Double Heterozygosity in the <i>BRCA1/2</i> Genes in a Turkish Patient with Bilateral Breast Cancer: A Case Report

BRCA1 and BRCA2 tumor suppressor genes are responsible for a quarter of hereditary breast cancers. Double heterozygous (DH) pathogenic variant carrier status in these genes is an extremely rare condition, especially in non-Askenazi individuals. We report a woman patient with bilateral breast cancer that carries DH disease-causing variants in BRCA1/2 genes. The 45-year-old patient who was followed up with the diagnosis of metachronous bilateral breast cancer was diagnosed with cancer at the age of 39 and 43, respectively. BRCA1/2 genes of the patient were evaluated using Next-Generation Sequencing. In the patient, the c.2800C>T (p.Gln934Ter) pathogenic variant in BRCA1 and the c.9648+1G>C likely pathogenic variant in BRCA2 were detected as DH. Segregation analysis in family members revealed that her two healthy siblings available for testing were heterozygous for either BRCA1 or BRCA2 variants, but her mother, who had a past diagnosis of ovarian cancer, was heterozygous for both BRCA1 and BRCA2 variants. Germline double heterozygosity in inherited cancer is a rare condition, and as far as we know it is reported for the first time from patient population in Turkey. Large-scale patient series are needed to determine the impact of double heterozygosity on diseases course, such as prognosis and treatment responses.     

BRCA1 and BRCA2 mutations in ovarian cancer patients from China: ethnic‐related mutations in BRCA1 associated with an increased risk of ovarian cancer

BRCA1/2 are cancer predisposition genes involved in hereditary breast and ovarian cancer (HBOC). Mutation carriers display an increased sensitivity to inhibitors of poly(ADP‐ribose) polymerase (PARP). Despite a number of small‐size hospital‐based studies being previously reported, there is not yet, to our knowledge, precise data of BRCA1/2 mutations among Chinese ovarian cancer patients. We performed a multicenter cohort study including 916 unselected consecutive epithelial ovarian cancer (EOC) patients from eastern China to screen for BRCA1/2 mutations using the next‐generation sequencing approach. A total of 153 EOC patients were found to carry pathogenic germline mutations in BRCA1/2, accounting for an overall mutation incidence of 16.7% with the predominance in BRCA1 (13.1%) compared with BRCA2 (3.9%). We identified 53 novel pathogenic mutations, among which the c.283_286delCTTG and the c.4573C > T of BRCA1 were both found in two unrelated patients. More importantly, the most common mutation found in this study, c.5470_5477del8 was most likely to be Chinese population‐related without an apparent founder origin. This hot‐spot mutation was presumably associated with an increased risk of ovarian cancer. Taken together, germline BRCA1/2 mutations were common in Chinese EOC patients with distinct mutational spectrum compared to Western populations. Our study contributes to the current understanding of BRCA1/2 mutation prevalence worldwide. We recommend BRCA1/2 genetic testing to all Chinese women diagnosed with EOC to identify HBOC families, to provide genetic counseling and clinical management for at‐risk relatives. Mutation carriers may also benefit from PARP‐targeted therapies.     

Reproductive factors in hereditary breast cancer

Background: An early age at menarche, a short menstrual cycle length, and a high age at first full term pregnancy or nulliparity are known risk factors for breast cancer. These risk factors have previously been reported to differ between breast cancer patients with and without a family history of breast cancer and also between breast cancer patients and controls. Methods: Self-administered questionnaires were filled out by 95 women belonging to 24 families with known BRCA1 mutations, 16 women belonging to nine families with known BRCA2 mutations, and 95 women belonging to 65 families with hereditary breast cancer where no BRCA1 or BRCA2 mutations could be detected. Thirty-nine women were BRCA1 mutation carriers and 56 women were BRCA1 negative, 11 women were BRCA2 carriers and five BRCA2 negative. All women were born between 1905 and 1979. Results: Age at menarche, physiological menstrual cycle length at age 30 or at current age in younger women (when not using oral contraceptives), age at first full term pregnancy, and nulliparity did not significantly differ between BRCA1 mutation carriers and BRCA1 negative women. Too few women were BRCA2 negative to serve as a control group. BRCA2 mutation carriers were therefore compared with BRCA1 negative and BRCA2 negative women. None of the above reproductive factors did significantly differ between BRCA2 mutation carriers and from BRCA1 and BRCA2 families. Women from non-BRCA1/BRCA2 hereditary breast cancer families had a higher age at menarche, but this was no longer significant after adjustment for other factors in a multivariate model. Conclusion: Our results suggest that reproductive risk factors of breast cancer are not related to BRCA1 or BRCA2 carrier status. There was also no indication that these factors differ in carriers of unknown susceptibility genes compared with non-carriers from BRCA1 and BRCA2 families.     

Hereditary ovarian cancer in Ashkenazi Jews

Ovarian cancer is the fourth leading cause of cancer deaths among American women. While women in both the Ashkenazi and non-Ashkenazi populations have an estimated 1.7% lifetime risk of acquiring malignancy, the proportion of hereditary ovarian cancer is much higher in the Ashkenazim. Most of this increased proportion of hereditary ovarian cancer risk is accounted for by inherited mutations in the BRCA1 and BRCA2 genes. In the Ashkenazi Jewish population, 29 to 41% of ovarian cancer is believed to be secondary to inheriting one of three founder mutations in BRCA1 and BRCA2, while only 10% of ovarian cancer is attributed to mutations of these genes in non-Ashkenazim. In the US population in general, it is estimated that between 1 out of 345 and 1 out of 1000 individuals carries a BRCA mutation, compared with approximately 1 in 40 individuals of Ashkenazi Jewish descent. The ovarian cancer risk up to age 70 associated with BRCA mutation carriers has been reported to be as high as 66% for BRCA1 and 27% for BRCA2mutation carriers. Ovarian cancer in Ashkenazi kindreds has served as a model for the study of the histopathology of inherited ovarian cancers as well as for the study of risk reduction and screening among all women at inherited risk of ovarian cancer.     

Single‐nucleotide polymorphisms in the p53 pathway genes modify cancer risk in BRCA1 and BRCA2 carriers of Jewish‐Ashkenazi descent

Germline mutations in the BRCA1 and BRCA2 genes are associated with a significantly increased lifetime risk for developing breast and/or ovarian cancer. However, incomplete penetrance and substantial variability in age of disease onset among carriers of the same mutation suggests the involvement of additional modifier genes and/or environmental factors. Somatic inactivating mutations in the p53 gene and genes of the p53 pathway often accompany BRCA1/2‐associated tumors. Therefore, we assessed whether these genes are modifiers of penetrance. We genotyped Jewish‐Ashkenazi women for functional single‐nucleotide polymorphisms (SNPs) in the AKT1 (C>T rs3730358) and the PERP (C>T rs2484067) genes that affect p53‐mediated apoptosis, as well as two tag‐SNPs in the CHEK2 (C>T rs743184) and the ZBRK1/ZNF350 (G>A rs2278414) genes that encode for proteins involved in growth arrest following DNA damage. The study population included 138 healthy women, 148 breast/ovarian cancer BRCA1/2 mutation carriers, 121 asymptomatic BRCA1/2 mutation carriers, and 210 sporadic noncarrier breast cancer patients. Utilizing λ² and Kaplan–Meier analysis revealed a hazard ratio (HR) of 3.23 (95% CI: 1.44–54, P = 0.0184) for the TT genotype of AKT (rs3730358), HR = 2.105 (95% CI: 1.049–7.434, P = 0.039) for CHEK2 CC genotype (rs743184), and HR = 2.4743 (95% CI: 1.205–11.53, P = 0.022) for the AG genotype of ZBRK1/ZNF350 (rs2278414). No significant association between PERP variants and cancer was identified HR = 0.662 (95% CI: 0.289–1.324, P = 0.261). Our results suggest that genes that act upstream of p53, or participate in the DNA damage response, may modify the risk of cancer in women with mutant BRCA1/2 alleles. © 2010 Wiley‐Liss, Inc.     

A high frequency of germline <Emphasis Type="Italic">BRCA1/2</Emphasis> mutations in western Sweden detected with complementary screening techniques

Dominant inheritance is presumed in 6–10% of breast and ovarian cancers. Mutations in BRCA1 and BRCA2 genes are the most commonly identified causative genes in such families. The frequency of mutation carriers with breast/ovarian cancer depends on the population studied, and display considerable variation that coincides with ethnic and geographical diversity. Mutation analyses were performed in 143 families registered at the Cancer Genetic Counseling Clinic of western Sweden. In a thorough mutation screening procedure, the entire BRCA1 and BRCA2 genes were analyzed using a combination of complementary mutation detection techniques. Mutations in either BRCA1 or BRCA2 were detected in 36% (52 out of 143) of all screened families. All families were clinically evaluated regarding age at diagnosis, type of cancer and number of cancer cases in the family. Among high-risk families, the mutation detection rate was 39% (46 out of 117). The detection rate observed among families with cases of ovarian cancer (42 out of 62, 68%), was substantially higher than in families with only breast cancer (10 out of 81, 12%). Age at ovarian cancer did not seem to have an effect on the detection rate. The analyses revealed 11 frameshift mutations, 4 nonsense mutations and 2 large deletions. Notably, the BRCA1 c.3171ins5 mutation accounted for 34 of 52 (65%) identified mutations. Seven mutations are novel: BRCA1c.409_410del; c.1912T>G; c.2228_2229del; c.3029delA; c.3433delA, a large deletion covering exons 1–3 of BRCA1and one BRCA2 mutation; BRCA2c.6287_6290del. We have shown that the founder mutation BRCA1 c.3171ins5 has a great influence on western Swedish breast/ovarian cancer families along with a high number of mutations unique for the region. In order to achieve a high mutation detection rate we suggest a combination of several detection techniques.     

A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer

Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. De novo mutations such as multiple exon deletion are rarely occurred in BRCA1 and BRCA2. During our mutation screening for BRCA1/2 genes to Chinese women with risk factors for hereditary breast/ovarian cancer, we identified a novel germline mutation, consisting of a deletion from exons 1 to 12 in BRCA1 gene, in a patient diagnosed with early onset triple negative breast cancer with no family history of cancer. None of her parents carried the mutation and molecular analysis showed that this novel de novo germline mutation resulted in down-regulation of BRCA1 gene expression.     

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.     

Prevalence and clinical outcomes of germline mutations in BRCA1/2 and PALB2 genes in 2769 unselected breast cancer patients in China

To gain more information on the prevalence of germline mutations in BRCA1/2 and PALB2 genes in the Chinese population, and to explore the effects of the mutation status of these genes on clinical outcomes in patients with breast cancer, we performed a screening for BRCA1/2 and PALB2 mutations in a consecutive series of unselected breast cancer patients in the Chinese population. A total of 2,769 cases were enrolled between June 1993 and September 2017. All of the exons and exon–intron boundaries of the BRCA1/2 and PALB2 genes were screened with next-generation sequencing. Of the 2,769 breast cancer patients, BRCA1, BRCA2 and PALB2 mutations accounted for 2.7% (n = 74), 2.7% (n = 76), and 0.9% (n = 24), respectively. The BRCA1 gene had the highest mutation frequency in patients with triple-negative breast cancer (TNBC), which was 9.6% (n = 42), while the BRCA2 gene had the highest mutation frequency in patients with Luminal, which was 3.2% (n = 58). The disease-free survival (DFS) of BRCA1 mutation carriers was significantly lower than that of noncarriers (adjusted HR = 2.20, 95% CI = 1.15–4.18, p = 0.017). The mutation status of the PALB2 gene was significantly associated with the decline in overall survival (OS) (adjusted HR = 8.38, 95% CI = 2.19–32.11, p = 0.002). No significant difference was found between BRCA2 pathogenic mutation carriers and noncarriers. These results demonstrate that BRCA1 mutation status may be associated with a worse disease progression in patients with breast cancer, and women who harbored a PALB2 mutation might be at a higher risk of death due to breast cancer compared to noncarriers.     

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.     

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.     

Prevalence and characterization of <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> germline mutations in Chinese women with familial breast cancer

Although there are some studies to investigate germline mutations in BRCA1/2 genes in Chinese women with familial breast cancer, many of them suffer relatively small sample size. In this study, we screened germline mutations in BRCA1/2 genes in a cohort of 409 Chinese women with familial breast cancer from north China by using a PCR-sequencing assay. A total of 43 deleterious mutations in BRCA1/2 genes were identified in this cohort, including 17 novel mutations and 6 recurrent mutations. The frequencies of BRCA1 and BRCA2 mutations were 3.9% (16/409) and 6.6% (27/409), respectively; the mutation rate of BRCA2 was 1.7-fold higher than that of BRCA1. The entire mutation rate of BRCA1/2 was 10.5% in this cohort; however, the mutation rate of BRCA1/2 genes was 23.0% in 78 familial breast cancer patients whose tumors were diagnosed at or before the age of 40. The mean age at diagnosis of breast cancer in BRCA1 carriers (42.8 years) and BRCA2 carriers (45.1 years) was younger than non-carriers (51.0 years) in this cohort (P = 0.005; P = 0.01, respectively). In addition, both BRCA1 carriers and BRCA2 carriers were more likely to exhibit triple-negative breast cancer (ER-, PgR-, and HER2-) than non-carriers (BRCA1 carriers vs. non-carriers, 69.2 vs. 23.0%, P = 0.001; BRCA2 carriers vs. non-carriers, 45.8 vs. 23.0%, P = 0.01). Our study suggested that the spectrum and characteristics of BRCA1/2 mutations in Chinese familial breast cancer exhibit some unique features, and Chinese women with familial breast cancer whose tumors are diagnosed at or before the age of 40 are good candidates for BRCA1/2 testing.     

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.

     

Large <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> genomic rearrangements in Danish high risk breast-ovarian cancer families

BRCA1 and BRCA2 germ-line mutations predispose to breast and ovarian cancer. Large genomic rearrangements of BRCA1 account for 0–36% of all disease causing mutations in various populations, while large genomic rearrangements in BRCA2 are more rare. We examined 642 East Danish breast and/or ovarian cancer patients in whom a deleterious mutation in BRCA1 and BRCA2 was not detected by sequencing using the multiplex ligation-dependent probe amplification (MLPA) assay. We identified 15 patients with 7 different genomic rearrangements, including a BRCA1 exon 5–7 deletion with a novel breakpoint, a BRCA1 exon 13 duplication, a BRCA1 exon 17–19 deletion, a BRCA1 exon 3–16 deletion, and a BRCA2 exon 20 deletion with a novel breakpoint as well as two novel BRCA1 exon 17–18 and BRCA1 exon 19 deletions. The large rearrangements in BRCA1 and BRCA2 accounted for 9.2% (15/163) of all BRCA1 and BRCA2 mutations in East Denmark. Nine patients had the exon 3–16 deletion in BRCA1. By SNP analysis we find that the patients share a 5 Mb fragment of chromosome 17, including BRCA1, indicating that the exon 3–16 deletion represents a Danish founder mutation. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

A novel de novo BRCA2 mutation of paternal origin identified in a Spanish woman with early onset bilateral breast cancer

Germ line mutations in either of the two major breast cancer predisposition genes, BRCA1 and BRCA2, account for a significant proportion of hereditary breast/ovarian cancer. Identification of breast cancer patients carrying mutations in any of these genes is primarily based on a positive family history of breast/ovarian cancer or early onset of the disease. In the course of mutation screening of the BRCA1 and BRCA2 genes in a hospital based series of patients with risk factors for hereditary breast/ovarian cancer, we identified a novel germ line mutation in the BRCA2 gene (c.51dupA) in a patient with early onset bilateral breast cancer and no family history of the disease. None of her parents carried the mutation, and paternity was confirmed. Subsequent molecular analysis demonstrated that the mutation was a novel de novo germ line mutation located in the paternal allele of the BRCA2 gene.     

Clinical,Molecular and Geographical Features of Hereditary Breast/Ovarian Cancer in Latvia

Introduction

The aim of the study is to evaluate the incidence and phenotype-genotype characteristics of hereditary breast and ovarian cancer syndromes in Latvia in order to develop the basis of clinical management for patients and their relatives affected by this syndrome.

Materials and methods

In 2002-2004 in two Latvian oncology hospitals (Liepãja Oncology Hospital and Daugavpils Oncology Hospital) cancer family histories were collected from 287 consecutive patients with breast and ovarian cancer. In all cases, when it was possible to obtain the blood sample, DNA testing for founder mutations in the BRCA1 gene was performed.

Results

Among 287 family cancer histories analysed in 8 (2.8%) cases criteria of hereditary breast cancer (HBC) were fulfilled and in 5 (1.7%) cases hereditary breast and ovarian cancer (HBOC) was diagnosed. In 50 (17.4%) cases we have suspicion of hereditary breast cancer (HBC susp.) and in 8 (2.8%) cases - suspicion of hereditary breast and ovarian cancer (HBOC susp.). We have one (0.3%) case with hereditary ovarian cancer (HOC). DNA testing of founder mutations in the BRCA1 gene (exon 20 (5382 insC) exon 5 (300T/G), exon 11, 17 (4153delA)) for 178/287 (62%) patients was performed. In 9/287 (4.9%) cases we found a mutation in the BRCA1 gene. 4 mutations were detected in exon 11, 17 (4153delA) and 4 mutations in exon 20 (5382 insC) and 1 in exon 5.

Conclusions

Existing pedigree/clinical data suggest that in Latvia the clinical frequency of hereditary breast and ovarian cancer is around 5% of consecutive breast and ovarian cancer patients and suspicion of the syndrome is observed in another 20% of cases. Frequency of BRCA1 founder mutations is 5% of all consecutive breast and ovarian cancers. Considerable geographical differences in the clinical and molecular frequency of hereditary breast ovarian cancer have been observed in Latvia.

     

Nuclear morphometric features in benign breast tissue and risk of subsequent breast cancer

Germ-line mutations in BRCA1 and BRCA2 are responsible for about 30–60% of the hereditary breast and ovarian cancer (HBOC). A large number of point mutations have been described in both genes. However, large deletions and duplications that disrupt one or more exons are overlooked by point mutation detection approaches. Over the past years several rearrangements have been identified in BRCA1, while few studies have been designed to screen this type of mutations in BRCA2. Our aim was to estimate the prevalence of large genomic rearrangements in the BRCA2 gene in Spanish breast/ovarian cancer families. The multiplex ligation-dependent probe amplification (MLPA) was employed to search gross deletions or duplications of BRCA2 in 335 Spanish moderate to high-risk breast/ovarian cancer families previously screened negative for point mutations by conventional methods. Four different and novel large genomic alterations were consistently identified by MLPA in five families, respectively: deletions of exon 2, exons 10–12 and exons 15–16 and duplication of exon 20 (in two families). RT-PCR experiments confirmed the deletion of exons 15–16. All patients harbouring a genomic rearrangement were members of high-risk families, with three or more breast/ovarian cancer cases or the presence of breast cancer in males. We provide evidence that the BRCA2 rearrangements seem to account for a relatively small proportion of familial breast cancer cases in Spanish population. The screening for these alterations as part of the comprehensive genetic testing can be recommended, especially in multiple case breast/ovarian families and families with male breast cancer cases.     

Molecular characterization and clinical interpretation of <Emphasis Type="Italic">BRCA1/BRCA2</Emphasis> variants in families from Murcia (south-eastern Spain) with hereditary breast and ovarian cancer: clinical–pathological features in <Emphasis Type="Italic">BRCA</Emphasis> carriers and non-carriers

This is the first study performed in Murcia (south-eastern Spain) in which 592 families with hereditary breast and ovarian cancer were identified thanks to Genetic Counselling Units from this area over 6 years. Diagnostic performance was 18.1% and 194 different genetic variants were obtained. Variants with uncertain significance accounted for only 5.6% of the total number of reports, so our population has been well characterised. In BRCA1 gene, two novel variants were found (c.1859delT and c.3205C?>?T) and the most frequently detected mutations were c.68_69delAG, c.212?+?1G?>?A, c.5123C?>?A, c.211A?>?G and c.1918C?>?T, which together represented 56.67% of total pathogenic mutations. In BRCA2 gene, four recurrent variants were described (deletion of entire exon 2, c.9117G?>?A, c.3264dupT and c.3455T?>?G) representing 43.5% of the mutations in this gene. Mutation c.68_69delAG and deletion of entire exon 2 in BRCA1 and BRCA2 genes respectively were the most prevalent variants in our population. Regarding the genotype-phenotype relation, mutation c.212?+?1G?>?A appeared in an important percentage of breast and ovarian cancer cases, c.5123C?>?A in bilateral breast cancer and c.9117G?>?A in bilateral breast cancer and ovarian cancer. With respect to clinical–pathological characteristic, BRCA1/BRCA2 mutation carriers showed earlier onset age of breast tumour and higher risk of developing contra lateral breast cancer than non-informative cases. Moreover, association between either molecular subtype triple negative breast cancer or ovarian cancer and BRCA1 carriers was obtained.