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Double Heterozygotes for the Ashkenazi Founder Mutations in BRCA1 and BRCA2 Genes

1998; Elsevier BV; Volume: 63; Issue: 4 Linguagem: Inglês

10.1086/302040

1537-6605

Eitan Friedman, Revital Bruchim, Anna Kruglikova, S Risel, Ephrat Levy‐Lahad, David Halle, Elchanan Bar-On, Ruth Gershoni‐Baruch, E. Dagan, Ilana Kepten, Tamar Peretz, Israela Lerer, Naomi Wienberg, Asher Shushan, Dvorah Abeliovich,

CRISPR and Genetic Engineering

To the Editor: Three Jewish founder mutations, 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 genes, have been identified in breast cancer (BC) and ovarian cancer (OC) Ashkenazi patients. In the Ashkenazi general population, the carrier frequencies of these founder mutations are 1% for 185delAG (Struewing et al., 1995Struewing JP Abeliovich D Peretz T Avishai N Kaback MK Collins FS Brody LC The carrier frequency of the BRCA1 185delAG is approximately 1 percent in Ashkenazi Jewish individuals.Nat Genet. 1995; 11: 198-200Crossref PubMed Scopus (602) Google Scholar), 0.13% for 5382insC, and 1.35% for 6174delT (Roa et al., 1996Roa BB Boyd AA Volcik K Richards CS Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2.Nat Genet. 1996; 14: 185-187Crossref PubMed Scopus (633) Google Scholar; Oddux et al., 1996Oddux C Strewing JP Clayton MC Neuhausen S Brody LC Kaback M Haas B et al.The carrier frequency of the BRCA2 6174delT mutation among Ashkenazi Jewish individuals is approximately 1%.Nat Genet. 1996; 14: 188-190Crossref PubMed Scopus (333) Google Scholar). Given these high population frequencies, one would expect to find individuals homozygous for the mutations 185delAG/185delAG, 6174delT/6174delT, and 5382insC/5382insC, compound heterozygous for 185delAG/5382insC, or double heterozygous for 185delAG/6174delT or 5382insC/6174delT, provided the individuals are viable. The effect of two mutations in a single individual is important both for an understanding of the mode of action and interaction between the BRCA1 and BRCA2 genes and for appropriate genetic counseling. To date, two double heterozygous patients (185delAG/6174delT; Ramus et al., 1997Ramus SJ Friedman LS Gayther SA Ponder AJ Bobrow LG van der Looji Papp J et al.A breast/ovarian cancer patient with germline mutations in both BRCA1 and BRCA2.Nat Genet. 1997; 15: 14-15Crossref PubMed Scopus (60) Google Scholar; Gershoni-Baruch et al., 1997Gershoni-Baruch R Dagan E Kepten I Fried G Co-segregation of BRCA1 185delAG mutation and BRCA2 6174delT in one single family.Eur J Cancer. 1997; 33: 2283-2284Abstract Full Text PDF PubMed Scopus (12) Google Scholar) and one patient homozygous for a mutation in exon 11 of the BRCA1 gene (Boyd et al., 1995Boyd M Harris F McFarlene R Davidson RH Black DM A human BRCA1 gene knockout.Nature. 1995; 375: 541-542Crossref PubMed Scopus (83) Google Scholar) have been reported. By pooling results from four cancer/genetics centers in Israel, we have analyzed ∼1,500 BC/OC Ashkenazi patients. All subjects received genetic counseling and signed informed consent forms in compliance with institutional ethics committees (institutional review boards). Each patient was tested for the three Ashkenazi founder mutations: in BRCA1, the mutations 185delAG and 5382insC, and in BRCA2, the mutation 6174delT (Abeliovich et al., 1997Abeliovich D Kaduri L Lerer I Weinberg N Amir G Sagi M Zlotogora J et al.The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women.Am J Hum Genet. 1997; 60: 505-514PubMed Google Scholar; Levy-Lahad et al., 1997Levy-Lahad E Catane R Eisenberg S Kaufman B Hornreich G Lishinsky E Shohat M et al.Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and breast-ovarian cancer families.Am J Hum Genet. 1997; 60: 1059-1067PubMed Google Scholar; Bruchim Bar-Sade et al., 1998Bruchim Bar-Sade R Kruglikova A Modan B Gak E Hirsh-Yechezkel G Theodor L Novikov I et al.The 185delAG BRCA1 mutation originated before the dispersion of Jews in the Diaspora and is not limited to Ashkenazim.Hum Mol Genet. 1998; 7: 801-805Crossref PubMed Scopus (114) Google Scholar). Four patients were found to be double heterozygotes. Summaries of their clinical status and pedigrees are presented in table 1 and figure 1.Table 1Genotypes and Clinical Status of the PatientsIndividualGenotypeClinical StatusAge at Diagnosis (years)Patient 1185delAG/6174delTBC38Mother of Patient 1185delAG/6174delTaInferred genotype.OC50Patient 2185delAG/6174delTOC57Patient 3185delAG/6174delTHealthy50Patient 45382insC/6174delTBC45a Inferred genotype. Open table in a new tab Patient 1 is an Ashkenazi mother of two children who was diagnosed with unilateral breast cancer at the age of 38 years. Her family history was positive for both OC, with which her mother was diagnosed at the age of 50 years, and breast cancer, with which her paternal aunt was diagnosed at the age of 60 years and her daughter at the age of 35 years. Her paternal grandfather had lung cancer at the age of 45 years. A test for 185delAG/6174delT in her father revealed neither mutation; DNA could not be retrieved from the paraffin block of her mother. Analysis of the polymorphic markers D17S855, D17S1322, D17S1323, D9S55, and D11S1337 in the father and in Patient 1 confirmed paternity. It was thus assumed that she had inherited both mutations from her double heterozygous mother. Patient 2 is a 57-year-old Ashkenazi woman who presented with stage IV OC. The patient is alive with no evidence of disease 5 years after treatment. Her family history includes breast cancer in her mother (age at diagnosis unknown). No further information was available. Patient 2 had irregular menses and primary sterility, which were treated with low doses of steroids. Patient 3 is a 50-year-old asymptomatic Ashkenazi woman who was referred for evaluation of her breast cancer risk before starting hormonal replacement therapy for increasing loss in bone density. The maternal family history was positive for ovarian, breast, pancreas, stomach, and laryngeal cancers. Her father had prostate cancer. The patient had idiopathic premature menopause at the age of 37 years after bearing three children. Patient 4 is a 46-year-old Ashkenazi woman who was diagnosed with breast-infiltrating ductal carcinoma. The family history was positive for cancer: hepatic carcinoma at the age of 59 years in her mother and breast cancer in her maternal grandmother. Two of her maternal cousins and two more distant relatives had breast cancer at the ages of 45, 48, and 42 years (the age at diagnosis of one of the relatives is unknown). One of them is a carrier of the mutation 5382insC. The others were not available for mutation analysis. As compared with carriers of single mutations, the four double heterozygotes we observed did not have a particularly severe phenotype, based on the tumor types and age at diagnosis: one was unaffected at the age of 50 years; two were affected with unilateral breast cancer, one at the age of 38 years and one at the age of 46 years; and one was diagnosed with OC at the age of 57 years. An inferred double heterozygote (the mother of Patient 1) had OC at the age of 50 years. None had more than one primary tumor, and tumor histology and clinical course were unremarkable. Two other 185delAG/6174delT carriers were reported: one had BC and OC diagnosed at the ages of 48 and 50 years, respectively (Ramus et al., 1997Ramus SJ Friedman LS Gayther SA Ponder AJ Bobrow LG van der Looji Papp J et al.A breast/ovarian cancer patient with germline mutations in both BRCA1 and BRCA2.Nat Genet. 1997; 15: 14-15Crossref PubMed Scopus (60) Google Scholar); the other had bilateral BC at the ages of 41 and 50 years, respectively (Gershoni-Baruch et al., 1997Gershoni-Baruch R Dagan E Kepten I Fried G Co-segregation of BRCA1 185delAG mutation and BRCA2 6174delT in one single family.Eur J Cancer. 1997; 33: 2283-2284Abstract Full Text PDF PubMed Scopus (12) Google Scholar). Although the small number of cases precludes definite conclusions, our results suggest that the phenotypic effects of double heterozygosity for BRCA1 and BRCA2 germ-line mutations are not cumulative. This is in agreement with the observation that the phenotype of mice that were homozygote knockouts for the BRCA1 and BRCA2 genes was similar to that of mice that were BRCA1 knockouts. This suggests that the BRCA1 mutation is epistatic over the BRCA2 mutation (Ludwig et al., 1997Ludwig T Chapman D Papaioannou VE Efstratiadis A Targeted mutations of breast cancer susceptibility gene homologes in mice: lethal phenotypes of BRCA1, BRCA2, BRCA1/BRCA2, BRCA1/p53, and BRCA2/p53 nullizygous embryos.Genes Dev. 1997; 11: 1226-1241Crossref PubMed Scopus (461) Google Scholar). Interestingly, two of the double heterozygotes described have had reproductive problems: one (Patient 2) had primary sterility and irregular menses, and another (Patient 3) had premature menopause at the age of 37 years. This latter patient was asymptomatic at the age of 50 years. These preliminary observations raise the possibility of hormonal effects in double heterozygotes, including the possibility that the lack of estrogen may have a protective effect. At the population level, given the known heterozygote frequencies in Ashkenazi Jews, the expected frequencies of double heterozygotes would be the multiplication of the heterozygote frequencies 185delAG/6174delT (1.35 × 10−4) and 5382insC/6174delT (1.75 × 10−5). The expected frequencies of BRCA1 and BRCA2 homozygotes will be the multiplication of the mutation frequencies (approximately one-half of the heterozygote frequency), which are 2.5 × 10−5 for 185delAG homozygotes and 4.6 × 10−5 for 6174delT homozygotes. Therefore the ratio of 185delAG/6174delT double heterozygotes and 6174delT and 185delGA homozygotes is 3:1:0.5, respectively. Namely, the double heterozygotes should be about three to six times more common than the homozygotes 185delAG or 6174delT. In this respect, we might have expected to observe 185delAG or 6174delT homozygotes. The fact that we did not observe these or any other homozygotes may be due to chance, and more patients should be tested before a homozygous patient is found or, alternatively, before homozygosity for 185delAG or 6174delT decreases viability or causes different phenotypic consequences. The clinical implication of this study is that mutation analysis in Ashkenazi Jews should include all known founder mutations. Identification of additional carriers of more than one mutation will increase our understanding of the interaction between various mutations and will improve genetic counseling.