mutations that occur relatively frequently reaction was mixed with 55 p1 of denaturing solution (0.4 among high-risk families arise independently or have a M NaOH, 25 mM EDTA) in a 96-well plate format. Fifty common ancestral origin can begin to be addressed. microliters of each sample was loaded into a 96-well dot- Families with four or more cases of breast or breast blot vacuum apparatus containing a prewetted Genescreen and ovarian cancer were selected for BRCA1 mutation nylon filter (1 x 10 mM Tris-Cl, 1 mM EDTA [TE] for analysis. Linkage to BRCA1 and BRCA2 was tested in 10 min), and vacuum was applied. Wells were washed 34 of the 37 families, but BRCA1 was screened for muta- with 100 ,l 1 x TE, with vacuum. DNA was fixed onto tions in each family, regardless of the magnitude or sign the filter by exposure to UV light for 2 min. Ten picomoles of the lod score. Complementary techniques were used of oligonucleotides specific to each mutation and its wild- to identify germ-line mutations in 16 families. The geno- type sequence were end-labeled with 32P by using Gibco mic causes of two "inferred regulatory" mutations were T4 PNK according to manufacturer's instructions. ASOs identified as nonsense substitutions in exons 11 and 13, for known mutations are given in table 1. suggesting a possible mechanism leading to the absence Dot-blot filters carrying amplified DNA were incu- of BRCA1 transcript. Haplotype analysis of kindreds bated with 50 ml of tetramethylammonium chloride that share commonly occurring mutations revealed a (TMAC) hybridization solution (50 mM Tris, pH 8, 3 founder mutation in families of Jewish descent. M TMAC, 2 mM EDTA pH 8, 5 X Denhardts solution, 0.1% SDS, and 100 ,ug/ml salmon sperm DNA) (Wood Material and Methods et al. 1985). Prehybridization was at 56°C for 30-60 min. The ASO probe was then added to hybridization SSCP and Sequencing mix and incubated with the filters at 56°C for 1-3 h. PCR was carried out 50-pl volumes containing 50 ng Filters were washed twice for 10 min in 2 x SSPE, 0.1% cDNA or gDNA; 1 x PCR buffer (Boehringer Mann- SDS, then washed three times for 10-30 min at tempera- heim); 200 gM dATP, dGTP, and dTTP (Boehringer tures ranging from 25°C to 56°C (stringent wash) in a Mannheim); 10 ,uM dCTP (Boehringer Mannheim); 50 solution of 50 mM Tris pH 8, 3 M TMAC, 2 mM EDTA pmol each primer (Operon); 0.5 gCi 32P-dCTP (NEN pH 8, 0.1% SDS.
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