Italian family with two independent mutations: 3358T/A in BRCA1 and 8756delA in BRCA2 genes

Hereditary breast/ovarian cancer is a well-characterized clinical entity, largely attributed to the inheritance of BRCA1 or BRCA2 mutations. Among general population, the mutation's frequency of these genes is very low; therefore, the identification of two independent mutations in the same family is a rare event. This study reports the presence of two mutations, one in the BRCA1 and the second in the BRCA2 gene in an Italian Caucasian kindred. This family is composed of more than 250 individuals, spanning through five generations, among which endogamy was a common phenomenon. Considering the tumor spectrum, this family is characterized by a high incidence of different types of cancer. In our study, we considered only three out of seven family units for BRCA1 and BRCA2 analysis. In one of the family units, we found independent mutations of both BRCA genes. The BRCA1 mutation on exon 11 (3358T-->A) was identified originally in the index case and subsequently in 18 members of this family, whereas the same mutation was not detected in a related family member with male breast cancer. The male breast cancer patient led to the identification, through mutational analysis, of a new BRCA2 mutation (8756delA). This BRCA2 mutation was also found in the male breast cancer patient's daughter. The discovery of the BRCA2 mutation allowed us to alert the patient's daughter who, otherwise, could be falsely reassured since she had a negative BRCA1 test.     

A family with three germline mutations in BRCAl and BRCA2

Liede A, Metcalfe K, Offit K, Brown K, Miller S, Narod SA, Moslehi R. A family with three germline mutations in BRCAl and BRCA2 . Clin Genet 1998: 54: 215–218. 0 Munksgaard. 1998
Several cancer genetics centres offer testing for specific BRCAl and BRCAZ mutations to Ashkenazi Jewish individuals with a family history of breast and ovarian cancers. Testing involves screening for three common mutations found in this population, namely BRCA I 185delAG, 5382insC and BRCA2 6174delT (Struewing et al., Nat Genet 1995: 11: 198–200; Roa et al., Nat Genet 1996: 14 185–187; Oddoux et al., Nat Genet 1996: 14 188–190). We have identified a large Ashkenazi Jewish kindred (W9170) with ten cases of breast cancer and four cases of ovarian carcinoma. Initially, mutation analysis for this family identified a BRCAl 185delAG mutation in the proband diagnosed with three separate primary cancers of the breast, ovary and colon. Another individual in this family diagnosed with two primary cancers of the ovary and breast, was identified as having a second mutation, BRCA I 5382insC. Subsequent work found that two sisters (cousins of the proband), both diagnosed with carcinoma of the breast, had a third mutation, BRCAZ 6174delT. These three mutations have previously been found to be more common in the Ashkenazi Jewish population (References as above). The identification of all three mutations in one family, raised new implications for the manner in which testing and counselling should be offered. In our opinion, Ashkenazi Jewish individuals in breast-ovarian cancer families should be offered complete testing for the three common Ashkenazi Jewish mutations regardless of previous identification of one of these mutations in the family.     

Three independent mutations in the TSC2 gene in a family with tuberous sclerosis

Tuberous sclerosis complex (TSC) is a rare autosomal dominant disorder characterized by hamartomas and hamartias in multiple organs. TSC is caused by a wide spectrum of mutations within the TSC1 and TSC2 genes. Here, we report a unique family with three independent pathological mutations in TSC2. A c.1322G>A mutation in exon 12 created a stop codon, whereas a second mutation in exon 23 (c.2713C>T) was a missense change. The third mutation was a 4 base pair deletion in intron 20 of TSC2. We showed that this mutation was responsible for abnormal splicing. The three mutations were most likely de novo, as parents of affected patients did not present any features of TSC. In addition, we showed gonadal mosaicism in a branch of the family. To our knowledge, several independent mutations in TSC2 have never been observed in a single family. The probability of finding a family with three different pathological TSC2 mutations is extremely low. We discuss two main hypotheses that may be raised to explain this recurrence: (i) the TSC2 mutation rate is underestimated. In such a case, the likelihood of finding a family with three independent mutations in TSC2 may not be dramatically low; (ii) a heritable defect in a DNA repair gene (eg, mismatch repair gene) segregating in the family that is unlinked to the TSC2 gene might predispose to the occurrence of multiple TSC2 gene mutations, used as a specific target during embryogenesis.     

中国上海家族性乳腺癌BRCA1和BRCA2基因的突变

目的研究上海地区家族性乳腺癌中BRCA1／BRCA2基因的突变位点及携带情况。方法研究对象来自35个汉族家族性乳腺癌家系，家系中至少有一个一级亲属乳腺癌患病史。共35例患者，其中13例发病年龄≤加岁。由静脉血提取基因组DNA，对BRCA1／BRCA2基因的全部编码序列进行扩增。扩增产物突变分析先由变性高效液相色谱分析进行筛查，之后进行DNA直接测序证实。结果在BRCA1基因中发现有4个突变位点，其中2个为新发现位点——拼接点突变（IVS17-1G〉T；IVS21＋1G〉C）；另两个为已报道的致病突变位点——移码突变（1100delAT；5640delA）。BRCA2基因的1个致病突变位点位于11号外显子上，为移码突变（5802delAATT）。另外，共发现有12个新的单核苷重复多态位点，都未引起氨基酸编码改变；其中，8个在BRCA1基因上，4个在BRCA2基因上。在家族性乳腺癌中，BRCA1突变频率（11．4％）高于BRCA2基因（2．9％）。结论新发现的2个BRCA1基因的拼接点突变可能是中国上海人群家族性乳腺癌的特有突变位点；在我国上海地区人群中，BRCA1基因突变起着比BRCA2基因更大的作用；该研究丰富了中国人群中BRCA基因的突变谱，并为未来的临床基因检测提供了筛查模式。     

Founder BRCA1 and BRCA2 mutations in French Canadian ovarian cancer cases unselected for family history

The breast cancer susceptibility genes, BRCA1 and BRCA2, differ in their contribution to ovarian cancer. Recently, founder mutations in each of these genes were identified in Canadian breast cancer and breast ovarian cancer families of French ancestry. We have examined the prevalence of the founder mutations in a series of 113 French Canadian women with ovarian cancer unselected for family history. Germline mutations were found in eight of 99 invasive carcinomas and in none of the 14 tumors of borderline malignancy. Five cases carried the BRCA1 C4446T mutation and two cases carried the BRCA2 8765delAG mutation which are the most common mutations that have been described in French Canadian breast cancer and breast ovarian cancer families. All of these cases reported a family history of at least one first-degree relative with breast cancer, diagnosed below age 60 years, or with ovarian cancer. The identification of founder BRCA1 and BRCA2 mutations in ovarian cancer cases unselected for family history can facilitate carrier detection when the expected yield of a comprehensive screen may be low.     

Haplotype analysis of a BRCA1: 185delAG mutation in a Chilean family supports its Ashkenazi origins

At least 25% of Ashkenazi Jewish families with two or more cases of premenopausal breast cancers are attributable to one of three founder mutations in BRCA1 or BRCA2. As these three founder mutations are common in the Ashkenazi Jewish population ( approximately 2.5%) and can easily be tested for in a multiplex assay, establishing ethnicity can expedite genetic testing. It is not always possible, however, to conclusively establish ethnicity before offering testing. We report here the occurrence of a founder Ashkenazi Jewish BRCA1 mutation, 185delAG (also known as 187delAG), in a non-Jewish Chilean family with no reported Jewish ancestry. The linked haplotype present in this family was identical to that identified in the Ashkenazi Jewish population. This case report not only illustrates the problem of the definition of ethnicity but also points to the possibility of further studies of the frequency of founder Ashkenazi Jewish mutations in populations not generally considered to be of Ashkenazi Jewish origin.     

An unaffected individual from a breast/ovarian cancer family with germline mutations in both BRCA1 and BRCA2

Currently many centers offer testing for three specific mutations, 185delAG, 5382insC, and 6174delT, in the BRCA1 and BRCA2 genes to Ashkenazi Jewish individuals at high risk for breast and ovarian cancer. We recently tested members of a family with multiple cases of breast and ovarian cancer (Family R014). The proband in this family tested positive for the 185delAG mutation. The unaffected sister of the proband tested positive for both the 185delAG and the 6174delT mutations. Further testing and review of the family history suggest that both mutations may have come from a maternal grandfather and passed down for two generations. Counseling of the unaffected double heterozygote individual in this family is complicated by lack of information on the risk of breast, ovarian, and other cancers in such individuals. A better understanding of these risks will depend on the identification and study of more individuals carrying mutations in both the BRCA1 and BRCA2 genes. Our study emphasizes the importance of testing Ashkenazi Jewish individuals from high-risk breast and ovarian cancer families for all three common BRCA1 and BRCA2 mutations identified in this ethnic group.     

BRCA1 and BRCA2 founder mutations in patients with bilateral breast cancer

Bilateral breast cancer is traditionally considered an indirect indicator of inherited predisposition to cancer. To appreciate the contribution of genetic determinants to bilateral breast cancer in Jewish women we genotyped 55 such women for the three predominant mutations in BRCA1 (185delAG and 5382insC) and BRCA2 (6174delT) that account for the overwhelming majority of BRCA mutations in high-risk Jewish families. Among women with bilateral breast cancer, 17 mutation carriers (17/55; 29.6%) were identified. Individual mutation frequencies were 18.5% (10/55) for 185delAG, 3.7% (2/55) for 5382insC and 7.4% (5/55) for 6174delT. Carrier rate was significantly higher (P < 0.0016) in women with bilateral breast cancer whose first tumour was diagnosed at or before 42 years of age (82%; 14/17) than in women diagnosed after 42 years of age (7.9%; 3/38). Among patients with bilateral breast cancer and positive family history 45% (14/31) carried a BRCA mutation. Of these 86% (12/14) had one breast cancer diagnosed at or before 42 years of age. Our results suggest that bilateral breast cancer per se, in most cases, does not reflect genetic predisposition, unless associated with early age of onset (first tumour diagnosed at or before 42 years of age). Although the relationship between young age and carrier state in women with bilateral breast cancer is strong, no significant association between family history and carrier state was found. We can thus speculate that women with early onset breast cancer who carry a BRCA1 or BRCA2 mutation are prone to acquire a second breast tumour.     

Recurrent mutations of BRCA1 and BRCA2 in Poland: an update

Three founder alleles of BRCA1 (C61G, 4153delA, 5382insC) were reported in Poland in 2000, and these three mutations have comprised the standard testing panel used throughout the country. However, since 2000, other recurrent mutations of BRCA1 and BRCA2 have been reported. To establish if the inclusion of one or more of these mutations will increase the sensitivity of the standard test panel, we studied 1164 Polish women with unselected breast cancer diagnosed at age of 50 or below. All women were genotyped for 12 recurrent mutations of BRCA1 and BRCA2. We identified a mutation in 83 of 1164 patients (7.1%) including 61 women with one of the original three mutations (C61G, 4153delA, 5382insC) and 22 women with a different mutation (1.9%). Three new mutations (3819del5, 185delAG and 5370C>T) were seen in multiple families. By including these three mutations in the extended panel, the mutant frequency increased from 5.2 to 6.7%. Polish women with breast cancer diagnosed at age of 50 or below should be screened with a panel of six founder mutations of BRCA1 (C61G, 4153delA, 5382insC, 3819del5, 185delAG and 5370C>T).     

BRCA1 and BRCA2 mutations in Russian familial breast cancer

We have screened index cases from 25 Russian breast/ovarian cancer families for germ‐line mutations in all coding exons of the BRCA1 and BRCA2 genes, using multiplex heteroduplex analysis. In addition we tested 22 patients with breast cancer diagnosed before age 40 without family history and 6 patients with bilateral breast cancer. The frequency of families with germline mutations in BRCA was 16% (4/25). One BRCA1 mutation, 5382insC, was found in three families. The results of present study, and those of a separate study of 19 breast‐ovarian cancer families, suggest that BRCA1 5382insC is a founder mutation in the Russian population. Three BRCA2 mutations were found in patients with breast cancer without family history: two in young patients and one in patients with bilateral breast cancer. Four novel BRCA2 mutations were identified: three frameshift (695insT, 1528del4, 9318del4) and one nonsense (S1099X). © 2002 Wiley‐Liss, Inc.     

BRCA1 and BRCA2 mutations in a South American population

A sample of 64 high-risk breast and/or ovarian cancer families from Chile were screened for germline mutations in the coding sequences and exon-intron boundaries of BRCA1 (MIN no. 113705) and BRCA2 (MIN no. 600185) genes using conformation-sensitive gel electrophoresis, and the mutations found were confirmed with direct sequencing. Seven families (10.9%) were found to carry BRCA1 mutations and three families (4.7%) had BRCA2 mutations. Six different pathogenic mutations were detected in BRCA1, four that had been reported previously (c.187_188delAG; c.300T-->G, c.3450_3453delCAAG and IVS17-1G-->A) and two novel mutations (c.2605_2606delTT and c.4185_4188delCAAG). In BRCA2, we found three different pathogenic mutations, two previously described (c.6174delT and c.6503_6504delTT) and one novel mutation (c.5667delT). We also identified nine variants of unknown significance (five in BRCA1 and four in BRCA2). These findings indicate that the Chilean population has a heterogeneous spectrum of prevalent BRCA mutations. Given the results obtained in our study, the screening of the entire BRCA1 and BRCA2 coding regions is necessary for the molecular genetic testing of Chilean high-risk breast/ovarian cancer patients. To our knowledge, this is the first genetic study of BRCA gene mutations conducted in Chile. The Chilean population has a well-known admixed Amerindian-Caucasian ratio and, therefore, our findings are not only important per se, but they constitute the basis for improved and more specific genetic counselling, as well as to support for preventive campaigns geared toward the Chilean population.     

BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer

In order to evaluate the role of BRCA1 and BRCA2 germline mutations in Korean patients with sporadic breast cancer, 97 patients with sporadic breast cancer were analyzed for mutations in the BRCA1 and BRCA2 coding regions, by using a combination of fluorescent-conformation sensitive gel electrophoresis (F-CSGE) and direct sequencing. Fifty-five distinct sequence variants were detected, which included three pathogenic truncating mutations, 15 missense mutations, 16 polymorphisms, and 21 intronic variants. Twenty-six of these variants have never been previously reported and may be of Korean-specific origin. Two pathogenic BRCA1 mutations (c.922_924delinsT, c.5445G>A) and one pathogenic BRCA2 mutation (c.2259delT) were observed, and two of these (BRCA1 c.5445G>A and BRCA2 c.2259delT) are novel. The total prevalence of germline pathogenic mutations in BRCA1 and/or BRCA2 in Korean sporadic breast cancer is estimated to be about 3.1%. Considering that the majority of breast cancer cases are sporadic, the present study will be helpful in the evaluation of the need for the genetic screening of germline BRCA mutations in sporadic breast cancer patients. Further study using a larger sample size is required to determine the merits of genetic diagnosis and counseling in breast cancer patients.     

Founder BRCA1 mutations and two novel germline BRCA2 mutations in breast and/or ovarian cancer families from North-Eastern Poland

Germline mutations in the BRCA1 and BRCA2 genes account for the majority of high-risk breast/ovarian cancer families, depending on the population studied. Previously, BRCA1 mutations were described in women from Western Poland. To further characterize the spectrum of BRCA1 mutations and the impact of BRCA2 mutations in Poland, we have analyzed 25 high-risk breast and/or ovarian cancer families from North-Eastern Poland for mutations in all coding exons of the BRCA1 and BRCA2 genes, using combined heteroduplex analysis/SSCP followed by direct DNA sequence analysis. Out of 25 probands a total of five (20%) carried three recurrent BRCA1 mutations (300T>G, 3819del5, 5382insC). The 300T>G mutation accounted for 60% (3/5) of BRCA1 mutations and allelotyping suggested a common founder of this mutation. No unique mutations were found. In addition, we identified three BRCA2 (12%) mutations, one recurrent 4075delGT, and two novel frameshift mutations, 7327ins/dupl19 and 9068delA. We conclude that 30% of high-risk families from North-Eastern Poland may be due to recurrent BRCA1 and unique BRCA2 mutations. Intriguingly, the BRCA1 mutation spectrum seems to be different within subregions of Poland.     

Breast and ovarian cancer risks to carriers of the BRCA1 5382insC and 185delAG and BRCA2 6174delT mutations: a combined analysis of 22 population based studies

A recent report estimated the breast cancer risks in carriers of the three Ashkenazi founder mutations to be higher than previously published estimates derived from population based studies. In an attempt to confirm this, the breast and ovarian cancer risks associated with the three Ashkenazi founder mutations were estimated using families included in a previous meta-analysis of populatrion based studies. The estimated breast cancer risks for each of the founder BRCA1 and BRCA2 mutations were similar to the corresponding estimates based on all BRCA1 or BRCA2 mutations in the meta-analysis. These estimates appear to be consistent with the observed prevalence of the mutations in the Ashkenazi Jewish population.     

Low frequency of recurrent BRCA1 and BRCA2 mutations in Spain

BRCA1 and BRCA2 mutations underlie a substantial proportion of all hereditary breast cancer. The mutational spectrum in these genes is very broad, with hundreds of different BRCA mutations reported worldwide. However, high frequency founder mutations make up a substantial fraction of all mutations in some ethnic groups. We directly sequenced BRCA1 and BRCA2 in 35 Spanish breast/ovarian cancer families and found 13 mutations of which 3 had been reported previously in Spain. The ten novel mutations are: IVS5+1 G>A, 1491delA, Leu1086Ter, and Gln895Ter in BRCA1; Glu49Ter, 5373delGTAT, 5947delCTCT, 6672delTA, 8281insA, and Pro3039Leu (which also involves a splice site) in BRCA2. Our data, in combination with previous reports, indicate that 14 mutations have been seen recurrently in Spanish families. Analyzing these 14 mutations in 42 previously untested breast/ovarian cancer families revealed only two families testing positive, one for BRCA1 185delAG and one for BRCA2 9254delATCAT. While several mutations have been found recurrently in Spain, none appear to be high frequency founder mutations based on studies of breast and ovarian cancer families.     

BRCA1 and BRCA2 mutations and the risk for colorectal cancer

Women who carry a BRCA1 or BRCA2 mutation are at high risk of breast and ovarian cancer, and may be at moderately increased risk of other cancer types. This review examines studies to date that have evaluated the risk of BRCA1 and BRCA2 mutations for colorectal cancer. Accurate knowledge of colorectal cancer risk in BRCA1/2 carriers is important, because colonoscopy screening can prevent colorectal cancer through the removal of adenomatous polyps. Most studies that have identified an increased risk for colorectal cancer in BRCA1/2 mutation carriers were in high‐risk cancer families, while studies that found no association were conducted in specific populations and involved the analysis of founder mutations. A recent prospective study of 7015 women with a BRCA1 or BRCA2 mutation identified significant fivefold increased risk of colorectal cancer among BRCA1 mutation carriers younger than 50 years [standardized incidence ratio (SIR): 4.8; 95% CI: 2.2–9], but not in women with a BRCA2 mutation or in older women. Based on this evidence, women with BRCA1 mutations should be counseled about their increased risk for early‐onset colorectal cancer, and offered colonoscopy at 3‐ to 5‐year intervals between the ages of 40 and 50 years, and should follow population guidelines thereafter.