BRCA germline mutations in Jewish women with uterine serous papillary carcinoma

Shaare Zedek Medical Center, Yerushalayim, Jerusalem, Israel
Gynecologic Oncology (Impact Factor: 3.77). 03/2004; 92(2):521-4. DOI: 10.1016/j.ygyno.2003.11.009
Source: PubMed


Our recent study determined the possible effects and incidence of BRCA1 and BRCA2 germline mutations in uterine serous papillary carcinoma (USPC). The purpose of this study was to determine the incidence of these mutations in an enlarged series of USPC.
We screened DNA from 27 women with USPC for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1-185delAG and 5382 insC,BRCA2-6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity (LOH) at the appropriate loci.
Women (20) were of Jewish Ashkenazi origin and seven were non-Ashkenazi. Four of 20 (20%) Ashkenazi women were carriers of germline mutations: three 185delAG mutation and one 5382insC mutation. All carriers had strong family histories of breast-ovarian carcinoma. Seven out of 20 (35%) women had been diagnosed for breast carcinoma before diagnosis of USPC. Family histories of 12 women (60%) showed at least one first-degree relative with breast, ovarian, or colon carcinoma. Loss of heterozygosity analysis found a loss of the wild-type BRCA1 allele in three of the four primary uterine tumors that were examined.
Our findings further support our previous published data suggesting a high incidence of BRCA carriers among USPC Ashkenazi Jewish patients. The loss of heterozygosity in the tumor tissue of carriers coupled with the high frequency of patient and family history of breast and ovarian malignancies suggest that USPC might be part of the manifestation of familial breast-ovarian cancer in Ashkenazi Jewish patients.

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    • "So not only does the finding of asymptomatic occult endometrioid endometrial carcinomas, particularly in patients who have received tamoxifen, have implications in managing women at hereditary risk for HBOC, but even more significant may be the possibility that endometrium, as well as ovarian fallopian tube epithelium, might be a site of primary transformation to serous carcinoma in carriers of cancer-associated BRCA1 and BRCA2 mutations (Casey and Bewtra, 2004). Apropos our observations, Hornreich et al. (1999) reported a case of uterine serous papillary carcinoma in an Israeli woman who carried the same Ashkenazi germline BRCA1 mutation as her sister who also was diagnosed with ovarian papillary serous carcinoma, and subsequently this group found that BRCA1 mutations were carried by 4 of their 20 patients (20%) with papillary serous uterine carcinoma (Lavie et al., 2004). Ashkenazi BRCA1 or BRCA2 founder mutations were found in 7/22 (32%) consecutive cases of papillary serous uterine carcinoma in Jewish women studied by Biron-Shental et al. (2006). "
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    ABSTRACT: Hereditary ovarian cancer accounts for at least 5% of the estimated 22,000 new cases of this disease during 2009. During this same time, over 15,000 will die from malignancy ascribed to ovarian origin. The bulk of these hereditary cases fits the hereditary breast-ovarian cancer syndrome, while virtually all of the remainder will be consonant with the Lynch syndrome, disorders which are autosomal dominantly inherited. Advances in molecular genetics have led to the identification of BRCA1 and BRCA2 gene mutations which predispose to the hereditary breast-ovarian cancer syndrome, and mutations in mismatch repair genes, the most common of which are MSH2 and MLH1, which predispose to Lynch syndrome. These discoveries enable relatively certain diagnosis, limited only by their variable penetrance, so that identification of mutation carriers through a comprehensive cancer family history might be possible. This paper reviews the subject of hereditary ovarian cancer, with particular attention to its molecular genetic basis, its pathology, and its phenotypic/genotypic heterogeneity.
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    • "Ashkenazi Jewish women with uterine serous papillary carcinoma, and another case with a BRCA2 mutation [8] [9]. Goshen et al. were unable to confirm this association in their study of 56 non-Jewish women with papillary serous endometrial cancer [10]. "
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    ABSTRACT: To evaluate the risk of endometrial cancer in women who carry a deleterious mutation in the BRCA1 or BRCA2 genes. Women known to carry a BRCA1 or BRCA2 mutation, aged 45 to 70, were identified from an international registry and were followed prospectively. A total of 857 women completed a baseline questionnaire and one or more follow-up questionnaires. Study subjects were followed until diagnosis of endometrial cancer, ovarian cancer, death or the date of completion of the last questionnaire. The expected number of endometrial cancers was calculated using age and country-specific incidence rates. After an average follow-up period of 3.3 years, six women were diagnosed with endometrial cancer, compared to 1.13 cancers expected (SIR=5.3, p=0.0011). Four of these six patients used tamoxifen in the past. The risk among women who were never exposed to tamoxifen treatment was not significantly elevated (SIR=2.7, p=0.17), but among the 226 participants who had used tamoxifen (220 as treatment and six for the primary prevention of breast cancer) the relative risk for endometrial cancer was 11.6 (p=0.0004). The main contributor to the increased risk of endometrial cancer among BRCA carriers is tamoxifen treatment for a previous breast cancer. The risk and benefits of prophylactic hysterectomy should be discussed with women with a BRCA mutation considering tamoxifen therapy.
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    • "cervical cancer RR = 3.72, 95% CI 2.26-6.10) [12,13]. Even though early detection of these cancers is often possible, women already planning to undergo BRRO may consider whether they wish to eliminate uterine and cervical cancer risks by undergoing TAH at the time of their BRRO. "
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    ABSTRACT: In writing the letter to readers of our journal three months ago I was asking about opinions concerning the use of hormone replacement therapy (HRT) in BRCA1/2 carriers after prophylactic adnexectomy, because at that time it was practically impossible to present evidence-based recommendations. Actually, most of the responses we have received have been opinions. It is important to recognise that the situation is now much clearer with studies performed by Tim Rebbeck et al which are to be published in the Journal of Clinical Oncology. The following responses have been received:
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