Loss of heterozygosity in BRCA1 and BRCA2 markers and high‐grade malignancy in breast cancer

Silva, José M.; González, R. N.; Provencio, Mariano; Domínguez, G.; García, José M.; Gallego, Isabel; Palacios, José; España, Pilar; Bonilla, Félix

doi:10.1023/a:1006082117266

Cited by 32 publications

(20 citation statements)

References 26 publications

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“…Only 1 of them (5.5%) showed LOH at the BRCA1 locus, which could be explained either by the presence of an undetected mutation in the gene or by the occurrence of spontaneous LOH for the BRCA1 gene in a case not associated with this gene. Our results suggest that, unlike the sporadic cases, in which the rate of LOH for the BRCA1 locus is at least 30%, 8,12,13,24,25 in the familial cases not associated with the BRCA genes, the occurrence of LOH was very uncommon, confirming the idea of different mechanisms of tumorigenesis.…”

Section: Discussionsupporting

confidence: 71%

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Osorio

Hoya

Rodríguez‐López

et al. 2002

Intl Journal of Cancer

108

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The BRCA1 and BRCA2 genes are responsible for a high proportion of familial breast cancer; germline mutations in these genes confer a lifetime risk of about 70% for developing breast cancer. Most of the described deleterious mutations are small deletions or insertions that originate a truncated protein; however, in many cases, they are amino acid changes whose significance is unknown. In these cases, there are some tests that can analyze the meaning of these variants, but most remain unclassified. The BRCA genes are tumor supressors and it is beleived that complete loss of the wild-type allele is a common mechanism of inactivation in tumors from patients carrying a germline deleterious mutation in these genes; if this is true, loss of heterozygosity (LOH) analysis in the tumor sample could help to distinguish if a rare variant is either a deleterious mutation or a common polymorphism. In the present study, we performed LOH analysis at the BRCA loci in 47 tumors from patients who belonged to highrisk breast cancer families and were carriers of any type of alteration in these genes. Our results suggest that (i) loss of the wild-type allele is the most common mechanism of inactivation in tumors from patients who carry a deleterious mutation in any of the genes, (ii) this loss is not common when we analyze familial tumors not associated with mutations in BRCA and (iii) LOH can be used to clarify variants of unknown significance in the BRCA genes.

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Section: Discussionsupporting

confidence: 71%

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Osorio

Hoya

Rodríguez‐López

et al. 2002

Intl Journal of Cancer

108

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“…Previous studies have reported that an excess of grade III carcinomas was concordant for BRCA1 and BRCA2 loss or retention, suggesting a combined role for BRCA1 and BRCA2 in the development of some familial and sporadic breast cancers. 28,29 The data for the older cohort support this finding, as all 3 cases that exhibited combined loss were grade III. However, the 15 cases from women aged 26 -35 years that exhibited concordant LOH comprised 7 grade I or II and 8 grade III tumours, suggesting no significant association with grade III in 208 this group.…”

Section: Association With Clinicopathologic Variablesmentioning

confidence: 56%

“…This contrasts with the data for the older cohort, which showed an association between LOH at BRCA1 and grade III tumour status and with previous studies of unselected sporadic breast cancers, which have shown a correlation between LOH at BRCA1 and BRCA2 and grade III tumours. 28,29 Moreover, there were no differences in LOH between ER/PgR-positive and -negative cases from the young cohort. This contrasts with the older cohort, which exhibited more frequent LOH in ER-negative and PgR tumours and previous studies of unselected breast cancers that showed more frequent LOH in ER negative and PgR negative cases.…”

Section: Association With Clinicopathologic Variablesmentioning

confidence: 86%

Sporadic breast cancer in young women: Prevalence of loss of heterozygosity at p53, BRCA1 and BRCA2

Johnson

Shaw

Walker

2001

Intl Journal of Cancer

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Previous studies have shown that breast cancers have more aggressive pathologic features in young women. In order to examine genetic alterations associated with earlyonset breast cancer, 31 patients with no known family history, aged 26 -35 years at diagnosis, were examined for loss of heterozygosity (LOH) at 3 key chromosomal intervals: 17p (p53), 17q 21 (BRCA1) and 13q12-13 (BRCA2) using polymerase chain reaction analysis of polymorphic microsatellite markers. These were compared with 31 patients aged 55-72 years that were matched for size, type and grade. All young breast cancer cases exhibited LOH for at least 1 marker and 20 cases (64.5%) exhibited LOH at 1 or more markers from each interval. Although the incidence of breast cancer in younger women is low, with the Surveillance, Epidemiology and End Results (SEER) programme in the United States finding that only 6.5% of breast cancers occur by the age of 40 years, 1 there is evidence from several studies that it is biologically different. Carcinomas occurring in women under 35 years have a significantly higher chance of being grade III (poorly differentiated), lacking steroid receptors and having high proliferation rates. [2][3][4][5] The poorer prognosis reported for this age group may be related to the biologic nature of the tumours. 6 -9 A higher frequency of stabilised p53 protein, as detected by immunohistochemistry, has been demonstrated in breast cancers from women younger than 35 years, but more detailed molecular characterisation is required that could provide insight into the different biologic and behavioural features of breast cancers in this young age group. One approach that can be used is loss of heterozygosity (LOH) analysis of key chromosomal regions that have been implicated in breast cancer.Germline mutations in the BRCA1 gene account for approximately 45% of inherited breast cancers. 10 Although somatic mutation of BRCA1 has not been found, BRCA1 protein expression is reduced in about 30% of sporadic breast carcinomas. 11 LOH of the region on the long arm of chromosome 17, which includes BRCA1, has been found in sporadic breast cancer at frequencies ranging from 20 to 63%. [12][13][14][15][16] Similarly, mutations in the BRCA2 gene are rare in sporadic breast cancer, 17 but LOH in chromosome 13q12 region has been reported in 20 -54% of sporadic cases. 12,14,15,18 The p53 gene is located on the short arm of chromosome 17 and this region also shows a high frequency of LOH in breast cancer. 15,19 A high rate of allelic loss at the 3 chromosomal regions relating to BRCA1, BRCA2 and p53 has been associated with features in breast cancer that are linked to more aggressive clinical behaviour, such as large size, high grade and lack of oestrogen receptors. 12,14,19 In view of the high incidence of these clinicopathologic features in breast cancers from young women, our study investigated the frequency of LOH at chromosomes 17q21 (BRCA1), 13q12-13 (BRCA2) and 17p13 (p53), using 10 different polymorphic microsatellite markers, in a series of spora...

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“…They found that eight out of eleven (73%) informative tumors from BRCA1-mutation carriers had BRCA2 LOH, and that five out of six informative tumors from BRCA2-mutation carriers had BRCA1 LOH. Combined LOH in BRCA1 and BRCA2 genes was seen in twelve of the 17 (71%) informative hereditary breast tumors, whereas this situation was only seen in 32 and 47% (Silva 50 and Kelssel, 51 respectively) of sporadic tumors (Table 3).…”

Section: Loh At Brca1 and Brca2 Loci And Other Chromosome Alterationsmentioning

confidence: 99%

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

2005

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Cancer arising in carriers of mutations in the BRCA1 and BRCA2 genes differs from sporadic breast cancer of age-matched controls and from non-BRCA1/2 familial breast carcinomas in its morphological, immunophenotypic and molecular characteristics. Most BRCA1 carcinomas have the basal cell phenotype, a subtype of highgrade, highly proliferating, estrogen receptor-and HER2-negative breast carcinomas, characterized by the expression of basal or myoepithelial markers such as basal keratins, P-cadherin, epidermal growth factor receptor, etc. This phenotype is rarely found in BRCA2 carcinomas, which are of higher grade than sporadic age-matched controls, but tend to be estrogen receptor-and progesterone receptor-positive. The expression of the cell-cycle proteins cyclins A, B1 and E and SKP2 is associated with a BRCA1 phenotype, whereas cyclin D1 and p27 expression is associated with BRCA2 carcinomas. Recent studies have shown that hereditary carcinomas that are not attributable to BRCA1/2 mutations have phenotypic similarities to BRCA2 tumors, but tend to be of lower grade and proliferation index. Somatic mutations in the BRCA genes are rarely found in hereditary tumors; by contrast, BRCA1 and BRCA2 loss of heterozygosity (LOH) is found in almost all BRCA1 and BRCA2 carcinomas, respectively. Furthermore, all types of hereditary breast carcinomas have a low frequency of HER2 expression. Finally, comparative genomic hybridization studies have revealed differences in chromosomal gains and losses between genotypes. The pathological and molecular features of hereditary breast cancer can drive specific treatments and influence the process of mutation screening. In addition, detecting molecular changes such as BRCA1/2 LOH in nonatypical cells obtained by random fine-needle aspiration, ductal lavage or nipple aspirate fluid may help to earlier identify carrier women who are at an even higher risk of developing breast carcinoma. Keywords: hereditary breast cancer; BRCA1; BRCA2; molecular pathology; histopathology; immunohistochemistry It is currently estimated that 5-10% of all breast cancers are hereditary and attributable to mutations in high-penetrance susceptibility genes, but only two of these have been identified: BRCA1 (OMIM 113705) 1 and BRCA2 (OMIM 600185). 2 BRCA1 mutations are associated with families with breast and ovarian cancer, while families with male breast tumors are associated with mutations in the BRCA2 gene.While early estimates suggested that BRCA1 and BRCA2 mutations were responsible for 75% of multiple-case breast cancer families and for the majority of families with multiple breast and ovarian cancers, 3,4 recent data have shown that these percentages may have been overestimated. In fact, the percentage of high-risk families associated with mutations in these genes seems to be around 25% in all series investigated, including the Spanish population. 5 Mutations are found in a high percentage (about 45%) of families with breast and ovarian tumors, while the mutation rate in families with only breast can...

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Loss of heterozygosity in BRCA1 and BRCA2 markers and high‐grade malignancy in breast cancer

Cited by 32 publications

References 26 publications

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Loss of heterozygosity analysis at the BRCA loci in tumor samples from patients with familial breast cancer

Sporadic breast cancer in young women: Prevalence of loss of heterozygosity at p53, BRCA1 and BRCA2

The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications

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