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ORIGINAL RESEARCH |
From the Division of Gynecologic Surgery and Oncology and the Division of Medical Genetics, Shaare Zedek Medical Center, Jerusalem; and the Department of Obstetrics and Gynecology, Kaplan Medical Center, Rehovot, Israel.
Address reprint requests to: Ofer Lavie, MD, Shaare Zedek Medical Center, Division of Gynecologic Surgery and Oncology, PO Box 3235, Jerusalem, 91031, Israel, E-mail: olavie{at}internet-zahav.net
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Abstract |
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Methods: We screened DNA from 12 women with uterine serous papillary carcinoma for BRCA1 and BRCA2 germline mutations common in the Jewish population (BRCA1–185delAG and 5382insC, BRCA2–6174delT). In women with germline mutations, tumor DNA was screened for loss of heterozygosity at the appropriate loci.
Results: Nine women were of Jewish Ashkenazi origin and three were non-Ashkenazi. Two of nine Ashkenazi women were carriers of germline mutations: one 185delAG mutation and one 5382insC mutation. Five women had histories of breast carcinoma before diagnosis of uterine serous papillary carcinoma. Family histories of seven women had at least one first-degree relative with malignant disease. Of those, four had at least one first-degree relative with breast, ovarian, or colon carcinoma. Both carriers had strong family histories of breast-ovarian carcinoma. Loss of heterozygosity analysis found loss of the wild-type BRCA1 allele in the primary uterine tumors.
Conclusion: BRCA1 germline mutations were observed in two of nine of the women in this series. The loss of heterozygosity in the tumor tissue of the carriers, coupled with the high frequency of family and patient histories of breast or ovarian malignancies, suggest that uterine serous papillary carcinoma might be a manifestation of familial breast-ovarian cancer.
Uterine serous papillary carcinomas were described as a distinct histologic subtype of endometrial carcinoma by Lauchlan1 and Hendrickson et al2 in 1982, accounting for 5%3 of endometrial cancers and histologically resembling papillary serous adenocarcinoma of the ovary.4,5 Several studies documented the aggressive nature and poor prognosis of uterine serous papillary carcinomas.4,5 Compared with endometrial adenocarcinoma, uterine serous papillary carcinomas are more likely to spread to the peritoneal cavity early in the disease course, have a propensity for deep myometrial invasion, and have extensive lymphatic involvement.6
Lynch et al first suggested in 19677 that inheritance of certain genetic factors might contribute to endometrial cancer. They then described the Lynch type II familial cancer syndrome, also known as hereditary nonpolyposis colorectal cancer, which consists of uterine, colon, ovarian, and other multiple malignancies.8–10 In 1990, Boltenberg et al11 noted that endometrial carcinoma, in conjunction with multiple neoplasia and other "familial" expressions of cancer predisposition, was associated with anaplastic, poorly differentiated tumors, advanced stages, and poor prognoses. Sandles et al in 199212 noted the possibility that familial cases of endometrial adenocarcinoma were associated with a more advanced stage at presentation, or a poorer prognosis compared with sporadic cases. Those studies together suggest that family history and genetic predisposition might be particularly relevant to aggressive uterine tumors, such as uterine serous papillary carcinomas.
Germline mutations in BRCA1 and BRCA2 genes have been studied extensively in families with breast and breast-ovarian familial cancer syndromes.13,14 Mutation analysis has shown over 100 deleterious mutations in each gene, most of which are private, ie, unique to single families.15 In the Ashkenazi Jewish population (Jews of Eastern European ancestry), however, three mutations are recurrent,16–18 and their combined frequency in the general Ashkenazi population has been estimated at 2.5%.19–21 That percentage is much higher than the epidemiologically estimated frequency of 1 in 300 to 1 in 800 BRCA carriers in the United States and United Kingdom populations.22 The common BRCA1 and BRCA2 germline mutations in Ashkenazi Jews are BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT.19–21 Those three mutations cover almost all cases of familial disease in this population. In Israel, where approximately half the Jewish population is of Ashkenazi origin, over 35,000 women are estimated to be BRCA1 or BRCA2 germline mutation carriers. Although there has been no excess of uterine tumors in women with BRCA1 and BRCA2 pedigrees,14 we reported a breast-ovarian cancer family segregating the BRCA1 5382insC mutation in which one carrier developed uterine serous papillary carcinoma.23 Uterine tumor DNA from that carrier showed loss of the wild-type BRCA1 allele, suggesting a causal relationship between uterine serous papillary carcinoma and BRCA1 germline mutation. We surmised that the Israeli high-risk population could serve as a test group to evaluate the relationship between BRCA1 and BRCA2 germline mutations and uterine serous papillary carcinomas.
In this study, a series of women diagnosed with uterine serous papillary carcinoma were tested for the three BRCA1 and BRCA2 mutations common in our population. Results of testing were correlated with family histories to evaluate the possible role of genetic predisposition to uterine serous papillary carcinoma with familial breast-ovarian cancer.
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Materials and Methods |
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For mutation analysis, genomic DNA was extracted from peripheral blood samples by a standard salting-out procedure24 for the three mutations common in Ashkenazi Jews (BRCA1–185delAG and BRCA1–5382insC, BRCA2–6174delT) using published methods.23
Loss of heterozygosity analysis was done on uterine tumor tissue of germline carriers. DNA was extracted from paraffin-embedded tumor samples using the MasterPure DNA purification kit (Epicentre Technologies, Madison, WI). Tumor and genomic DNA samples were analyzed for D17S855, an intragenic BRCA1 dinu-cleotide repeat marker (Genome Database, http://www.gdm.org). The AFM248yg9m primer was 5' end-labeled with 32P using PNK (polynucleotide kinase; MBI Fermentas-LITTA). Amplification was with 1-µmol/L-labeled AFM248yg9m and 1-µmol/L-unlabeled AFM248yg9m primers. Polymerase chain reaction (PCR) conditions were 95C for 2 minutes, followed by 35 cycles of 94C for 20 seconds, 52C for 20 seconds, and 72C for 40 seconds. Genomic and tumor PCR products were run in tandem on 6% acrylamide denaturing gels containing 7 mol/L urea and 30% formamide. Alleles were detected by autoradiography.
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).
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). In both cases in which first-degree relatives had ovarian cancer, family history was highly suggestive of familial breast or ovarian cancer. In one woman, the subject of our recently published case report,23 history included ovarian carcinoma in two of her sisters (at ages 47 and 55), breast carcinoma in one second-degree relative (at age 48), and in four third-degree relatives (all in their thirties) and colon cancer in a second-degree relative. The second woman had a history of breast carcinoma and two first-degree relatives each with ovarian and prostatic cancer. Among the three women of Iraqi origin, two were suggestive of familial breast cancer, including a history of breast cancer in two women and breast cancer in two first-degree relatives of one.
Mutation analysis identified BRCA1 germline mutations in two patients, 5382insC in one, and 185delAG in the other. Thus, the overall frequency of BRCA1 or BRCA2 germline mutation carriers among our uterine serous papillary carcinoma patients was 17% (two of 12) and 22% (two of nine), respectively, among the Ashkenazi subset. As shown in Table 1, both carriers had family histories suggestive of familial breast or ovarian cancer.
In both BRCA1 germline mutation carriers, endometrial tumor tissue was screened for loss of heterozygosity as described. Tumor DNA from one woman showed complete loss of heterozygosity for the wild-type allele of a BRCA1 intragenic marker (D17S855)23 (Figure 1). Another woman’s tumor was extremely invasive and was impossible to isolate from normal tissue; therefore, in DNA extracted from the tumor sample, the wild-type allele is not completely absent but is significantly reduced compared with the germline sample. In the first woman, it was possible to identify the wild-type allele by comparing segregation of the D17S855 allele with the mutation status of two siblings.23 In the second woman, the wild-type allele was lost by testing the tumor sample directly for the 185delAG mutation (Figure 1). The BRCA1 185delAG germline mutation is the most common mutation in Jews of Iraqi origin (with a 1% population frequency).25 None of the three founder mutations was detected in the three women of Iraqi origin; however, two of them had personal histories of breast carcinoma and one had a family history of breast cancer in two first-degree relatives.
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Discussion |
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A surprisingly high frequency of personal and family histories of cancer were found in our study group. The relatively high rate of affected first-degree relatives in our uterine serous papillary carcinoma population could be a chance finding caused by sample size, or indicate preferential referral of women with strong family histories to tertiary care centers, but it is notably consistent with previous reports,11,12 that suggested family history, most likely a surrogate for genetic predisposition, is a risk factor for a subset of women with aggressive uterine cancers.
Two of 12 cases were BRCA1 germline mutation carriers, which was most likely an underestimate because one of the non-Ashkenazi women had a highly suggestive family history and the specific mutation analysis we did is not as sensitive in non-Ashkenazi Jews. Indeed, when only Ashkenazi women are considered, two of nine were positive for BRCA1 germline mutations. Our sample was small, but that frequency is close to one in larger series of ovarian cancer patients in Israel.19,20,25 Both BRCA1 germline mutation carriers had family histories suggestive of familial breast or ovarian cancer. In both, uterine tumor DNA had loss of heterozygosity for the wild-type allele in the tumor tissue, indicating that endometrial tumors in both carriers were not chance occurrences, but causally related to the germline mutation, in accordance with the classic tumor suppressor model.
No excess of uterine cancer was seen in previous studies of families with BRCA1 and BRCA2 germline mutations,13,14 which might indicate the rarity of uterine serous papillary carcinoma as a manifestation of BRCA-related cancer syndrome. A less likely possibility is that a true excess of uterine serous papillary carcinoma in BRCA1 germline mutation carriers was obscured by regarding all uterine tumors as single entities, without differentiating uterine serous papillary carcinoma from the more common endometrioid endometrial cancer. Uterine serous papillary carcinoma also might have been misclassified as advanced ovarian carcinoma, particularly in families with ovarian cancer histories.
Our series suggests that BRCA1 germline mutations might be frequent in uterine serous papillary carcinoma patients and related to its pathogenesis. The high frequency of previous breast cancers and strong family histories, with the observations of high BRCA1 germline mutation rates and loss of heterozygosity in carriers’ uterine tumors, suggest that uterine serous papillary carcinoma also might be a manifestation of BRCA1 familial breast-ovarian cancer syndrome.
Our observation requires further investigation in a larger sample with uterine serous papillary carcinoma, and, if substantiated, might have implications for decision making on surgical and medical prophylaxis. For women who have prophylactic oophorectomies because of breast-ovarian cancer family histories or positive BRCA germline mutation carrier status, hysterectomy also might have to be considered.
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Footnotes |
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Received September 21, 1999. Received in revised form January 18, 2000. Accepted February 1, 2000.
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2. Hendrickson M, Ross J, Eifel PJ, Cox RS, Martinez A, Kempson R. Adenocarcinoma of the endometrium: Analysis of 256 cases with carcinoma limited to the uterine corpus. Pathology review and analysis of prognostic variables. Gynecol Oncol 1982;13:373–92.[Medline]
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20. Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, Lishinsky E, et al. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: Frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families [see comments]. Am J Hum Genet 1997;60:1059–67.[Medline]
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22. Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, Collins FS, et al. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals [see comments] [published erratum appears in Nat Genet 1996 Jan;12:110]. Nat Genet 1995;11:198–200.[Medline]
23. Hornreich G, Beller U, Lavie O, Renbaum P, Cohen Y, Levy-Lahad E. Is uterine serous papillary carcinoma (USPC) a BRCA1 related disease? Case report and review of the literature. Gynecol Oncol 1999:300–4.
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