Frequency of recurrent BRCA1 and BRCA2 mutations in Ashkenazi Jewish breast cancer families

Tonin, Patricia N.; Weber, Barbara; Offit, Kenneth; Couch, Fergus J.; Rebbeck, Timothy R.; Neuhausen, Susan L.; Godwin, Andrew K.; Daly, Mary B.; Wagner-Costalos, J.; Berman, David B.; Grana, Generosa; Fox, Edward A.; Kane, Michael F.; Kolodner, Richard D.; Krainer, Michael; Haber, Daniel A.; Struewing, Jeffery P.; Rosen, Barry P.; Lerman, Caryn; Peshkin, Beth N.; Norton, Larry; Serova, Olga; Foulkes, William D.; Lynch, Henry T.; Lenoir, Gilbert; Narod, Steven A.; Garber, Judy E.

doi:10.1038/nm1196-1179

Cited by 288 publications

(174 citation statements)

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“…Given that our testing criteria were lenient (3 or more cases of breast or ovarian cancer diagnosed at any age), this is among the highest mutation frequency for any population studied to date and is comparable to that of the Ashkenazi Jews. 4 Mutation surveys from other Slavic countries (Russia, 20 Czech Republic, 21 Latvia, 22 Belarus 23 ) show a similar pattern of frequent BRCA1 mutations and rare BRCA2 mutations (Table V). Interestingly, the 5382insC mutation is common in both the Ashkenazi Jewish and Slavic populations.…”

Section: Discussionmentioning

confidence: 81%

A high proportion of founder BRCA1 mutations in Polish breast cancer families

Górski

Jakubowska

Huzarski

et al. 2004

Intl Journal of Cancer

179

148

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Three mutations in BRCA1 (5382insC, C61G and 4153delA) are common in Poland and account for the majority of mutations identified to date in Polish breast and breast-ovarian cancer families. It is not known, however, to what extent these 3 founder mutations account for all of the BRCA mutations distributed throughout the country. This question has important implications for health policy and the design of epidemiologic studies. To establish the relative contributions of founder and nonfounder BRCA mutations, we established the entire spectrum of BRCA1 and BRCA2 mutations in a large set of breast-ovarian cancer families with origins in all regions of Poland. We sequenced the entire coding regions of the BRCA1 and BRCA2 genes in 100 Polish families with 3 or more cases of breast cancer and in 100 families with cases of both breast and ovarian cancer. A mutation in BRCA1 or BRCA2 was detected in 66% of breast cancer families and in 63% of breast-ovarian cancer families. Of 129 mutations, 122 (94.6%) were in BRCA1 and 7 (5.4%) were in BRCA2. Of the 122 families with BRCA1 mutations, 119 (97.5%) had a recurrent mutation (i.e., one that was seen in at least 2 families). In particular, 111 families (91.0%) carried one of the 3 common founder mutations. The mutation spectrum was not different between families with and without ovarian cancer. These findings suggest that a rapid and inexpensive assay directed at identifying the 3 common founder mutations will have a sensitivity of 86% compared to a much more costly and labor-intensive full-sequence analysis of both genes. This rapid test will facilitate large-scale national epidemiologic and clinical studies of hereditary breast cancer, potentially including studies of chemoprevention. Germline mutations in BRCA1 (MIM 113-705) and BRCA2 (MIM 600185) account for familial clustering in the majority of families with both breast and ovarian cancers and in approximately one-half of families with site-specific breast cancer. 1-3 Of the more than 1,000 BRCA mutations reported to the Breast Cancer Information Core (BIC) database, many are unique but there are also numerous examples of founder mutations. Founder mutations have been reported in genetic isolates such as Ashkenazi Jews 4,5 and the Icelandic, 6 Finnish, 7 Dutch 8,9 and French Canadian 10 populations. Founder mutations have also been noted in Slavic countries, including Poland. 11 Three BRCA1 mutations (5382insC, C61G and 4153delA) are common in Poland, 11 but several other BRCA1 and BRCA2 mutations have also been reported in one or a few families. 11-17 Our goal was to describe the frequency of BRCA1 and BRCA2 constitutional mutations in a series of 200 breast cancer and breast-ovarian cancer families representing all regions of

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Section: Discussionmentioning

confidence: 81%

A high proportion of founder BRCA1 mutations in Polish breast cancer families

Górski

Jakubowska

Huzarski

et al. 2004

Intl Journal of Cancer

179

148

View full text Add to dashboard Cite

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“…However, this rate varies significantly among ethnic groups. One notable group is the Ashkenazi Jewish population, in which the estimated carrier frequency is 1 in 40 individuals (Tonin et al, 1996).…”

Section: Hereditary Breast/ovarian Cancer (Hboc) and Brca Gene Mutationsmentioning

confidence: 99%

“…Women carrying a mutation in BRCA1 or BRCA2 have a 50-87% risk of developing breast cancer by age 70 (Domchek et al, 2003;Ford et al, 1998), up to a 27-44% risk of developing ovarian cancer (Domchek et al, 2003;Ford et al, 1998), and an elevated risk of a second cancer (Berliner et al, 2007). They also have smaller risks for other types of cancer (Thull and Vogel, 2004 (Tonin et al, 1996). …”

mentioning

confidence: 99%

The Effect of BRCA Gene Testing on Family Relationships: A Thematic Analysis of Qualitative Interviews

Douglas¹,

Hamilton

Grubs³

2009

Journal of Genetic Counseling

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Individuals with a personal or family history of cancer can pursue testing for mutations in BRCA1 and BRCA2, breast and ovarian cancer susceptibility genes, in order to help them make decisions about cancer risk-reducing surgeries and other management options. However, this genetic testing can also have emotional consequences, not only for the tested individual but also for his or her relatives since testing can provide risk information for them as well. Thus, this study investigated the impact of BRCA testing on family dynamics and family relationships. A qualitative research design was employed, in which a secondary analysis was conducted on interview transcripts. In the initial study, two open-ended, tape-recorded interviews were performed using grounded theory methodology with each of 12 participants approximately three years apart. All participants had tested positive for a mutation in either BRCA1 or BRCA2.Thematic analysis of interview transcripts was conducted in the current secondary analysis to characterize family relationships after BRCA testing. Three main themes were identified: 1.That the first in the family to have testing or seek genetic counseling takes on a special family role that can be difficult for them; 2. That discussions in the family, especially those associated with BRCA testing, often change after genetic testing; and 3. That individuals may feel more or less connected to certain family members after genetic testing has occurred in the family. These changes in family dynamics seem to depend on the family history of cancer, prior relationships within the family, emotional coping strategies of relatives, value placed on particular iv communication patterns, and sharing or not sharing the family's BRCA mutation. The results of this study highlight the profound changes in family life that can occur after BRCA testing.Health professionals can use the insight they gain from this study in their management of patients considering BRCA testing. This work also has public health relevance since it describes how genetic testing for susceptibility to a common disease can influence family dynamics. Such an understanding will be important as the genetic basis of common disease becomes better understood and tests for additional susceptibility genes become available. PREFACEFirst and foremost, I would like to acknowledge all of the participants in this study for sharing their experiences so openly. These individuals were truly an inspiration to me and have greatly The preliminary interviews were supported by a research grant to Dr. Rebekah J.Hamilton from Sigma Theta Tau International. INTRODUCTIONIn the 1990s, the discovery of the BRCA genes offered an explanation for the clustering of ovarian cancer and early onset breast cancer in some families. In these families, it was found that individuals who inherited a mutated copy of a BRCA gene had a lifetime risk of cancer much higher than that of the general population, while those who did not inherit a gene mutation had no elevated risk (Ford et al., ...

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“…6 -21 Among recurrent BRCA1/2 mutations, some are population-specific, whereas others occur in DNA sequences that may represent mutational hot-spot regions. [22][23][24] The proportion of recurrent mutations to unique mutations varies in different populations and subpopulations, reflecting historic influences on migration, population structure, and geographic and cultural isolation. 23 Such differences in mutation prevalence clearly indicate that there is a need to define the risk of breast cancer in population-based studies as well as both the type and frequency of BRCA1/2 mutations within every cohort or country.…”

mentioning

confidence: 99%