<i>BRCA1</i>Mutations in a Population-Based Sample of Young Women with Breast Cancer

Langston, Amelia; Malone, Kathleen E.; Thompson, Jennifer; Daling, Janet R.; Ostrander, Elaine A.

doi:10.1056/nejm199601183340301

Cited by 264 publications

(143 citation statements)

References 26 publications

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“…This figure is remarkably similar to the proportion of women with breast cancer under 40 years of age estimated by genetic epidemiological methods to be caused by mutations in the BRCAJ gene of 5.3% (Ford 1995) and found in practice by others (Langston et al, 1996;Struewing et al, 1996;Couch et al, 1997).…”

Section: Discussionsupporting

confidence: 82%

BRCA1 mutations in southern England

Eccles

Englefield²,

Soulby³

et al. 1998

Br J Cancer

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Summary If genetic testing for breast and ovarian cancer predisposition is to become available within a public health care system there needs to be a rational and cost-effective approach to mutation analysis. We have screened for BRCA 1 mutations in 230 women with breast cancer, all from the Wessex region of southern England, in order to establish the parameters on which to base a cost-effective regional mutation analysis strategy. Truncating mutations were detected in 10/155 (6.5%) consecutive cases selected only for diagnosis under the age of 40 (nine of these ten women had a strong family history of breast or ovarian cancer), 3/61 (4.9%) bilateral-breast cancer cases (all three mutations occurring among women for whom the first cancer was diagnosed under 40 years) and 8/30 (26.6%) breast cancer cases presenting to the genetics clinic (for whom a strong family history of breast and/or ovarian cancer was present). Ten different mutations were detected in 17 families, but three of these accounted for 10/17 (59%) of the families. The cost of screening the population for mutations in the entire BRCA 1 gene is unacceptably high. However, the cost of screening a carefully selected patient cohort is low, the risk of misinterpretation much less and the potential clinical benefits clearer.Keywords: BRCA 1; breast cancer; ovarian cancer; mutation analysisWith the cloning of BRCAI in 1994 (Miki et al, 1994) and BRCA2 in 1995(Wooster et al, 1995 it is now possible to screen breast or ovarian cancer patients for the presence of germline mutations. Together these genes account for about 75% of families with a highly penetrant dominantly inherited breast and/or ovarian cancer family history. There is at least one other highly penetrant breast cancer predisposition gene to be discovered (Rebbeck et al, 1997;Schubert et al, 1997;Serova et al, 1997) and undoubtedly many others of lower penetrance. Mutations in BRCAJ and BRCA2 are scattered throughout these very large genes and current methods of mutation analysis are far from perfect. Most of the available techniques detect only about 70-80% of causative mutations. A negative result from a mutation screen, in most circumstances, means very little in terms of altering the breast cancer risk to other relatives (Eeles, 1996; Healy, 1997). In families with a striking occurrence of apparently dominantly inherited breast cancer, however, the finding of a mutation can greatly refine the prediction of cancer risk and help to inform clinician and patient alike when making decisions about, for example, preventive surgery or cancer treatment.Mutation analysis is already available in a few genetics centres in the UK as part of a comprehensive molecular genetics service. As referrals for advice about inherited cancer risks escalate so do expectations for genetic testing to be provided. A rational approach to such testing is needed. We have reviewed three clinically selected groups for whom testing might be indicated and performed a comprehensive screen for mutations in BRCA 1. Using these ...

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Section: Discussionsupporting

confidence: 82%

BRCA1 mutations in southern England

Eccles

Englefield²,

Soulby³

et al. 1998

Br J Cancer

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“…The contribution of such carriers to the overall incidence of BRCA1 mutations is as yet unknown. In two recent studies the incidence of mutations was found to be 13% in women with breast cancer diagnosed before the age of 30 (FitzGerald et al, 1996) and 10% in women diagnosed with breast cancer under the age of 35 (Langston et al, 1996a). Two out of six mutation carriers from the latter study did not report any family history of breast or ovarian cancer.…”

Section: Discussionmentioning

confidence: 86%

“…The observed high frequency of the 12 bp insertionduplication in intron-20 and its distribution in the studied groups is intriguing. In earlier reports this insertion was in each case associated with the serious medical history of malignant conditions and was not detected in numerous controls (Takahashi et al, 1995;Langston et al, 1996a;Langston et al, 1996b). In one of these studies the carrier was a woman with both breast and ovarian cancer who had ®ve maternal relatives with breast cancer (Takahashi et al, 1995).…”

mentioning

confidence: 73%

“…In one of these studies the carrier was a woman with both breast and ovarian cancer who had ®ve maternal relatives with breast cancer (Takahashi et al, 1995). In the other study this insertion was found in a young 31-year-old women diagnosed with breast and cervical cancer (Langston et al, 1996a). Most recently two other cases of this insertion were found in men with prostate cancer (Langston et al, 1996b).…”

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confidence: 78%

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Novel BRCA1 mutations and more frequent intron-20 alteration found among 236 women from Western Poland

et al. 1997

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Three di erent novel BRCA1 mutations, ®ve independent cases of the same 12 bp insertion-duplication in intron-20 and two novel rare BRCA1 sequence variants were identi®ed among 122 Polish women with positive, in most cases moderate family history of breast and/or ovarian cancer, 80 controls and 34 unselected breast cancer tissue specimens. All mutations and variants were germline. The 4153 delA frameshift mutation, the Tyr105Cys missense mutation and two cases of the alteration in intron-20 were found in the group of healthy women with positive family history. Two other cases of the intronic insertion were found in unselected controls. Their carriers had no family history of breast or ovarian cancer but other cancers occurred in their families. The 1782 Trp/STOP nonsense mutation and one case of the insertion in intron-20 were ®rst found in tissue specimens of breast cancer patient and breast/ovarian cancer patient, respectively. Their carriers also had no family history of breast or ovarian cancer. The distribution of the insertion in intron-20 in analysed groups and results of RT ± PCR experiments suggest a less prominent role for this variant considered earlier a splicing mutation. This study shows also, that more population-oriented research is needed, involving women with less profound or even no family history of breast and ovarian cancer, to better understand the role and signi®cance of di erent BRCA1 variants and mutations.Keywords: BRCA1; mutations and variants; SSCPheteroduplex analysis; Polish women; positive family history IntroductionApproximately one in ten women in western countries will develop breast cancer during their lifetime . In most cases the disease is sporadic; however, some 5 ± 10% of women with breast cancer inherit increased susceptibility to the disease (Claus et al., 1991). Within this fraction of breast cancer the germline mutations in BRCA1 (Miki et al., 1994) and BRCA2 genes most frequently form a favorable genetic background for the disease. Also at increased risk are the carriers of one abnormal allele of the ataxia telangiectasia gene (Swift et al., 1991), the carriers of rare minisatelite allele at the HRAS1 locus (Krontiris et al., 1993) and the members of Li Fraumeni families with germline mutation in the p53 gene (Srivastava et al., 1990).The BRCA1 gene located on chromosome 17q21 (Hall et al., 1990) is also linked to hereditary ovarian cancer (Narod et al., 1991). More than 400 BRCA1 sequence variants have been identi®ed thus far and deposited in Breast Cancer Information Core Database (Friend et al., 1995) which now contains about 150 di erent cancer predisposing mutations. Most of this knowledge comes from studies of breast and breastovarian cancer families. Therefore the known mutations are probably biased towards those with more severe e ects on phenotype. It is expected that less expressive mutations will be identi®ed when studies expand and include women with less profound family history and women from the general population. It is also very likely that the inciden...

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“…One implication of this is that quite a sizeable fraction of breast cancers below the age of 35 years may involve constitutive or inherited mutant genes. As some will be new mutants in the germ line, not all young patients will have a prior family history of breast cancer (Langston et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

BRCA1 germline mutations in Indian familial breast cancer

et al. 2002

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Germline mutation analysis of BRCA1 gene has demonstrated significant allelic heterogeneity. These differences represent historical influences of migration, population structure and geographic or cultural isolation. To date, there have been no reports of Indian families with mutations in BRCA1. We have screened for mutations in selected coding exons of BRCA1 and their flanking intron regions in three breast or breast and ovarian cancer families with family history of three or more cases of breast cancer under age 45 and/or ovarian cancer at any age. We have also analyzed 10 female patients with sporadic breast cancer regardless of age and family history, as well as 50 unrelated normal individuals as controls. Thus a total of 90 samples were analyzed for BRCA1 mutations using polymerase chain reaction-mediated site directed mutagenesis (PSM) and single stranded conformation polymorphism (SSCP) analysis for various selected exons followed by sequencing of variant bands. Eight point mutations were identified. Two deleterious pathogenic, protein truncating non-sense mutations were detected in exon 11 (E1250X) and exon 20 (E1754X) and six novel and unique amino acid substitutions (F1734S, D1739Y, V1741G, Q1747H, P1749A, R1753K). One complex missense mutation of exon 20 [V1741G; P1749A] was seen in two out of three families and another complex combination of missense and non-sense mutations of the same exon [V1741G; E1754X] was observed in only one family. These complex mutations exist only in breast cancer families but not in control populations of women. Three splice site variants (IVS20+3A>C, IVS20+4A>T, IVS20+5A>T) and two intronic variants (IVS20+21_22insG, IVS20+21T>G) were also detected. In the group of 10 sporadic female patients no mutations were found.

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BRCA1Mutations in a Population-Based Sample of Young Women with Breast Cancer

Cited by 264 publications

References 26 publications

BRCA1 mutations in southern England

BRCA1 mutations in southern England

Novel BRCA1 mutations and more frequent intron-20 alteration found among 236 women from Western Poland

BRCA1 germline mutations in Indian familial breast cancer

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