Factors Affecting Sensitivity and Specificity of Screening Mammography and MRI in Women with an Inherited Risk for Breast Cancer

Background The MRISC study is a screening study, in which women with an increased risk of hereditary breast cancer are screened by a yearly mammography and MRI, and half-yearly clinical breast examination. The sensitivity found in this study was 40% for mammography and 71% for MRI and the specificity was 95 and 90%, respectively. In the current subsequent study we investigated whether these results are influenced by age, a BRCA1/2 mutation, menopausal status and breast density.Patients and methods From November 1999 to October 2003, 1909 eligible women were screened and 50 breast cancers were detected. For the current analysis, data of 4134 screening rounds and 45 detected breast cancers were used. For both imaging modalities, screening parameters, receiver operating characteristic (ROC) curves and uni- and multivariate odds ratios (ORs) were calculated. All analyses were separately performed for age at entry (< 40, 40–49, ≥50), mutation status, menopausal status and breast density.Results Sensitivity of MRI was decreased in women with high breast density (adjusted OR 0.08). False-positive rates of both mammography (OR_adj 1.67) and MRI (OR_adj 1.21) were increased by high breast density, that of MRI by pre-menopausal status (OR_adj 1.70), young age (OR_adj 1.58 for women 40–49 years versus women ≥50 years) and decreased in BRCA1/2 mutation carriers (OR_adj 0.74).In all investigated subgroups the discriminating capacity (measured by the area under the ROC-curve) was higher for MRI than for mammography, with the largest differences for BRCA1/2 mutation carriers (0.237), for women between 40 and 49 years (0.227) and for women with a low breast density (0.237).Conclusions This report supports the earlier recommendation that MRI should be a standard screening method for breast cancer in BRCA1/2 mutation carriers.     

High Incidence of 4153delA <Emphasis Type="Italic">BRCA1</Emphasis> Gene Mutations in Lithuanian Breast- and Breast-ovarian Cancer Families

Summary BRCA1 and BRCA2 gene mutations confer a high lifetime risk to breast and ovarian cancers. We have screened cancer patients from 13 families with at least three breast and/or ovarian cancers from Lithuania for 5382insC, C61G and 4153delA BRCA1 gene mutations. One of three mutations was found in 9 of the 13 studied families (69%). 4153delA was the most frequently detected and accounted for 56% of all identified mutation. 5382insC and C61G accounted for 33% and 11% of found mutations, respectively. Significantly higher, than in other populations, incidence of 4153delA indicates that this may be founder BRCA1 mutation characteristic for Lithuanians. Our analysis shows that testing of 4153delA, 5382insC, C61G BRCA1 mutations should be extremely effective and inexpensive tool in testing Lithuanian population aimed to identify individuals with high risk of breast and ovarian cancers.     

Association of the C677T polymorphism in the MTHFR gene with breast and/or ovarian cancer risk in Jewish women

The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with reduced enzyme activity, hyperhomocysteinaemia and increased risk for atherosclerosis in homozygotes. We examined the frequency of this mutation and its association with disease pattern in 491 Jewish women with either sporadic (n=355; 72%) or hereditary (n=136; 28%) breast and/or ovarian cancer and in 69 asymptomatic BRCA1/2 mutation carriers, genotyped for the three predominant Jewish founder BRCA1/2 mutations (185delAG, 5382insC and 6174delT). 677T homozygotes were equally distributed among women with sporadic breast and/or ovarian cancer (71/355; 20.0%) and among BRCA1/2 mutation carriers (43/205; 21.0%) (P=non-significant). 677T homozygotes were equally distributed among women diagnosed with breast cancer prior to (22/122; 18.0%) and after 42 years of age (42/243; 17.3%). Among BRCA1/2 carriers, the rate of 677T homozygotes in manifesting cancer (32/136; 23.5%) and asymptomatic individuals (11/69; 15.9%) was not significantly different. The rate of 677T homozygotes (24/72; 33.3%) was higher (P=0.0026) among women with bilateral breast cancer and those with both breast and ovarian carcinoma than among those with unilateral breast cancer (64/365; 17.5%). Differences in morbidity (one versus multiple breast/ovarian tumours) are mainly attributed to 677T homozygosity and partly to BRCA1/2 mutations. Confirmation of these data, namely, that the 677T allele is significantly more common in cases of bilateral breast cancer or combined breast and ovarian cancer would have important clinical implications.     

Prevalence of two <Emphasis Type="Italic">BRCA1</Emphasis> mutations, 5382insC and 300T &gt; G,in ovarian cancer patients from Ukraine

Ovarian cancer is the seventh most common cancer in women worldwide and the leading cause of gynecological malignant diseases-related deaths in women. The most significant risk factor for ovarian cancer is an inherited genetic mutation in one of two genes: breast cancer gene 1 (BRCA1) or breast cancer gene 2 (BRCA2). The germline mutation c.5266dupC (also known as 5382insC or 5385insC) is the most common mutation among Slavic patients with breast and/or ovarian cancer. Missense mutation c.181T?>?G (also known as 300T?>?G or p.C61G) is regarded as the founder change in many Central European countries. We screened 306 ovarian cancer patients diagnosed at different ages by mutagenically separated polymerase chain reaction (PCR) and real-time PCR. A total of 25 BRCA1 mutations were detected (18 cases of 5382insC and 7 cases of 300 T?>?G). The frequency of the BRCA1 5382insC mutation is similar in breast and ovarian cancer patients from Ukraine, but the frequency of 300T?>?G was estimated in Ukraine at first time.     

No association of TGFB1 L10P genotypes and breast cancer risk in BRCA1 and BRCA2 mutation carriers: a multi-center cohort study

Background The transforming growth factor β-1 gene (TGFB1) is a plausible candidate for breast cancer susceptibility. The L10P variant of TGFB1 is associated with higher circulating levels and secretion of TGF-β, and recent large-scale studies suggest strongly that this variant is associated with breast cancer risk in the general population. Methods To evaluate whether TGFB1 L10P also modifies the risk of breast cancer in BRCA1 or BRCA2 mutation carriers, we undertook a multi-center study of 3,442 BRCA1 and 2,095 BRCA2 mutation carriers. Results We found no evidence of association between TGFB1 L10P and breast cancer risk in either BRCA1 or BRCA2 mutation carriers. The per-allele HR for the L10P variant was 1.01 (95%CI: 0.92–1.11) in BRCA1 carriers and 0.92 (95%CI: 0.81–1.04) in BRCA2 mutation carriers. Conclusions These results do not support the hypothesis that TGFB1 L10P genotypes modify the risk of breast cancer in BRCA1 or BRCA2 mutation carriers.     

Association of PHB 1630 C>T and MTHFR 677 C>T polymorphisms with breast and ovarian cancer risk in BRCA1/2 mutation carriers: results from a multicenter study

Background:

The variable penetrance of breast cancer in BRCA1/2 mutation carriers suggests that other genetic or environmental factors modify breast cancer risk. Two genes of special interest are prohibitin (PHB) and methylene-tetrahydrofolate reductase (MTHFR), both of which are important either directly or indirectly in maintaining genomic integrity.

Methods:

To evaluate the potential role of genetic variants within PHB and MTHFR in breast and ovarian cancer risk, 4102 BRCA1 and 2093 BRCA2 mutation carriers, and 6211 BRCA1 and 2902 BRCA2 carriers from the Consortium of Investigators of Modifiers of BRCA1 and BRCA2 (CIMBA) were genotyped for the PHB 1630 C>T (rs6917) polymorphism and the MTHFR 677 C>T (rs1801133) polymorphism, respectively.

Results:

There was no evidence of association between the PHB 1630 C>T and MTHFR 677 C>T polymorphisms with either disease for BRCA1 or BRCA2 mutation carriers when breast and ovarian cancer associations were evaluated separately. Analysis that evaluated associations for breast and ovarian cancer simultaneously showed some evidence that BRCA1 mutation carriers who had the rare homozygote genotype (TT) of the PHB 1630 C>T polymorphism were at increased risk of both breast and ovarian cancer (HR 1.50, 95%CI 1.10–2.04 and HR 2.16, 95%CI 1.24–3.76, respectively). However, there was no evidence of association under a multiplicative model for the effect of each minor allele.

Conclusion:

The PHB 1630TT genotype may modify breast and ovarian cancer risks in BRCA1 mutation carriers. This association need to be evaluated in larger series of BRCA1 mutation carriers.     

Selected Aspects of Molecular Diagnostics of Constitutional Alterations in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> Genes Associated with Increased Risk of Breast Cancer in the Polish Population

Objectives

This study was undertaken to determine: 1) Type and prevalence of founder mutations BRCA1 and BRCA2 genes in Polish families with strong aggregation of breast and/or ovarian cancer. 2) Risk of breast and/or ovarian cancer depending on type of BRCA1 gene mutation. 3) Prevalence of BRCA1 mutation and of other alleles presumably linked with predisposition to breast cancer in unselected Polish patients with breast cancer. 4) Risk of breast cancer in patients with 5972C/T polymorphism that alters the BRCA2 protein structure.

Summary of the results

1. Among 66 families from several regions in Poland with a strong aggregation of breast/ovarian cancer, founder mutation of the BRCA1 gene were disclosed in 34 families and of the BRCA2 gene in on family. Altogether, seven different mutations were disclosed. Five mutations were found in at least two families in this group. The most frequent mutation was 5382insC (18 families), followed by C61G (7 families) and 4153delA (4 families). 2. Among 200 families representative for Poland with strong aggregation of breast/ovarian cancer, mutation of the BRCA1 gene were found in 122 families (61%) and of the BRCA2 gene in seven families (3,5%). 119 out of 122 mutations of the BRCA1 gene (97,5%) were repeatable. Three recurrent mutations of the BRCA1 gene (5382insC, C61G, 4153delA) characteristic for the Polish population were disclosed in 111 families representing 86% of all pathogenic sequences of this gene. 3. The risk of ovarian cancer in carriers of the three most frequent recurrent mutation of the BRCA1 gene in Poland is similar (OR 43.6 for 5382insC and 50 for 4153delA). The risk of breast cancer is significantly different for 4153delA (OR 1) and for other mutations (OR 10.9). 4. Among 2012 unselected breast cancers diagnosed in hospitals of nine Polish cities, mutations of the BRCA1 gene (5382insC, C61G, 4153delA) were disclosed in 2.9% patients. CHEK2 alternation (1100delC, IVS2+1G>A, I157T) was discovered in 8.1% and NBS1 mutation (657del5) in 0.8% of the patients. The changes were more frequent in the study than the control group. However, the risk of breast cancer was significantly higher for only three of them. Two changes, namely 5382insC and C61G of the BRCA1 gene revealed a high penetrance (OR 6.2 and 15.0, respectively), while I157T of the CHEK2 gene was associated with a low risk of breast cancer (OR 1.4). Mutations of the BRCA1, CHEK2 and NSB1 genes were significantly more frequent in patients with breast cancer diagnosed prior to 50 years of age. The mean age at diagnosis was 47.2 years for carriers of the BRCA1 mutation, 50.7 years for NBS1 and 54.2 for CHEK2. The mean age at diagnosis in the group of patients without any if the mutations described above was 56.1 years. When breast cancer patients with the diagnosis before and after 50 years of age were compared, the greatest difference in the frequency of mutation was revealed for the BRCA1 gene (5.5% vs 1.5%).BRCA1 mutations were significantly more frequent I familial aggregates of the tumor (10.8%), but were also present in sporadic cases (1.8%). For the CHEK2 and NBS1 genes, there was no correlation between frequency and family history of cancer in probands. 5. A higher frequency of heterozygous carriers of 5972C/T polymorphism of the BRCA2 gene was demonstrated for breast cancer prior to 50 years of age (OR 1.4). the risk of breast cancer prior to 50 years of age was particularly high in 5972T/T homozygote (OR 4.7). This polymorphism was associated with breast cancer notable for intraductal growth.

Conclusions

1. Efficient molecular diagnostics of genetic predisposition to breast/ovarian cancer in Poland could be based on relatively simple tests disclosing some of the most frequent recurrent mutations of the BRCA1 gene. 2. The risk of breast cancer seems to be only slightly higher in carriers of some BRCA1 gene mutations. This finding should be taken into account during work on prevention schemes for carriers of the BRCA1 mutations. 3. 5382insC and C61G mutations of the BRCA1 gene are linked with high risk of breast cancer. Changes in the CHEK2 and NBS1 genes appear to be linked with a higher risk of breast cancers, particularly at young age. However, penetrance in this case is low. All patients with breast cancer should be tested for BRCA1 gene mutations because the percentage of mutations is also high in patients older than 50 years of age or without familiar aggregation of breast/ovarian cancer. 4. Polymorphic changes in the BRCA2 gene sequence previously regarded as non-pathogenic may nevertheless predispose, homozygotes in particular, to breast cancer. Apparently, the recessive character of these changes is responsible for the negative family history in most cases. The use of DNA tests is the only way to disclose increased risk of breast cancer in carriers of the 5972T/T mutation.

     

Genetic variations in transcription factor 7-like 2 (<Emphasis Type="Italic">TCF7L2)</Emphasis> gene: association of <Emphasis Type="Italic">TCF7L2</Emphasis> rs12255372(G/T) or rs7903146(C/T) with breast cancer risk and clinico-pathological parameters

The purpose of the present study was to evaluate the association between TCF7L2 rs12255372(G/T) or rs7903146(C/T) polymorphism and breast cancer risk, and clinico-pathologic characteristics of the patients. Genotyping of these polymorphisms was performed on 387 breast cancer patients and 252 normal and healthy women who had no history of any malignancy using polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) method in a hospital-based Malaysian population. The allele (P = 0.033) frequency of rs7903146 (T) polymorphism was significantly higher in the cancer patients than normal individuals. No significant association was demonstrated between CT (OR^adj = 1.386; 95% CI, 0.985–1.949) or TT (OR^adj = 1.579; 95% CI, 0.869–2.870) genotype and breast cancer risk. However, women who were carriers of T allele (OR^adj = 1.316; 95% CI, 1.022–1.695) or T allele genotype (OR^adj = 1.419; 95% CI, 1.027–1.960) showed significant increased risk of breast cancer. Women who were GT heterozygotes (OR^adj = 1.329; 95% CI, 0.948–1.862) or TT homozygotes (OR^adj = 1.574; 95% CI, 0.829–2.987), and carriers of T allele genotype (OR^adj = 1.365; 95% CI, 0.989–1.883) or T allele (OR^adj = 1.284; 95% CI, 0.995–1.657) were not associated with breast cancer risk. The rs7903146(T) allele genotype was significantly associated with nodal involvement (P = 0.003) but rs12255372 (T) allele genotype was not associated with the clinico-pathologic characteristics. In conclusion, our findings suggest that rs7903146 (T) variant may elevate the risk of breast cancer, thus could be a potential candidate for breast cancer susceptibility. The variant may also increase the metastatic potential of the tumor.     

High frequency of BRCA1 5382insC mutation in Russian breast cancer patients

BRCA1 5382insC variant was repeatedly detected in Jewish breast cancer (BC) families residing in USA and Israel as well as in non-Jewish familial BC patients from Poland, Latvia, Hungary, Russia and some other European countries. However, the distribution of BRCA1 5382insC mutation in unselected BC cases vs. controls has been systematically investigated mainly in Ashkenazi Jews. Here we applied a case-control study design in order to evaluate the impact of BRCA1 5382insC allele on BC incidence in St Petersburg, Russia. High frequency of the BRCA1 5382insC allele was detected in a group of bilateral breast cancer patients (10.4%; 15/144). Randomly selected unilateral BC cases demonstrated noticeable occurrence of BRCA1 5382insC mutation as well (3.7%; 32/857), with evident excess of the carriers in the early-onset (40 years) category (6.1%; 6/99) and in patients reporting breast and/or ovarian tumours in first-degree relatives (11.3%; 11/97). Strikingly, none of 478 middle-aged controls and 344 elderly tumour-free women carried the 5382insC variant. The presented data confirm a noticeable contribution of BRCA1 5382insC mutation in BC development in Russia, that may justify an extended BRCA1 5382insC testing within this population.     

Frequency of 5382insC mutation of BRCA1 gene among breast cancer patients: an experience from Eastern India

The incidence of breast cancer in India is on the rise and is rapidly becoming the number one cancer in females pushing the cervical cancer to the second position. The mutations in two breast cancer susceptibility genes, BRCA1 and BRCA2, are frequently associated with familial breast cancer. The main objective of the study was to determine the frequency of the mutation 5382insC in BRCA1 of eastern Indian breast cancer patients and also study the hormonal receptor status and histopathology of the patients. Altogether 92 patients affected with breast cancer were included in this study. ARMS-PCR based amplification was used to detect the presence of mutation. The mutations were considered only after pedigree analysis. Out of 92 patients (age range: 20–77 years) with family history (57 individuals) and without family history (35 individuals) were screened. Fifty controls have been systematically investigated. Seven patients and two family members were found to be carriers of 5382insC mutation in BRCA1 gene. We have found 42.64 % ER^?/PR^? cancer and 20.58 % triple negative cancer. Invasive ductal carcinoma is the most common histology among the investigated individuals. The presented data confirm a noticeable contribution of BRCA1 5382insC mutation in BC development in Eastern India, which may justify an extended BRCA1 5382insC testing within this patient population. We found HER-2/neu negativity and BRCA1 positivity associated with familial breast cancer. From the hospital’s patient history, it was revealed that the age of menarche plays an important role in development of breast cancer.     

Primary node negative breast cancer in BRCA1 mutation carriers has a poor outcome

Background:The association between BRCA1 germ-linemutations and breast cancer prognosis is controversial. A historical cohortstudy was designed to determine the prognosis for women with axillary lymphnode negative hereditary breast cancer. Patients and methods:We tested pathology blocks from 118Ashkenazi Jewish women with axillary lymph node negative breast cancer for thepresence of the two common BRCA1 founder mutations, 185delAG and5382insC. Patients were followed up for a median of 76 months. SomaticTP53mutations were screened for by immunohistochemistry, and directsequencing was performed in the BRCA1-positive tumours. Results:Sixteen breast cancer blocks (13.6%) carried aBRCA1 mutation. Young age of onset, high nuclear grade, negativeestrogen receptor status and over-expression of p53 were highly associatedwith BRCA1-positive status (P-values all <0.01).BRCA1 mutation carriers had a higher mortality than non-carriers(five-year overall survival, 50% and 89.6%, respectively,P = 0.0001). Young age of onset, estrogen receptor negative status,nuclear grade 3, and over-expression of p53 also predicted a poor outcome. Coxmultivariate analyses showed that only germ-line BRCA1 mutationstatus was an independent prognostic factor for overall survival (P= 0.01). Among nuclear grade 3 tumours, the BRCA1 mutation carrierstatus was a significant prognostic factor of death (risk ratio 5.8,95% confidence interval: 1.5–22, P = 0.009). Sequencingof BRCA1-related breast cancers revealed one TP53missensemutation not previously reported in breast cancer. Conclusions:Using a historical cohort approach, we haveidentified BRCA1 mutation status as an independent prognostic factorfor node negative breast cancer among the Ashkenazi Jewish women. Thosemanaging women carrying a BRCA1 mutation may need take these findingsinto consideration. Additionally, our preliminary results, taken together withthe work of others suggest a different carcinogenic pathway inBRCA1-related breast cancer, compared to non-hereditary cases.     

Greek BRCA1 and BRCA2 mutation spectrum: two BRCA1 mutations account for half the carriers found among high-risk breast/ovarian cancer patients

127 Greek breast/ovarian cancer families were screened for germline BRCA1/2 mutations by dHPLC followed by direct sequencing. Our results indicated 16 and 5 breast/ovarian cancer families bearing deleterious mutations in the BRCA1 and BRCA2 genes, respectively. Two novel BRCA2 germline mutations (G4X and 3783del10) are reported here for the first time. Subsequent compilation of our present findings with previously reported mutation data reveals that in a total of 287 Greek breast/ovarian cancer families, 46 and 13 carry a deleterious mutation in BRCA1 and BRCA2, respectively. It should be noted that two BRCA1 mutations, 5382insC and G1738R, both located in exon 20, account for 46% of the families found to carry a mutation. Based on our mutation analysis results, we propose here a hierarchical, cost-effective BRCA1/2 mutation screening protocol for individuals of Greek ethnic origin. The suggested protocol can impact on the clinical management of breast-ovarian cancer families on a national healthcare system level. Irene Konstantopoulou and Theodore Rampias equally contributed to this work.     

Ovarian cancer risk in Polish <Emphasis Type="Italic">BRCA1</Emphasis> mutation carriers is not associated with the prohibitin 3' untranslated region polymorphism

Background  

The variable penetrance of ovarian cancer in BRCA1 mutation carriers suggests that other genetic or environmental factors modify disease risk. The C to T transition in the 3' untranslated region of the prohibitin (PHB) gene alters mRNA function and has recently been shown to be associated with hereditary breast cancer risk in Polish women harbouring BRCA1 mutations.     

High prevalence of two BRCA1 mutations, 4154delA and 5382insC,in Latvia

Our aim was to characterise the germline BRCA1 mutation profile in Latvian breast cancer and ovarian cancer patients, to develop an effective BRCA1 gene mutation detection strategy, and to document genotype–phenotype correlations in mutation carriers. The entire BRCA1 gene was analysed in 75 breast cancer and 30 ovarian cancer patients. Screening for three mutations (5382insC, 4154delA and 300T>G) was carried out in 55 breast cancer and 66 ovarian cancer patients, and for two mutations, 5382insC and 4154delA, in 376 unselected patients with any cancer (including 51 breast cancer and 29 ovarian cancers) and 215 women with any gynaecological tumour. Mutation detection techniques used were SSCP/HD analysis or F-SSCP (ABI PRISM 310). Five different deleterious mutations were detected by analysis of the entire BRCA1 gene. The proportion of cases with mutations amongst 50 breast cancer patients diagnosed before 48 years was 26.0% (95% CI: 14.6–40.3%). Two mutations (5382insC and 4154delA) made up more than 80% of all mutations identified by the analysis of the entire BRCA1 gene in Latvia, at present. Further screening for only the prevalent mutations in different cancer patient groups resulted in the identification of 53 more mutation carriers. We conclude that breast cancer diagnosed before the age of 48 years and ovarian cancer before 65 years are criteria for DNA testing to be offered to women in Latvia, regardless of cancer history in the family. The observed associations of specific prevalent mutations with cancer site and age at onset of disease are discussed.     

Reproductive factors and ovarian cancer risk in Jewish BRCA1 and BRCA2 mutation carriers (United States)

Objective: To determine whether oral contraceptive (OC) use, childbearing, breastfeeding and tubal ligation differ between ovarian cancer cases with and without a BRCA1/2 mutation. Methods: A case-only study of 242 Jewish women with invasive epithelial ovarian cancer. Women were genotyped for three Ashkenazi founder mutations (185delAG and 5382insC in BRCA1 and 6174delT in BRCA2). We obtained data on OC use, childbearing, breastfeeding, gynecologic surgeries and other reproductive factors from each woman. We compared the frequencies of these risk factors in carriers and non-carriers using unconditional logistic-regression, controlling for other covariates. Results: Among the 242 cases, 64 (26.4%) carried one of the BRCA1 founder mutations, and 31 (12.8%) carried the BRCA2 mutation. Although there were no differences in the percent of nulliparous women between carriers and non-carriers, parous BRCA1 carriers reported fewer live births than non-carriers (average of 2.1 versus 2.5 live births, OR = 0.61, 95%CI = 0.39–0.95, adjusted for age at diagnosis, tubal ligation and duration of OC use). Carriers and non-carriers did not differ in their history of breastfeeding, or in their lifetime use of OCs. BRCA1 carriers were more likely than non-carriers to have had a tubal ligation (25.0 versus 10.2%, OR = 3.67, 95%CI = 1.55–8.70, adjusted for age at diagnosis, number of live births and OC duration). Conclusions: In general, OC use, childbearing and breastfeeding do not differ between BRCA1/2 carriers and non-carriers with ovarian cancer. However, the effects of tubal ligation may differ between BRCA1 carriers and non-carriers.     

Differences in the characteristics of families with BRCA1 and BRCA2 mutations in Israel.

Three specific mutations in the BRCA1 (185delAG, 5382insC) and BRCA2 (6174delT) genes have been reported to be of high prevalence in the Jewish Ashkenazi population. We studied the differences in phenotype of families carrying these mutations. All consecutive families found by the CHS Familial Cancer Service to carry one of the three 'Jewish' mutations of the BRCA1/BRCA2 genes were evaluated for phenotypic characteristics. Chi-squared and Student's t-test statistics were employed to study differences in a variety of clinical and demographic parameters. A total of 111 families with 1499 family members were included. Among them 454 cases of cancer (297 in breast/ovary) were reported. Ovarian cancer, but not breast cancer, was detected at a significantly younger age among carriers of 185delT compared with other mutation carriers. In families with 185delAG, 5382insC and 6174delT mutations, breast cancer was found in 20.2, 39.4 and 24.1% of all identified women (born between 1900 and 1975), correspondingly. The corresponding figures for ovarian cancer were 13.9, 6.8 and 4.9%. Families carrying the 5382insC mutation had the highest probability of expressing bilateral breast cancer (38.9% of families, 15.4% of women with cancer, 6.1% of all women in family) and metachronous breast and ovary tumours (22.2, 9.8 and 4.5% correspondingly). Other tumours were reported in 7.9, 9.1 and 12.0% of women and 9.5, 12.9 and 15.8% of men in families with 185delAG, 5382insC, 6174delT, correspondingly. Marked phenotypic differences were found between families carrying different BRCA mutations warranting mutation-specific counselling to families seeking risk-reduction advice. 5382insC emerged as a most aggressive mutation.     

Penetrance of breast cancer,ovarian cancer and contralateral breast cancer in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> families: high cancer incidence at older age

Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2–82.4%) in BRCA1 and 87.5% (82.4–92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5–64.3%) in BRCA1 and 34.5% (25.0–44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4–39.0%) in BRCA1 families and 29.2% (22.9–35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices.     

Age at menarche and the risk of breast cancer in BRCA1 and BRCA2 mutation carriers

Age at menarche is a strong and consistent predictor of breast cancer risk in the general population, but has not been well studied in women with a family history of breast cancer. We conducted this study to examine whether the presence of a deleterious BRCA1 or BRCA2 mutation influences age at menarche and to investigate whether or not there is an association between age at menarche and the risk of breast cancer in BRCA1 or BRCA2 mutation carriers. The presence of a deleterious BRCA1 or BRCA2 mutation did not appear to influence a woman’s age at menarche. A matched case–control study was conducted on 1311 pairs of women who have been identified to be carriers of a deleterious mutation in either the BRCA1 (n = 945 pairs) or the BRCA2 gene (n = 366 pairs). Information about age at menarche was derived from a questionnaire routinely administered to carriers of a mutation in either gene. Among women who carried a deleterious BRCA1 mutation, age at menarche was inversely associated with the risk of breast cancer (p trend = 0.0002). This association was not observed among BRCA2 mutation carriers (p trend = 0.49). Compared with BRCA1 carriers whose age at menarche was ≤11 years, women with a menarcheal age between 14 and 15 years old had a 54% reduction in risk (OR = 0.46; 95% CI 0.30–0.69). This study implicates early age at menarche as a determinant of breast cancer among women with a BRCA1 mutation. * Address correspondence to: Steven A. Narod, Centre for Research in Women’s Health, University of Toronto, 790 Bay Street, Room 750, 7th Floor, Women’s College Hospital, Toronto, Ontario, M5G 1N8, Canada. Ph.: +1-416-351-3765; Fax: +1-416-351-3767; E-mail: steven.narod@swchsc.on.ca     

Limited significance of family history for presence of BRCA1 gene mutation in Polish breast and ovarian cancer cases

It is estimated that about 5–10% of ovarian and 2–5% of all breast cancer patients are carriers of a germline BRCA1 or BRCA2 gene mutation. Most families with detected BRCA1 or BRCA2 gene mutation are qualified for molecular testing on the basis of family history of breast or ovarian cancers. The purpose of our study was to establish the frequency of positive family history of cancer in a series of Polish consecutive breast and ovarian cancer patients in two groups, with and without the BRCA1 gene mutations. We analysed the prevalence of four of the most common BRCA1 mutations: 5382insC (c.5266dupC), 300T>G (p.181T>G), 185delAG (c.68_69delAG) and 3819del5 (c.3700_3704del5). The patient group consisted of 1,845 consecutive female breast and 363 ovarian cancer cases. 19 out of 37 (51%) of BRCA1-positive ovarian cancer patients and 21 out of 55 (39%) BRCA1-positive breast cancer had negative family history of breast and/or ovarian cancer among first- and second-degree relatives. In ovarian cancer patients, negative family history was more frequent in those with 300T>G BRCA1 gene mutation than in 5382insC carriers. This finding indicates the necessity of searching for 300T>G mutation in families with a single diagnosis of ovarian cancer in family. The high frequency of mutations detected in breast cancer patients lacking obvious family history shows that breast cancer patients should be qualified for genetic testing on the basis of wide clinical and pathological criteria.