Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2

Ligtenberg, Marjolijn J. L.; Hogervorst, Frans B.L.; Willems, H.W.; Arts, Peer; Brink, Gijs R. van den; Hageman, S.; Bosgoed, Ermanno; Looij, Erica van der; Rookus, Matti A.; Devilee, Peter; Vos, E M A W; Wigbout, Gea; Struycken, P.M.; Menko, Fred H.; Rutgers, Emiel J. T.; Hoefsloot, Elisabeth H.; Mariman, E.C.M.; Brunner, Han G.; Veer, Laura J. van’t

doi:10.1038/sj.bjc.6690235

Cited by 41 publications

(29 citation statements)

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“…12,14,[23][24][25][26][27] The breast cancer linkage consortium (BCLC) estimates that 95% of breast/ovarian cancer families and 65% of female breast cancer families are related to BRCA1 or BRCA2. 4 We detected mutations in, respectively, 60% (8/13) and 23% (7/30) of our breast/ovarian and female breast cancer families with BCLC entry criteria (at least 4 breast cancer cases).…”

Section: Discussionmentioning

confidence: 99%

“…Probabilistic models of this kind are limited and restricted either to BRCA1 alone, 11,12 to the Ashkenazi Jewish population 13 or to certain mutation mechanisms. 14 Recently, a study involving both BRCA1 and BRCA2 genes in a series of Finish families with at least 3 cases of breast and/or ovarian cancer has been published. 15 Although a direct comparison of these models is not possible due to different entry criteria, target populations, mutation screening protocols and clinical parameters analyzed, different predictive values for some clinical parameters such as bilateral breast cancer, breast and ovarian cancer in a single woman or unilateral breast cancer are suggested.…”

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Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Hoya

Osorio

Godino

et al. 2001

Intl Journal of Cancer

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Index cases from a clinically relevant cohort of 102 Spanish families with at least 3 cases of breast and/or ovarian cancer (at least 1 case diagnosed before age 50) in the same lineage were screened for germline mutations in the entire coding sequence and intron boundaries of the breast cancer susceptibility genes BRCA1 and BRCA2. Overall, the prevalence of mutations was 43% in female breast/ovarian cancer families, 15% in female breast cancer families and 100% in male breast cancer families. Three recurrent mutations (185delAG, 589delCT and A1708E) explained 63% of BRCA1-related families. Early age at diagnosis of breast cancer, ovarian cancer, bilateral breast cancer, concomitant breast/ovarian cancer in a single patient and prostate cancer but not unilateral breast cancer were associated with BRCA1 and BRCA2 mutations. Male breast cancer was associated with BRCA2 mutations. The presence of male breast cancer was the only cancer phenotype that distinguished BRCA2-from BRCA1-related families. We have developed a logistic regression model for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The predictive positive and negative values of this model were 77.4% and 79%, respectively (probability cutoff of 30%). The findings of our work may be a useful tool for increasing the cost-effectiveness of genetic testing in familial cancer clinics. © 2002 Wiley-Liss, Inc. Key words: BRCA1; BRCA2; logistic regression modelCancer of the breast is the most common malignancy among women in Western countries. In 5-10% of these patients, the disease can be attributed to an inherited predisposition. 1 A linkagebased study estimated that the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2 account, respectively, for 52% and 32% of all hereditary breast and/or ovarian cancer families with at least 4 breast cancer cases. [2][3][4] Mutation-based studies indicated that defects in the 2 breast/ovarian cancer susceptibility genes account for a varying fraction of breast cancer families in different populations. 5 The risk of breast and ovarian cancer associated with mutations in these 2 genes has been estimated, 4 and other cancer types to which mutation carriers are predisposed have been identified. 6 -9 Today, many families with a moderate number of breast and/or ovarian cancer cases seek genetic testing in familial cancer clinics. Unfortunately, current laboratory methods are costly and timeconsuming due to the fact that BRCA1 and BRCA2 mutations are apparently randomly distributed over the large coding sequence of both genes. 10 A negative result does not indicate the absence of genetic predisposition in the family because PCR-based protocols do not detect genomic rearrangements and allele-specific transcription defects. Moreover, there is also evidence of other as yet unknown predisposing genes. 4 Management of these families does not defer either without testing or with a negative testing result. Ideally, one would prefer to t...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Hoya

Osorio

Godino

et al. 2001

Intl Journal of Cancer

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“…The presence of breast and ovarian cancer in the same patient was not significant in multivariate analysis, probably because it is closely associated with ovarian cancer cases overall. Bilateral breast cancer, another factor that has been correlated with a positive mutation status by for example Shattuck-Eidens et al (1997) and Ligtenberg et al (1999), was not significant in univariate analysis and, therefore, not included in further analysis.…”

Section: Factors Associated With Positive Mutation Statusmentioning

confidence: 99%

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

et al. 2001

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Mutations in the two breast-ovarian cancer susceptibility genes, BRCA1 and BRCA2, account for a varying fraction of breast cancer families in different populations (Szabo and King, 1997). Both BRCA1 and BRCA2 mutations are scattered throughout the large coding regions of the genes (Breast Cancer Information Core). In admixed populations, most mutations appear uniquely in single families only, making the mutation screening laborious and expensive. Furthermore, there is also evidence of other predisposing genes (Ford et al, 1998;Kainu et al, 2000). It is, therefore, important to find the clinical risk factors that could best predict the presence of BRCA1 and BRCA2 mutations, so that the screening could be directed to potential mutation carrier families. Several probability models for mutation detection have been developed. These are, however, based only on BRCA1 (Berry et al, 1997;Couch et al, 1997;Shattuck-Eidens et al, 1997), focus on specific founder mutations in the Ashkenazi population (Foulkers et al, 1999;Hodgson et al, 1999;Hopper and Jenkins, 1999), or require information such as penetrance estimations not available in all populations (Berry et al, 1997;Parmigiani et al, 1998; ChangClaude et al, 1999).Here we have developed a model for predicting the presence of a BRCA1 or BRCA2 mutation in families with 3 or more relatives affected with breast or ovarian cancer. We also compared this model with those of Shattuck-Eidens et al (1997) and Couch et al (1997) originally designed for BRCA1 only. Additionally, the frequency of BRCA1/2 mutations was studied in 295 families with two affected family members to evaluate the feasibility of genetic screening in families with moderate family history. PATIENTS AND METHODSThe cohort studied consisted of 148 families with 3 or more 1st or 2nd degree relatives affected with breast or ovarian cancer. The families were identified by patient interviews, and full pedigrees were constructed with the confirmation of all genealogy data through the Finnish population registration as well as diagnostic data through hospital records and/or Finnish Cancer Registry as previously described (Vehmanen et al, 1997a,b;Eerola et al, 2000). Additionally, 295 breast cancer cases with one 1st degree relative affected with breast or ovarian cancer and identified in the patient cohorts described in Eerola et al (2000) were also studied. In the following, these are called small families. The family history of these cases was based on information reported by the index patient. All patients participating in the study signed an informed consent before the blood sample for the genetic analysis was taken. This study has been approved by the Ethical Committees of Departments of Obstetrics and Gynaecology, and Oncology, HUCH, and appropriate permissions were obtained from the Ministry of Social Affairs and Health in Finland.The mutations identified by a complete mutation analysis of the whole coding sequences and exon/intron boundaries of the genes in 95 of these families have been previously reported...

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“…[1][2][3][4] BRCA1 and BRCA2 are typical tumor-suppressor genes and loss of a wild-type allele has been reported in almost all breast tumors arising in BRCA1 or BRCA2 germline mutation carriers. 5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint.…”

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High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

Egawa

Miyoshi

Taguchi

et al. 2002

Intl Journal of Cancer

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The prognostic significance of BRCA 2 mRNA levels in tumor tissues was studied in sporadic breast cancer patients. BRCA 2 mRNA levels were determined by real-time PCR. Histologic grade III tumors showed significantly (p ‫؍‬ 0.001) higher BRCA 2 mRNA levels (0.828 ؎ 0.102 BRCA 2/␤-glucuronidase mRNA ratio, mean ؎ SE) than histologic grade I and II tumors (0.438 ؎ 0.055) and estrogen receptor (ER)-negative tumors (0.773 ؎ 0.102) showed a nonsignificant (p ‫؍‬ 0.072) trend toward an increase in BRCA 2 mRNA levels compared to ER-positive tumors (0.541 ؎ 0.079). Other clinicopathologic parameters, such as menopausal status, lymph node status and tumor size, were not significantly associated with BRCA 2 mRNA levels. Patients with high BRCA 2 mRNA levels showed a significantly (p ‫؍‬ 0.006) lower 5-year disease free survival rate (63%) than those with low levels (94%). Lymph node metastases, ER negativity and high histologic grade were also significantly (p < 0.05) associated with poor prognosis. Multivariate analysis revealed that BRCA 2 mRNA levels were a significant prognostic factor, being independent of the other conventional prognostic factors. Our results suggest that BRCA 2 mRNA levels might serve as a clinically useful prognostic factor in breast cancer patients. © 2002 Wiley-Liss, Inc. Key words: breast cancer; BRCA2; prognosis; ER; histologic grade BRCA1 and BRCA2 are the well-established breast cancer susceptibility genes and germline mutations of these genes are found in 20 -30% of breast cancer families. 1-4 BRCA1 and BRCA2 are typical tumor-suppressor genes and loss of a wild-type allele has been reported in almost all breast tumors arising in BRCA1 or BRCA2 germline mutation carriers. 5,6 Although the function of these genes remains to be established, both have been implicated in the repair of double-stranded DNA breaks in cooperation with Rad51 as well as in regulation of the G 2 -M checkpoint. 7 In addition, the ubiquitin ligase activity of the BRCA1-BARD1 complex has been described. 8 Somatic mutations of BRCA1 and BRCA2 appear to be very rare, 9 -12 but loss of heterozygosity of BRCA1 and BRCA2 is frequently observed, suggesting involvement of these genes in the pathogenesis of sporadic breast cancers. BRCA1 mRNA levels are downregulated in sporadic breast cancers compared to normal breast tissues and hypermethylation of the promoter region of BRCA1 explains this downregulation in some cases. 13,14 However, BRCA2 mRNA levels do not show a consistent tendency and are both upregulated and downregulated among sporadic breast cancers. 15 Unlike BRCA1, the promoter region of BRCA2 is not hypermethylated. 16 Thus, the contributions of BRCA1 and BRCA2 to the pathogenesis of sporadic breast cancers might be different.Downregulation of BRCA1 mRNA and protein levels is associated with an aggressive phenotype of sporadic breast cancers 17,18 and poor prognosis. 19 In contrast, Bieche et al. 15 reported that high BRCA2 mRNA levels are associated with an aggressive phenotype of sporadic breast cancer. We have...

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Characteristics of small breast and/or ovarian cancer families with germline mutations in BRCA1 and BRCA2

Cited by 41 publications

References 9 publications

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

Association between BRCA1 and BRCA2 mutations and cancer phenotype in Spanish breast/ovarian cancer families: Implications for genetic testing

A probability model for predicting BRCA1 and BRCA2 mutations in breast and breast-ovarian cancer families

High BRCA2 mRNA expression predicts poor prognosis in breast cancer patients

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