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Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry

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Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-3058 Susceptibility and Prevention Clinical Cancer Research Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry Michael D. Walsh1,3, Daniel D. Buchanan1,3, Margaret C. Cummings4, Sally-Ann Pearson1, Sven T. Arnold1, Mark Clendenning1, Rhiannon Walters1, Diane M. McKeone1, Amanda B. Spurdle2, John L. Hopper7, Mark A. Jenkins7, Kerry D. Phillips9, Graeme K. Suthers9,10, Jill George11, Jack Goldblatt11,12, Amanda Muir13, Kathy Tucker13, Elise Pelzer5, Michael R. Gattas5, Sonja Woodall14, Susan Parry14,15, Finlay A. Macrae8, Robert W. Haile16, John A. Baron17, John D. Potter18, Loic Le Marchand19, Bharati Bapat20, Stephen N. Thibodeau21, Noralane M. Lindor21, Michael A. McGuckin6, and Joanne P. Young1,3 Abstract Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controver- sial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families. Experimental Design: This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon can- cer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mis- match repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing. Results: Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohisto- chemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor–negative (estrogen receptor, P = 0.031; progesterone recep- tor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups. Conclusions: MMR deficiency was identified in 51% of breast cancers arising in known mutation car- riers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking. Clin Cancer Res; 16(7); 2214–24. ©2010 AACR. Authors' Affiliation: 1Familial Cancer Laboratory, 2Molecular Cancer Note: Supplementary data for this article are available at Clinical Cancer Epidemiology Laboratory, Queensland Institute of Medical Research, Research Online (http://clincancerres.aacrjournals.org/). 3University of Queensland School of Medicine, 4University of Queensland Centre for Clinical Research, 5Genetic Health Queensland, A subset of this work, namely, the pathology features of 94 breast Royal Brisbane and Women's Hospital, Herston, 6Mater Medical cancers, was presented as a poster at the XXVII Congress of the Research Institute, South Brisbane, Queensland, Australia; 7School of International Academy of Pathology, Athens, Greece, 2008 [DNA Population Health, Centre for MEGA Epidemiology, University of Mismatch Repair Deficiency in Breast Cancers Arising in Breast/Colon Melbourne, Melbourne, Australia; 8Department of Colorectal Medicine Families. Walsh M, Cummings M, Buchanan D, Arnold S, McKeone D, and Genetics, The Royal Melbourne Hospital, Parkville, Victoria, Walters R, Jass J, Hopper J, Jenkins M, Spurdle A, McGuckin M, and Australia; 9South Australian Clinical Genetics Service, North Adelaide, Young J. Histopathology (2008) 53 (Suppl. 1):71.]. 10Department of Paediatrics, University of Adelaide, South Australia, The content of this manuscript does not necessarily reflect the views or Australia; 11Genetic Services of Western Australia, King Edward policies of the National Cancer Institute or any of the collaborating Memorial Hospital, Subiaco, 12School of Paediatrics and Child Health, centers in the CFRs, nor does mention of trade names, commercial University of Western Australia, Nedlands, Western Australia, Australia; products, or organizations imply endorsement by the U.S. Government or 13Clinical Genetics Service, Prince of Wales Hospital, Randwick, New the CFR. A portion of archival tissue for this project was obtained from South Wales, Australia; 14Northern Regional Genetics, Auckland The Jeremy Jass Memorial Pathology Bank. Hospital, 15University of Auckland, Auckland, New Zealand; 16Keck School of Medicine, University of Southern California, Los Angeles, Corresponding Author: Michael D. Walsh, Familial Cancer Laboratory, I California; 17Dartmouth Medical School, Hanover, New Hampshire; Floor, Bancroft Centre, Queensland Institute of Medical Research, Her- 18Fred Hutchinson Cancer Research Center, Seattle, Washington; ston Road, Herston, Queensland 4006, Australia. Phone: 61-73845- 19Cancer Research Center of Hawaii, University of Hawaii at Manoa, 3775; Fax: 61-73362-0107; E-mail: [email protected]. 20 Honolulu, Hawaii; Samuel Lunenfeld Research Institute, Mount Sinai doi: 10.1158/1078-0432.CCR-09-3058 Hospital, University of Toronto, Toronto, Canada; and 21Mayo Clinic, Rochester, Minnesota ©2010 American Association for Cancer Research. 2214 Clin Cancer Res; 16(7) April 1, 2010 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2010 American Association for Cancer Research. Published OnlineFirst March 9, 2010; DOI: 10.1158/1078-0432.CCR-09-3058 Breast Cancer in Lynch Syndrome a study of Brazilian Lynch syndrome families showed Translational Relevance an increased incidence of breast cancer equal in incidence to endometrial cancer cases (12), although this study Lynch syndrome predisposes individuals to in- used clinical criteria to define Lynch syndrome. In more creased rates of colorectal and endometrial cancer. recent times, both case reports (13, 14) and statistical Lynch syndrome tumors are characterized by loss of studies (15, 16) have shown that MMR-deficient breast DNA mismatch repair proteins, and it is this feature cancers can and do arise in mutation carriers. which can be used for the recognition of Lynch syn- Immunohistochemical screening of tumors for defi- drome among incident cancers in a population. ciency in MMR proteins is currently the most efficacious Whether breast cancers constitute part of the tumor method for the recognition of Lynch syndrome (17). Im- spectrum in this syndrome, and thus could be used munohistochemistry allows not only the identification of for molecular diagnosis of Lynch syndrome, remains potential Lynch syndrome patients, but also by its pat- controversial. In this report, we show that not only tern of staining, the most likely causative gene. This is do 50% of breast cancers arising in Lynch syndrome important because tracking down a mutation in MMR mutation carriers show loss of mismatch repair pro- genes is not a trivial exercise. Immunohistochemistry is teins, but also, that they have histologic features which generally applied to recognized Lynch syndrome spec- further alert pathologists to the possibility that a breast trum tumors such as those from the colorectum, endo- cancer may be arising in a person who has Lynch syn- metrium, ovary, stomach, and urothelial tissues. This drome. With families becoming smaller, the addition has also become increasingly important as family size de- of breast cancer to the repertoire of tissues which can creases and screening becomes more widespread, lessen- be used to identify patients and families at risk is likely ing the power of clinical criteria to detect Lynch to improve detection rates. syndrome, and highlighting the need to increase the po- tential sources of tissue that may be used for diagnosis. Breast cancers with both microsatellite instability (MSI) and/or immunohistochemical absence of MMR proteins Defects in autosomal dominant genes are suspected to have been reported by many authors (13, 14, 18–23), al- be responsible for up to 10% of all breast cancers (1, 2). though many of these reports contain small numbers of The most commonly affected known genes are BRCA1 and cases. In this study, we sought to establish the frequency BRCA2, whereas other genes such as p53, PTEN, STK11/ with which breast cancers occurring in mutation carriers LKB1,andCDH1 are implicated in fewer cases (3, 4). for Lynch syndrome display MSI as a consequence of loss There are, in addition, a significant number of cases of of DNA MMR proteins, and to examine the clinicopath- breast cancer that present at an earlier than usual age of ologic features of such tumors. This study represents the onset and with a conspicuous family history for which largest series of breast cancers with MMR deficiency re- the causative gene(s) has not been identified (5). ported to date, and attests to the utility of breast tissue Lynch syndrome, or hereditary nonpolyposis colorectal as a diagnostic sample in suspected Lynch syndrome cancer (6), was first identified nearly a century ago as fa- when colon or endometrial tissue is unavailable (13). milial clustering of cancers, particularly of the colon, small intestine, stomach, endometrium, upper urinary Patients and Methods tract, and sebaceous tumors of the
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