To the Editor: In Figure 1 of their article, Wooster and Weber(June 5 issue)1 ignore an important paradox by dismissing mutationsin the ATM (ataxia–telangiectasia mutated) gene as notcontributing to breast cancer. Current theories propose thatATM senses DNA damage and then signals BRCA1. For example, ATMphosphorylates BRCA1, signaling it to arrest the cell cycleafter DNA damage due to ionizing radiation. Pathogenic BRCA1mutations markedly increase the risk of breast cancer. The dependenceof BRCA1 on ATM thus makes it logical that mutations in theATM gene would also increase the risk of breast cancer. Similarly,mutations in the CHEK2 gene increase the risk of breast cancer,and CHEK2 may have functional links with ATM.2,3 The authorsaccept the idea of a "BRCA3" gene with little hesitation, althoughsuch a gene has not yet been identified. ATM could actuallyrepresent BRCA3, according to claims that heterozygotes forATM mutations may account for up to 20 percent of cases of breastcancer. Stipulations to these claims are required because ofdata that do not support the presence of excess truncating ATMmutations in early-onset breast cancer.4 However, a clearerdiscussion of at least the proposed relations among ATM, CHEK2,and BRCA1 would facilitate clinical application and help resolvethis confusing paradox.
Bernard Friedenson, Ph.D. University of Illinois–Chicago College of Medicine Chicago, IL 60612
References
Wooster R, Weber BL. Breast and ovarian cancer. N Engl J Med 2003;348:2339-2347. [Free Full Text]
Falck J, Mailand N, Syljuasen R, Bartek J, Lukas J. The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis. Nature 2001;410:842-847. [CrossRef][Medline]
Witt E, Ashworth A. D-day for BRCA2. Science 2002;297:534-534. [Free Full Text]
FitzGerald MG, Bean JM, Hegde SR. Heterozygous ATM mutations do not contribute to early onset of breast cancer. Nat Genet 1997;15:307-310. [CrossRef][Web of Science][Medline]
To the Editor: I take exception to Wooster and Weber's statement that "among mutation carriers, this procedure [prophylacticmastectomy or prophylactic oophorectomy] has been shown to reducethe risk of breast and ovarian cancer by more than 60 percentand 95 percent, respectively." Although it has been well documentedthat prophylactic mastectomy does not result in the removalof all breast tissue,1 ovarian cancer cannot develop in womenwho undergo prophylactic oophorectomy, with the very rare exceptionof cases in which some ovarian tissue is inadvertently leftin situ because of unrecognized adherence of a portion of theovary to the pelvic sidewall. What does happen in a small percentageof women who undergo prophylactic oophorectomy is the subsequentdevelopment of papillary serous carcinoma of the peritoneum,which is a diffuse involvement of the lining of the peritonealsurfaces with a carcinoma identical to papillary serous carcinomaof the ovary and in which there is no demonstrable primary ovariancarcinoma.2 This distinction is important because women whoundergo prophylactic oophorectomy still need postoperative surveillancefor the possible development of papillary serous carcinoma ofthe peritoneum.
M. Steven Piver, M.D. Sisters of Charity Hospital Buffalo, NY 14225 mpiver{at}chsbuffalo.org
References
Meijers-Heijboer H, van Geel B, van Putten WLJ, et al. Breast cancer after prophylactic bilateral mastectomy in women with a BRCA1 or BRCA2 mutation. N Engl J Med 2001;345:159-164. [Free Full Text]
Piver MS, Jishi MF, Tsukada Y, Nava G. Primary peritoneal carcinoma after prophylactic oophorectomy in women with a family history of ovarian cancer: a report of the Gilda Radner Familial Ovarian Cancer Registry. Cancer 1993;71:2751-2755. [CrossRef][Web of Science][Medline]
The authors reply: In response to Dr. Piver, we agree that papillaryserous carcinoma of the peritoneum is a more accurate term thanovarian cancer to describe the disseminated intraperitonealcancer that can occur after prophylactic oophorectomy. However,this clinical entity is indistinguishable in presentation andprognosis from the stage III papillary serous ovarian carcinomathat can occur in women with intact ovaries. The source of papillaryserous carcinoma of the peritoneum remains unknown, but regardlessof its origin, it most commonly appears as disseminated intraperitonealdisease, and almost never as a resectable tumor mass. In ourown series of 259 carriers of BRCA1 and BRCA2 mutations whounderwent prophylactic oophorectomy, 2 patients (0.7 percent)received a diagnosis of papillary serous carcinoma of the peritoneumafter a mean follow-up of 10.7 years.1 Thus, given the low incidenceof this carcinoma after prophylactic oophorectomy in the highest-riskpopulation studied to date, and given the absence of data showingthat the outcome of this carcinoma can be altered by surveillance,it is difficult to make a case for screening women at high riskfor papillary serous carcinoma of the peritoneum after prophylacticoophorectomy.
In response to Dr. Friedenson, we agree that ATM mutations havea plausible role in heritable susceptibility to breast cancer.A number of findings — the function of ATM in responseto DNA damage, susceptibility to breast cancer in associationwith genetic mutations in this pathway, the segregation of ATMmutations in a few families with breast cancer, the excess rateof breast cancer in female family members of ATM homozygotes,and findings in a recently developed murine model — allsupport this hypothesis.2,3 However, as we stated, these dataremain controversial because of conflicting reports3 and becauseof the absence of specific ATM sequence variants that are consistentlyassociated with a significantly increased risk of breast cancer.Thus, at present, we believe that ATM is best represented withinthe approximately 50 percent of genes associated with breast-cancersusceptibility that remain unidentified or uncharacterized.
Barbara L. Weber, M.D. Abramson Family Cancer Research Institute Philadelphia, PA 19104
Richard Wooster, Ph.D. Wellcome Trust Sanger Institute CambridgeCB10 1SA, United Kingdom
References
Rebbeck TR, Lynch HT, Neuhausen SL, et al. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N Engl J Med 2002;346:1616-1622. [Free Full Text]
Balmain A, Gray J, Ponder B. The genetics and genomics of cancer. Nat Genet 2003;33:Suppl:238-244.
Khanna KK. Cancer risk and the ATM gene: a continuing debate. J Natl Cancer Inst 2000;92:795-802. [Free Full Text]
Previous
