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Figure 1.
Relative Frequencies of Mutations in BRCA1, BRCA2, and Other Genes Among Ashkenazi Jewish Patients With Inherited Breast Cancer
Relative Frequencies of Mutations in BRCA1, BRCA2, and Other Genes Among Ashkenazi Jewish Patients With Inherited Breast Cancer
Figure 2.
Proportions of Ashkenazi Jewish Patients With Breast Cancer in the New York Breast Cancer Study With Damaging Mutations in BRCA1 or BRCA2 or in Another Breast Gene, by Age at Diagnosis and Family History of Breast or Ovarian Cancer
Proportions of Ashkenazi Jewish Patients With Breast Cancer in the New York Breast Cancer Study With Damaging Mutations in BRCA1 or BRCA2 or in Another Breast Gene, by Age at Diagnosis and Family History of Breast or Ovarian Cancer
Figure 3.
Family R in the New York Breast Cancer Study, With 3 Mutations in 2 Breast Cancer Genes
Family R in the New York Breast Cancer Study, With 3 Mutations in 2 Breast Cancer Genes

Participant IV-7 was diagnosed with her first breast cancer at 48 years of age, despite testing negative for BRCA2 6174delT, which had been identified in her cousins IV-1 and IV-3. Sequencing by BROCA revealed IV-7 to be compound heterozygous for 2 mutations in CHEK2, one or both of which were also present in each of her 3 affected sisters. The young women in generation V who carry one of the family’s 3 mutations can be offered screening appropriate to their genotypes. Dark blue symbols indicate affected individuals; white symbols, unaffected individuals; light blue symbols, other cancers; a diagonal slash, known deceased individuals; BilBr, bilateral breast cancer; Br, breast cancer; N, normal allele; Pan, pancreatic cancer; Pr, prostate cancer; St, stomach cancer; and V, variant allele.

Table 1.  
Characteristics of Patients in the New York Breast Cancer Study Cohort
Characteristics of Patients in the New York Breast Cancer Study Cohort
Table 2.  
Mutations Other Than BRCA1 and BRCA2 Founder Alleles in Ashkenazi Jewish Patients With Breast Cancer
Mutations Other Than BRCA1 and BRCA2 Founder Alleles in Ashkenazi Jewish Patients With Breast Cancer
1.
Kaufman  B, Shapira-Frommer  R, Schmutzler  RK,  et al.  Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.  J Clin Oncol. 2015;33(3):244-250.PubMedArticle
2.
Ledermann  JA, Harter  P, Gourley  C,  et al.  Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.  Lancet Oncol. 2016;17(11):1579-1589.PubMedArticle
3.
Domchek  SM, Friebel  TM, Neuhausen  SL,  et al.  Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study.  Lancet Oncol. 2006;7(3):223-229.PubMedArticle
4.
Daly  MB, Pilarski  R, Berry  M,  et al.  NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017.  J Natl Compr Canc Netw. 2017;15(1):9-20.PubMedArticle
5.
Human Genome Variation Society. Sequence variant nomenclature. http://varnomen.hgvs.org/. Accessed December 10, 2016.
6.
King  MC, Marks  JH, Mandell  JB; New York Breast Cancer Study Group.  Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2 Science. 2003;302(5645):643-646.PubMedArticle
7.
Gabai-Kapara  E, Lahad  A, Kaufman  B,  et al.  Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2 Proc Natl Acad Sci U S A. 2014;111(39):14205-14210.PubMedArticle
8.
Walsh  T, Lee  MK, Casadei  S,  et al.  Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing.  Proc Natl Acad Sci U S A. 2010;107(28):12629-12633.PubMedArticle
9.
Nord  AS, Lee  M, King  MC, Walsh  T.  Accurate and exact CNV identification from targeted high-throughput sequence data.  BMC Genomics. 2011;12:184.PubMedArticle
10.
National Center for Biotechnology Information, US National Library of Medicine. ClinVar. https://www.ncbi.nlm.nih.gov/clinvar/. Accessed December 9, 2016.
11.
Friedman  LS, Ostermeyer  EA, Szabo  CI,  et al.  Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.  Nat Genet. 1994;8(4):399-404.PubMedArticle
12.
Scholl  T, Pyne  MT, Russo  D, Ward  BE.  BRCA1 IVS16+6T→C is a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site.  Am J Med Genet. 1999;85(2):113-116.PubMedArticle
13.
Shaag  A, Walsh  T, Renbaum  P,  et al.  Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population.  Hum Mol Genet. 2005;14(4):555-563.PubMedArticle
14.
Adank  MA, Jonker  MA, Kluijt  I,  et al.  CHEK2* 1100delC homozygosity is associated with a high breast cancer risk in women.  J Med Genet. 2011;48(12):860-863.PubMedArticle
15.
Provenzale  D, Gupta  S, Ahnen  DJ,  et al.  Genetic/familial high-risk assessment: colorectal version 1.2016, NCCN Clinical Practice Guidelines in Oncology.  J Natl Compr Canc Netw. 2016;14(8):1010-1030.PubMedArticle
16.
King  MC, Levy-Lahad  E, Lahad  A.  Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award.  JAMA. 2014;312(11):1091-1092.PubMedArticle
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Original Investigation
July 20, 2017

Genetic Predisposition to Breast Cancer Due to Mutations Other Than BRCA1 and BRCA2 Founder Alleles Among Ashkenazi Jewish Women

Author Affiliations
  • 1Division of Medical Genetics, Department of Medicine, University of Washington, Seattle
  • 2Department of Genome Sciences, University of Washington, Seattle
  • 3Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Washington, Seattle
JAMA Oncol. Published online July 20, 2017. doi:10.1001/jamaoncol.2017.1996
Key Points

Question  Among patients of Ashkenazi Jewish ancestry with breast cancer who do not carry one of the founder mutations in BRCA1 or BRCA2, what is the likelihood of carrying another cancer-predisposing mutation in BRCA1, BRCA2, or another breast cancer gene?

Findings  In this cohort study, 1007 patients of Ashkenazi Jewish ancestry with breast cancer were evaluated by multiplex genomic sequencing for all known and candidate breast cancer genes. Among patients without a founder mutation in BRCA1 or BRCA2, 0.8% carried a different mutation in BRCA1 or BRCA2 and 3.4% carried a mutation in another gene.

Meaning  Ashkenazi Jewish patients with breast cancer can benefit from genetic testing for all breast cancer genes.

Abstract

Importance  Among Ashkenazi Jewish women, 3 mutations in BRCA1 and BRCA2 severely increase the risk of breast and ovarian cancer. However, among Ashkenazi Jewish patients with breast cancer who do not carry one of these founder mutations, the likelihood of carrying another pathogenic mutation in BRCA1 or BRCA2 or another breast cancer gene is not known. This information would be valuable to the patient and family for cancer prevention and treatment.

Objective  To determine the frequency of cancer-predisposing mutations other than the BRCA1 and BRCA2 founder alleles among patients of Ashkenazi Jewish ancestry with breast cancer.

Design, Setting, and Participants  In this cohort study, genomic DNA of women from 12 major cancer centers with a first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish and participated in the New York Breast Cancer Study (NYBCS) from 1996 to 2000 was sequenced for known and candidate breast cancer genes. Data analysis was performed from July 10, 2014, to March 10, 2017.

Main Outcomes and Measures  Genomic DNA from all 1007 NYBCS probands was sequenced for 23 known and candidate breast cancer genes using BROCA, a targeted multiplexed gene panel.

Results  Of the 1007 probands in the study, 903 probands had no founder mutations in BRCA1 or BRCA2; of these probands, 7 (0.8%) carried another pathogenic mutation in BRCA1 or BRCA2, and 31 (3.4%) carried a pathogenic mutation in another breast cancer gene (29 in CHEK2, and 1 each in BRIP1 and NBN). Of all inherited predispositions to breast cancer in the NYBCS, 73.8% (104 of 142) were due to a BRCA1 or BRCA2 founder allele, 4.9% (7 of 142) to another BRCA1 or BRCA2 mutation, and 21.8% (31 of 142) to a mutation in another gene. Overall, 14.1% (142 of 1007) of Ashkenazi Jewish patients with breast cancer in the NYBCS carried a germline mutation responsible for their disease: 11.0% (111 of 1007) in BRCA1 or BRCA2, and 3.1% (31 of 1007) in CHEK2 or another breast cancer gene. Of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 patients (48.6%) did not.

Conclusions and Relevance  Comprehensive sequencing would provide complete relevant genetic information for Ashkenazi Jewish patients with breast cancer.

Introduction

Inherited loss-of-function mutations in BRCA1 (GenBank NM_007294) and BRCA2 (GenBank NM_000059) confer severe risks of breast and ovarian cancer on women who carry them. Knowing whether a patient with breast or ovarian cancer carries a cancer-predisposing mutation in BRCA1 or BRCA2 is valuable for both the patient and her family. The patient may be well served by targeted treatment,1,2 and as-yet unaffected sisters and daughters who learn that they also carry the mutation can undertake risk-reducing preventive strategies.3,4 Thousands of different cancer-predisposing mutations in BRCA1 and BRCA2 have been identified, and every population that has been evaluated harbors such mutations, nearly all individually extremely rare. In the Ashkenazi Jewish population, the mutation profile of BRCA1 and BRCA2 is distinctive, with the following 3 ancient founder mutations in these 2 genes: BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT. Notation for these variants based on Human Genome Variation Society conventions5 are NM_007294.3(BRCA1):c.68_69delAG (p.Glu23Valfs), NM_007294.3(BRCA1):c.5266dupC (p.Gln1756Profs), and NM_000059.3(BRCA2):c.5946delT (p.Ser1982Argfs). We will use the original names for the variants because they are more widely recognized. Combined, these 3 mutations are responsible for 10% of invasive breast cancer among Ashkenazi Jewish women.6,7

The relatively high frequency of the Ashkenazi Jewish founder mutations in BRCA1 and BRCA2 has enabled the effective use of cancer genetics services by Jewish women. However, for Ashkenazi Jewish patients with breast cancer who do not carry one of these 3 founder alleles, the chance of carrying some other pathogenic mutation in BRCA1 or BRCA2, or a pathogenic mutation in a different breast cancer gene, is not known. Should Ashkenazi Jewish women with breast or ovarian cancer who have negative results (ie, have wild-type sequences) for the 3 founder alleles obtain complete sequencing of BRCA1 and BRCA2 so as not to miss some other mutation? Should these Ashkenazi Jewish patients also be tested for mutations in other breast cancer genes?

We addressed these questions by sequencing all known breast and ovarian cancer genes in genomic DNA provided by participants of the New York Breast Cancer Study (NYBCS), a longstanding cohort of Ashkenazi Jewish women with a primary diagnosis of invasive breast cancer.5 Participants in the NYBCS were not selected for family history or age at diagnosis. Their genomic DNA had been evaluated for the founder mutations of BRCA1 and BRCA2, revealing one of these mutations in 104 of the 1007 probands. For the present project, we sequenced genomic DNA from these 1007 patients for all known breast cancer genes using our BROCA gene panel, then determined the frequency of cancer-predisposing mutations in BRCA1, BRCA2, and other breast cancer genes among patients with none of the founder mutations and with various family histories and ages at diagnosis.

Methods

Participants in the NYBCS were identified from 12 major cancer centers in the New York metropolitan area between 1996 and 2000, as previously described.5 Participants were women experiencing their first diagnosis of invasive breast cancer who identified themselves and all 4 grandparents as Ashkenazi Jewish. Eligible women were invited to participate regardless of age at diagnosis, family history, or prior genetic testing, which was still infrequent when these patients were enrolled. Patients provided pedigree information, permission to review records of pathologic findings for their breast cancer, and a blood sample for extraction of DNA. Of the 1007 index cases in the NYBCS, 987 (98.7%) requested information about their original genetic results and were provided this information by us in consultation with their hospital’s genetic counselors. Participants also gave consent for their DNA to be used for future studies of breast cancer genetics, as better sequencing technology became available. Some participants requested that their identifying information remain with their sample so that they or their family could be informed of results of future genetic testing; others agreed to the use of their DNA with basic risk factor information retained, but with their identifying information removed. The NYBCS was approved by the institutional review boards of the participating hospitals and by the University of Washington. Patients provided written informed consent.

For the present project, DNA extracted from blood was sequenced using BROCA, a targeted capture and massively parallel sequencing test developed at the University of Washington.8 For this project, we created a version of BROCA specifically targeting 23 established and candidate breast cancer genes: BRCA1, BRCA2, ATM (GenBank NM_000051), ATR (GenBank NM_001184), BAP1 (GenBank NM_004656), BARD1 (GenBank NM_000465), BRIP1/FANCJ (GenBank NM_032043), CDH1 (GenBank NM_004360), CHEK1 (GenBank NM_001114122), CHEK2 (GenBank NM_007194), FAM175A/ABRAXAS (GenBank NM_016067), FANCM (GenBank NM_020937), MRE11A (GenBank NM_005590), NBN (GenBank NM_002485), PALB2/FANCN (GenBank NM_024675), PTEN (GenBank NM_000314), RAD51B (GenBank NM_133509), RAD51C (GenBank NM_058216), RAD51D (GenBank NM_002878), RINT1 (GenBank NM_021930), SLX4/FANCP (GenBank NM_032444), TP53 (GenBank NM_000546), and XRCC2 (GenBank NM_005431). Sequencing results were aligned to human reference genome hg19. Variants were identified after realignment of insertion-deletion variants (indels) and base quality recalibration. Single nucleotide variants, small indels, and copy number variants were identified as previously described.9 The consequences of mutations near splice junctions were tested in RNA isolated from patients’ blood. Missense mutations were included only if they were proven experimentally to be damaging, either as part of this project or previously. Data analysis was performed from July 10, 2014, to March 10, 2017. Allele frequencies were compared by 2-tailed χ2 tests, Mantel-Haenszel tests for linear trend, or Fisher exact tests, as appropriate.

Results

The clinical characteristics for the NYBCS cohort are provided in Table 1. As previously reported,6 patients carrying one of the founder mutations in BRCA1 or BRCA2 were younger at diagnosis (mean [SD] age, 46.7 [10.7] years, vs 53.8 [11.1] years) and more likely to have a family history of breast or ovarian cancer (76 of 104 [73.1%]) than were patients with no founder mutation (519 of 903 [57.5%]).

Of the 903 patients with none of the 3 founder mutations in BRCA1 or BRCA2, 7 (0.8%) carried a different pathogenic mutation in BRCA1 or BRCA2 and 31 (3.4%) carried a damaging mutation in another breast cancer gene (Table 2). Of the 7 mutations in BRCA1 or BRCA2, 1 (BRCA2 c.8635del5) has not been previously reported, and therefore may be private, and the other 6 have been reported as rare alleles in non-Jewish populations.1012 Family history was suggestive for only 4 of the 7 BRCA1 or BRCA2 mutation carriers. The frequencies of these other BRCA1 and BRCA2 mutations were higher among patients diagnosed before 40 years of age (2 of 68 [2.9%]) compared with those diagnosed at 40 to 49 years of age (3 of 285 [1.1%]), 50 to 59 years of age (1 of 283 [0.4%]), or 60 years of age or older (1 of 267 [0.4%]) (P = .03, determined by use of the Mantel-Haenszel test).

Of the 32 patients with a damaging mutation in another breast cancer gene, 29 were in CHEK2, and there was 1 each in BRIP1 and NBN (Table 2). Of the 29 CHEK2 mutations, 24 were CHEK2 p.S428F, previously identified as an Ashkenazi Jewish founder allele that increases breast cancer risk 2- to 3-fold13; 4 were CHEK2 c.1100delC, and 1 was CHEK2 c.444(+1)G>A, both of which appear widely in Europe. Combined frequencies of mutations in these genes were somewhat, although not significantly, higher among patients diagnosed before 60 years of age (25 of 636 [3.9%]) than at 60 years of age or older (6 of 267 [2.2%]; P = .20), and among patients with a first-degree relative with breast cancer (14 of 295 [4.8%]) compared with those with no such family history (17 of 608 [2.8%]; P = .10) (eTable in the Supplement).

One patient who carried BRCA1 185delAG and 1 patient who carried BRCA2 6174delT also carried CHEK2 p.S428F. The ages at diagnosis of these 2 patients were 34 and 36 years, respectively, among the youngest carrying one of the founder alleles. No clearly pathogenic mutations were found in any other sequenced gene, and no damaging copy number variants were found in any gene.

Integrating information from all genetic testing in the cohort reveals the distribution of mutations among genes (Figure 1) and the association among genotype, age at diagnosis, and family history (Figure 2). As expected, there is a strong association between age at breast cancer diagnosis and the likelihood of carrying a mutation in BRCA1 or BRCA2, whether a founder mutation or another damaging allele. However, age at diagnosis is not associated with the likelihood of carrying a damaging mutation in the other genes. The mean (SD) ages at diagnosis were 44.2 (9.9) years for patients with a BRCA1 mutation; 46.4 (12.4) years for patients with a BRCA2 mutation; 52.6 (7.7) years for patients with a mutation in CHEK2, BRIP1, or NBN; and 53.9 (11.2) years for patients with no damaging mutation in any sequenced gene. Also, as expected, patients with a mother or sister with breast or ovarian cancer were more likely than those without such a family history to carry a damaging mutation in BRCA1 or BRCA2. However, approximately half of the patients with a damaging mutation in BRCA1 or BRCA2 had no close family history of breast or ovarian cancer; of the 111 patients with BRCA1 or BRCA2 mutations, 57 (51.4%) had a mother or sister with breast or ovarian cancer and 54 (48.6%) did not. Also, of 31 patients with a damaging mutation in CHEK2, BRIP1, or NBN, 14 (45.2%) had a mother or sister with breast or ovarian cancer and 17 (54.8%) did not.

Figure 3 illustrates extended family R. Participant IV-7 was diagnosed with bilateral breast cancer at 48 years of age, with a recurrence at 59 years. She had negative test results for the BRCA1 and BRCA2 founder mutations, including BRCA2 6174delT, which had been identified in her cousin (IV-1). Sequencing the genomic DNA of participant IV-7 for all known breast cancer genes revealed that she is compound heterozygous for 2 mutations in CHEK2. All 3 of her sisters had also been diagnosed with breast cancer, despite prior negative test results for the BRCA2 mutation of the family. Each sister also proved to carry 1 or both CHEK2 mutations. Homozygosity or compound heterozygosity for damaging alleles of CHEK2 is associated with breast cancer risk similar to that seen with BRCA1 or BRCA2.14 All daughters of the compound heterozygous sisters inevitably carry one of the CHEK2 mutations. Surveillance for these daughters will be more frequent than for a young woman whose mother had breast cancer with no genetic predisposition.4

Discussion

Many Ashkenazi Jewish patients with breast cancer have been tested for the founder mutations of BRCA1 and BRCA2. If a patient is negative (ie, has a normal sequence) for these mutations, should she and her physician consider additional testing? Our results offer perspectives on this question. First, for an Ashkenazi Jewish patient with breast cancer who does not carry a founder mutation in BRCA1 or BRCA2, the chance of carrying a different, equally damaging mutation in BRCA1 or BRCA2 is about 1%. If she was diagnosed before 40 years of age, this chance increases to about 3%. Patients with such mutations should be counseled for preventive salpingo-oophorectomy and may be considered for poly–(adenosine diphosphate–ribose) polymerase (PARP) inhibitor therapy. Their mutations also offer an opportunity for testing and cancer prevention for daughters and sisters. However, a likelihood of 1%, or even 3%, may be below the threshold of consideration for additional testing for most patients. Second, the chance that an Ashkenazi Jewish patient with breast cancer and no BRCA1 or BRCA2 founder mutation carries a damaging mutation in CHEK2 or another moderate penetrance gene is 3% to 4%. Most of these mutations are associated with a 2-fold increase in risk of breast cancer and no increase in risk of ovarian cancer,13 so they are not likely to affect the treatment of a patient already under care for her breast cancer.

On the other hand, family R (Figure 3) offers an extreme example of the value of genotyping beyond the 3 founder alleles. The lesson of family R is that if multiple cases of breast cancer in a family remain unresolved by the mutation of the proband, then comprehensive sequencing is strongly suggested to identify other causal mutations. The identification of CHEK2 mutations in family R likely did not alter treatment for the patients already diagnosed with breast cancer, but it was highly informative for the daughters of these patients. The most recent National Comprehensive Cancer Network guidelines recommend that cancer-free carriers of mutations in CHEK2 and other moderate penetrance genes undertake annual mammography or breast magnetic resonance imaging with contrast beginning at 40 years of age4 and that they be aware of a moderate increase in the risk of colon cancer.15 These recommendations are germane for the young women of family R who carry a CHEK2 mutation.

Many healthy, cancer-free Ashkenazi Jewish women have been tested for the Ashkenazi Jewish founder mutations of BRCA1 and BRCA2, with negative (ie, normal) results. Should these cancer-free women be tested again to identify any other mutations? The chance that an Ashkenazi Jewish patient with breast cancer harbors a nonfounder mutation in BRCA1 or BRCA2 is less than 1%; therefore, the chance that a cancer-free Ashkenazi Jewish woman harbors such a mutation is much less than 1%. Based on the results of a previous study,13 the chance that a cancer-free Ashkenazi Jewish woman carries CHEK2 p.S284F is 1.4%; therefore, the chance that a cancer-free Ashkenazi Jewish woman carries any CHEK2 mutation, with a corresponding 2-fold increased risk of breast cancer, is approximately 1.7%. For cancer-free Ashkenazi Jewish women with no founder mutation in BRCA1 or BRCA2 who are particularly concerned with remaining genetic risk, comprehensive genetic testing with a multigene panel would identify all CHEK2 mutations, as well as private mutations in any other gene.

An additional consideration for genetic testing for Ashkenazi Jewish women is the evolution of admixture in Ashkenazi Jewish populations. In the New York Ashkenazi Jewish population of the present study, the contribution of founder alleles to the risk of breast cancer was very strong: 128 of 142 patients (90.1%) with a mutation in any gene carried an Ashkenazi Jewish founder allele, whether in BRCA1, BRCA2, or CHEK2. The relative importance of founder vs nonfounder mutations reflects both the antiquity and the historic endogamy of this population. The median birth year of the participants in the NYBCS was 1940. It will be important to keep changing marriage patterns in mind when considering genetic testing for future generations of Jewish women, whose ancestries may be more admixed than the ancestries of their grandmothers.

These considerations suggest that Ashkenazi Jewish women who have not yet been tested for any mutations in any breast cancer gene be offered comprehensive testing for all mutations in all genes. Given that complete sequencing of all breast cancer genes is now straightforward and inexpensive, its use as the primary testing tool offers a uniform approach for women of all ancestries and precludes the need to consider additional testing for Ashkenazi Jewish women with negative results for only the BRCA1 and BRCA2 founder alleles.

Limitations

There are 2 limitations to this study. First, because probands were ascertained for a diagnosis of breast cancer, only genes known or suspected to harbor mutations increasing the risk of breast cancer were sequenced. Genes that harbor mutations predisposing to cancers other than breast, such as genes for Lynch syndrome, were not sequenced. Second, the BROCA panel enables detection of all mutations in coding regions, untranslated regions, or introns of all targeted genes, but does not include sequence for still-unidentified distant regulatory regions of these genes. Identification of mutations in distant regulatory regions of cancer genes is an important next step in genomic analysis of inherited predisposition to cancer.

Conclusions

Among NYBCS participants, approximately half of the patients with a damaging mutation in any breast cancer gene did not have a family history suggesting inherited predisposition. Mutations in these families were likely inherited from fathers, and the combination of small family size and chance in genetic transmission yielded few female relatives carrying mutant alleles. Therefore, to limit genetic testing to patients with a suggestive family history is to miss about 50% of patients with actionable mutations. The most recent national screening guidelines recommend genetic testing for all Ashkenazi Jewish patients with breast cancer.4 This recommendation is fine, but testing women only after they develop cancer severely limits the power of precision medicine. To discover a mutation only after cancer is diagnosed is a missed opportunity to have prevented that cancer. Many of these cancers could be prevented by offering genetic testing as described here to all women before they develop breast cancer, as part of routine medical care.16

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Article Information

Corresponding Author: Mary-Claire King, PhD, Department of Medicine, University of Washington, PO Box 357720, Seattle, WA 98195 (mcking@uw.edu).

Accepted for Publication: May 17, 2017.

Published Online: July 20, 2017. doi:10.1001/jamaoncol.2017.1996

Author Contributions: Drs Walsh and King had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Walsh, King.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Gulsuner, King.

Critical revision of the manuscript for important intellectual content: Walsh, Mandell, Norquist, Casadei, Lee, King.

Statistical analysis: Gulsuner, Lee, King.

Obtained funding: King.

Administrative, technical, or material support: Walsh, Mandell, Casadei, Lee, King.

Study supervision: King.

Conflict of Interest Disclosures: Dr King reported being an American Cancer Society Research Professor. No other disclosures were reported.

Funding/Support: This work was supported by the Breast Cancer Research Foundation and by grants R35CA197458 and R01CA175716 from the National Institutes of Health.

Role of the Funder/Sponsor: The funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We thank the oncologists and genetic counselors from cancer centers of the greater New York area and the participants in the New York Breast Cancer Study for their contributions to the development of this cohort.

References
1.
Kaufman  B, Shapira-Frommer  R, Schmutzler  RK,  et al.  Olaparib monotherapy in patients with advanced cancer and a germline BRCA1/2 mutation.  J Clin Oncol. 2015;33(3):244-250.PubMedArticle
2.
Ledermann  JA, Harter  P, Gourley  C,  et al.  Overall survival in patients with platinum-sensitive recurrent serous ovarian cancer receiving olaparib maintenance monotherapy: an updated analysis from a randomised, placebo-controlled, double-blind, phase 2 trial.  Lancet Oncol. 2016;17(11):1579-1589.PubMedArticle
3.
Domchek  SM, Friebel  TM, Neuhausen  SL,  et al.  Mortality after bilateral salpingo-oophorectomy in BRCA1 and BRCA2 mutation carriers: a prospective cohort study.  Lancet Oncol. 2006;7(3):223-229.PubMedArticle
4.
Daly  MB, Pilarski  R, Berry  M,  et al.  NCCN guidelines insights: genetic/familial high-risk assessment: breast and ovarian, version 2.2017.  J Natl Compr Canc Netw. 2017;15(1):9-20.PubMedArticle
5.
Human Genome Variation Society. Sequence variant nomenclature. http://varnomen.hgvs.org/. Accessed December 10, 2016.
6.
King  MC, Marks  JH, Mandell  JB; New York Breast Cancer Study Group.  Breast and ovarian cancer risks due to inherited mutations in BRCA1 and BRCA2 Science. 2003;302(5645):643-646.PubMedArticle
7.
Gabai-Kapara  E, Lahad  A, Kaufman  B,  et al.  Population-based screening for breast and ovarian cancer risk due to BRCA1 and BRCA2 Proc Natl Acad Sci U S A. 2014;111(39):14205-14210.PubMedArticle
8.
Walsh  T, Lee  MK, Casadei  S,  et al.  Detection of inherited mutations for breast and ovarian cancer using genomic capture and massively parallel sequencing.  Proc Natl Acad Sci U S A. 2010;107(28):12629-12633.PubMedArticle
9.
Nord  AS, Lee  M, King  MC, Walsh  T.  Accurate and exact CNV identification from targeted high-throughput sequence data.  BMC Genomics. 2011;12:184.PubMedArticle
10.
National Center for Biotechnology Information, US National Library of Medicine. ClinVar. https://www.ncbi.nlm.nih.gov/clinvar/. Accessed December 9, 2016.
11.
Friedman  LS, Ostermeyer  EA, Szabo  CI,  et al.  Confirmation of BRCA1 by analysis of germline mutations linked to breast and ovarian cancer in ten families.  Nat Genet. 1994;8(4):399-404.PubMedArticle
12.
Scholl  T, Pyne  MT, Russo  D, Ward  BE.  BRCA1 IVS16+6T→C is a deleterious mutation that creates an aberrant transcript by activating a cryptic splice donor site.  Am J Med Genet. 1999;85(2):113-116.PubMedArticle
13.
Shaag  A, Walsh  T, Renbaum  P,  et al.  Functional and genomic approaches reveal an ancient CHEK2 allele associated with breast cancer in the Ashkenazi Jewish population.  Hum Mol Genet. 2005;14(4):555-563.PubMedArticle
14.
Adank  MA, Jonker  MA, Kluijt  I,  et al.  CHEK2* 1100delC homozygosity is associated with a high breast cancer risk in women.  J Med Genet. 2011;48(12):860-863.PubMedArticle
15.
Provenzale  D, Gupta  S, Ahnen  DJ,  et al.  Genetic/familial high-risk assessment: colorectal version 1.2016, NCCN Clinical Practice Guidelines in Oncology.  J Natl Compr Canc Netw. 2016;14(8):1010-1030.PubMedArticle
16.
King  MC, Levy-Lahad  E, Lahad  A.  Population-based screening for BRCA1 and BRCA2: 2014 Lasker Award.  JAMA. 2014;312(11):1091-1092.PubMedArticle
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