BRCA Germline Mutations in Jewish Women with Uterine Serous Papillary Carcinoma

Abstract & Commentary

Synopsis: 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 Jews.

Source: Lavie O, et al. Gynecol Oncol. 2004;92: 521-524.

Lavie and colleagues previously described a possible link between germline mutation in the BRCA genes and the occurrence of the uncommon, but aggressive uterine papillary serous carcinoma (UPSC). The purpose of the current study was to expand the investigation, evaluate the incidence of personal breast cancer and family history and to determine if tumor tissues harbored similar genetic mutations as the germline. To do this, they retrospectively identified 27 women consecutively diagnosed with UPSC over a 2½ year interval at 3 institutions. Identified cases were interviewed for family history and given genetic counseling. Peripheral blood was taken for genomic DNA analysis and paraffin-embedded tissue was harvested for loss of heterozygosity analysis (LOH). Mutational analysis was conducted for one of the 3 well-characterized founder mutations for women of Ashkenazi decent. Overall, 4 of 20 (20%) Ashkenazi and 0 of 7 non-Ashkenazi women were identified with a founder mutation. Personal history of breast cancer was identified in 7 (35%). Family history of breast (65%), and ovarian (20%) cancer were common. The diagnosis of breast cancer preceded uterine cancer by 11.5 years. LOH analysis identified loss of the wild-type allele in 3 of the 4 BRCA1 mutations. Lavie et al concluded that Ashkenazi women diagnosed with UPSC have a high incidence of BRCA founder mutations. LOH analysis coupled with the significant family history reported in this cohort suggested that UPSC might be a clinical manifestation of the familial breast-ovarian cancer syndrome in Ashkenazi women.

Comment by Robert L. Coleman, MD

There is little underestimation of the clinical significance conveyed in identifying a familial cancer syndrome for a particular patient. Once hidden from public record for fear of "genetic discrimination," the knowledge of an inherited predisposition has allowed physicians and patients to not only critically assess cancer risk but also evaluate potential preventive strategies that could impact that risk over time. As more sophisticated models assessing risk are developed and acceptance for available testing is increased, greater precision in counseling can be realized. A necessary component of this counseling is understanding how to interpret risk estimates and where this risk may manifest.

As obstetrician/gynecologists, our closest clinical experience in this regard comes in the care of women with mutation in the BRCA family of genes. The familial breast-ovarian cancer syndrome, most commonly characterized by an increase in lifetime risk of both breast and ovarian cancer, is infrequently diagnosed (about 10% of primary ovarian cancers), yet it is the subject of intense investigation. Important information from this work has identified, for instance, that a wide range of variable penetrance exists between different families; specific cohorts are at risk because of their ethnicity (Ashkenazi Jews); and intervention strategies such as oral contraceptives and prophylactic surgery (salpingoophorectomy, mastectomy) appear to reduce the risk of cancer at both sites. New developments continually shape our understanding of the disease process and with this knowledge, new recommendations.

Lavie et al raise another consideration in the current article. They reasoned that since UPSC and serous epithelial ovarian cancer have similar morphology and clinical behavior and since ovarian cancer in Ashkenazi Jewish women is associated with the high background incidence of BRCA founder mutations, there might be an association between UPSC occurrence and BRCA mutation. Although only 4 women with mutations were identified in the cohort of Israeli Ashkenazi Jews, the 20% incidence is dramatically different than the Ashkenazi population risk in general (2%) and surprising similar to the incidence of mutation in their women diagnosed with either ovarian (30%) or breast (10%) cancer. Loss of heterozygosity analysis suggests the germline mutation was potentially causally related to their cancer occurrence. The clinical implication of documenting UPSC as a potential clinical manifestation of the cancer syndrome lies in screening and prophylactic surgery. That is, if the disease is a future risk for women identified with or at risk for mutation of BRCA, should our recommendation for risk reduction include hysterectomy?

To answer this question appropriately, more clinical data are needed. The association documented in the current report is far from congruent with other investigations. For instance, in the largest series of UPSC patients for whom BRCA analysis was conducted, no BRCA1 or BRCA2 mutations were found; in a smaller series of UPSC tumors by Goldman et al, 3 of 9 cases were identified with BRCA2 mutations, whereas in the current report, only mutations in BRCA1 were found. Nonetheless, management of women undergoing prophylactic surgery for known or suspected BRCA mutation is more complex when uterus is left in situ. It has been documented that along with ovarian cancer, the relative risk for tubal malignancy is significantly elevated. Although most tubal cancers are distally situated, removal of the entire tubal segment cannot be completely accomplished by salpingoophorectomy—a theoretical consideration. In addition, newly castrated young women will likely choose hormone therapy for symptomatic indications. Generally, this medication is prescribed as a combination in those with a uterus to offset the risk for endometrial cancer. However, the associated risks for subsequent breast cancer with combination hormone replacement therapy have been suggested in recent reports from the Women’s Health Initiative trials. Future reports from the estrogen-alone cohort in particular regard to breast cancer risk are awaited. If a modulated risk is seen in this latter cohort, the advocacy for hysterectomy may gain support, albeit recognizably, a more invasive procedure.

Nonetheless, if clear association of UPSC as a clinical manifestation of the familial syndrome can be made, it should prompt us to expand our discussions with these high-risk women and potentially modify our recommendations for prophylactic surgery. At the end of the day, provocative data, as that raised by Lavie et al, need to be critically evaluated. The recommendation for universal hysterectomy in affected patients wanting prophylactic surgery is premature. Data from additional analytical trials will help to further refine this recommendation, hopefully, improving the lives of women identified with familial cancer risk.

Suggested Reading

  • Goshen R, et al. Gynecol Oncol. 2000;79:477-481.
  • Grann VR, et al. J Clin Oncol. 2002;20:2520-2529.
  • Rossouw JE, et al. JAMA. 2002;288:321-333.
  • Rebbeck TR, et al. N Engl J Med. 2002;346:1616-1622.
  • Goldman NA, et al. ASCO Proc. 2002;21:221a.

Dr. Coleman is Professor, Dept. of Gynecologic Oncology, University of Texas Southwestern Medical Center, Dallas, TX.