Skip to main content
  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

AACR logo

  • Register
  • Log in
  • My Cart
Advertisement

Main menu

  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

  • AACR Publications
    • Blood Cancer Discovery
    • Cancer Discovery
    • Cancer Epidemiology, Biomarkers & Prevention
    • Cancer Immunology Research
    • Cancer Prevention Research
    • Cancer Research
    • Clinical Cancer Research
    • Molecular Cancer Research
    • Molecular Cancer Therapeutics

User menu

  • Register
  • Log in
  • My Cart

Search

  • Advanced search
Clinical Cancer Research
Clinical Cancer Research
  • Home
  • About
    • The Journal
    • AACR Journals
    • Subscriptions
    • Permissions and Reprints
  • Articles
    • OnlineFirst
    • Current Issue
    • Past Issues
    • CCR Focus Archive
    • Meeting Abstracts
    • Collections
      • COVID-19 & Cancer Resource Center
      • Breast Cancer
      • Clinical Trials
      • Immunotherapy: Facts and Hopes
      • Editors' Picks
      • "Best of" Collection
  • For Authors
    • Information for Authors
    • Author Services
    • Best of: Author Profiles
    • Submit
  • Alerts
    • Table of Contents
    • Editors' Picks
    • OnlineFirst
    • Citation
    • Author/Keyword
    • RSS Feeds
    • My Alert Summary & Preferences
  • News
    • Cancer Discovery News
  • COVID-19
  • Webinars
  • Search More

    Advanced Search

Susceptibility and Prevention

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

Michael D. Walsh, Daniel D. Buchanan, Margaret C. Cummings, Sally-Ann Pearson, Sven T. Arnold, Mark Clendenning, Rhiannon Walters, Diane M. McKeone, Amanda B. Spurdle, John L. Hopper, Mark A. Jenkins, Kerry D. Phillips, Graeme K. Suthers, Jill George, Jack Goldblatt, Amanda Muir, Kathy Tucker, Elise Pelzer, Michael R. Gattas, Sonja Woodall, Susan Parry, Finlay A. Macrae, Robert W. Haile, John A. Baron, John D. Potter, Loic Le Marchand, Bharati Bapat, Stephen N. Thibodeau, Noralane M. Lindor, Michael A. McGuckin and Joanne P. Young
Michael D. Walsh
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Daniel D. Buchanan
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Margaret C. Cummings
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sally-Ann Pearson
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sven T. Arnold
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark Clendenning
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Rhiannon Walters
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Diane M. McKeone
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amanda B. Spurdle
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John L. Hopper
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Mark A. Jenkins
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kerry D. Phillips
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Graeme K. Suthers
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jill George
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Jack Goldblatt
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Amanda Muir
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Kathy Tucker
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Elise Pelzer
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael R. Gattas
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Sonja Woodall
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Susan Parry
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Finlay A. Macrae
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Robert W. Haile
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John A. Baron
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
John D. Potter
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Loic Le Marchand
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Bharati Bapat
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Stephen N. Thibodeau
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Noralane M. Lindor
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Michael A. McGuckin
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
Joanne P. Young
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
DOI: 10.1158/1078-0432.CCR-09-3058 Published April 2010
  • Article
  • Figures & Data
  • Info & Metrics
  • PDF
Loading

Abstract

Purpose: The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. 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 cancer 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 mismatch 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 immunohistochemical 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 receptor, 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 carriers. 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.

Translational Relevance

Lynch syndrome predisposes individuals to increased rates of colorectal and endometrial cancer. Lynch syndrome tumors are characterized by loss of DNA mismatch repair proteins, and it is this feature which can be used for the recognition of Lynch syndrome among incident cancers in a population. Whether breast cancers constitute part of the tumor spectrum in this syndrome, and thus could be used for molecular diagnosis of Lynch syndrome, remains controversial. In this report, we show that not only do 50% of breast cancers arising in Lynch syndrome mutation carriers show loss of mismatch repair proteins, but also, that they have histologic features which further alert pathologists to the possibility that a breast cancer may be arising in a person who has Lynch syndrome. With families becoming smaller, the addition of breast cancer to the repertoire of tissues which can be used to identify patients and families at risk is likely to improve detection rates.

Defects in autosomal dominant genes are suspected to be responsible for up to 10% of all breast cancers (1, 2). The most commonly affected known genes are BRCA1 and BRCA2, whereas other genes such as p53, PTEN, STK11/LKB1, and CDH1 are implicated in fewer cases (3, 4). There are, in addition, a significant number of cases of breast cancer that present at an earlier than usual age of onset and with a conspicuous family history for which the causative gene(s) has not been identified (5).

Lynch syndrome, or hereditary nonpolyposis colorectal cancer (6), was first identified nearly a century ago as familial clustering of cancers, particularly of the colon, small intestine, stomach, endometrium, upper urinary tract, and sebaceous tumors of the skin. Approximately 80% of Lynch syndrome–associated cancers are attributable to defects in the DNA mismatch repair (MMR) genes MLH1 and MSH2, with the majority of the remaining cases occurring in carriers of mutations in MSH6 and, to a lesser extent, PMS2 (7). The consideration of breast cancer as a spectrum tumor in Lynch syndrome has been controversial, with evidence for and against constituting a rigorous debate over time. An extensive study published in 2002 excluded breast cancer as part of the Lynch syndrome spectrum of tumors (8). Another study, while demonstrating no increased risk for developing mammary cancers, found that tumors in known carriers presented at an earlier age (9). This led de Leeuw et al. to postulate that, whereas MMR deficiency does not in itself initiate breast tumors, the increased rate of mutation accelerates their progress leading to an earlier presentation (10). In contrast to these observations, Scott et al. reported a significant 15-fold increased risk of breast cancer in MLH1 mutation carriers (but not MSH2 carriers; ref. 11), and a study of Brazilian Lynch syndrome families showed an increased incidence of breast cancer equal in incidence to endometrial cancer cases (12), although this study used clinical criteria to define Lynch syndrome. In more recent times, both case reports (13, 14) and statistical studies (15, 16) have shown that MMR-deficient breast cancers can and do arise in mutation carriers.

Immunohistochemical screening of tumors for deficiency in MMR proteins is currently the most efficacious method for the recognition of Lynch syndrome (17). Immunohistochemistry allows not only the identification of potential Lynch syndrome patients, but also by its pattern of staining, the most likely causative gene. This is important because tracking down a mutation in MMR genes is not a trivial exercise. Immunohistochemistry is generally applied to recognized Lynch syndrome spectrum tumors such as those from the colorectum, endometrium, ovary, stomach, and urothelial tissues. This has also become increasingly important as family size decreases and screening becomes more widespread, lessening the power of clinical criteria to detect Lynch syndrome, and highlighting the need to increase the potential sources of tissue that may be used for diagnosis. Breast cancers with both microsatellite instability (MSI) and/or immunohistochemical absence of MMR proteins have been reported by many authors (13, 14, 18–23), although many of these reports contain small numbers of cases. In this study, we sought to establish the frequency with which breast cancers occurring in mutation carriers for Lynch syndrome display MSI as a consequence of loss of DNA MMR proteins, and to examine the clinicopathologic features of such tumors. This study represents the largest series of breast cancers with MMR deficiency reported to date, and attests to the utility of breast tissue as a diagnostic sample in suspected Lynch syndrome when colon or endometrial tissue is unavailable (13).

Patients and Methods

Patients

One hundred and seven cases of breast cancer (arising in 102 females and 2 males) from 90 colorectal cancer families were identified from the Colorectal Cancer Family Registry (Colon CFR), a National Cancer Institute–supported consortium established in 1997 to create a comprehensive collaborative infrastructure for interdisciplinary studies of the genetic and molecular epidemiology of colorectal cancer (see detailed information about the registry at the CFR web site;22 ref. 24). All patients in this study had institutional review board approval under the policies and procedures of the Colon CFR for recruitment of participants and protocols for carrying out research projects. The average age of patients with breast cancer was 56.1 ± 11.3 y, ranging from 36.1 to 86.7 y of age.

Families were selected for study in which (a) both breast and colon cancer co-occurred, with at least one breast cancer regardless of age at diagnosis; (b) families met either modified Amsterdam criteria (ACII), or had at least one early-onset (<50 y) colorectal cancer; and (c) breast tissue was available within the biospecimen repository for MMR testing, thereby limiting the number of families which could be analyzed. Comprehensive cancer histories and tissue were available for 90 families recruited through the Australasian Colorectal Family Registry and the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies. The majority of families (n = 86) were enrolled in the Colon CFR on the basis of a strong family history of colorectal cancers compatible with Lynch syndrome, and the remaining four families were identified following enrollment of participants with early-onset (<50 y) colorectal cancer.

Fifty-four of 90 (60%) families met modified ACII, and the remainder had multiple cancers including at least one early-onset (<50 y) colorectal cancer per family. In 13 cases (13%), the breast cancer patient was also affected with early-onset colorectal cancer, 58 individuals (56%) were first-degree relatives of an individual with early-onset colorectal cancer, 25 individuals (24%) were second-degree relatives, and the remaining 8 cases (8%) were more distantly related. All reported tumors (breast and other sites) were verified by either examination of the original histopathology material or histopathology reports for all affected kindred members where possible. In three cases, bilateral metachronous tumors were available for testing. In no instance was there evidence of familial adenomatous polyposis. No deleterious mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 were detected in the small minority of families (n = 7) tested. As the Colon CFR recruits families on the basis of colorectal cancer, it is unlikely that families enrolled in this registry would be of the type of configuration that would trigger BRCA1 testing.

Histopathologic review

One consultant histopathologist (M.C. Cummings) reviewed material from 104 of the 107 cases of breast cancer to confirm diagnosis and score histopathologic features. Clinicopathologic data for the remaining three cases was abstracted from histopathology reports. Noting the following features: tumor location, size, primary histologic type, tumor grade (using the Nottingham modification of the Bloom-Richardson system; ref. 25), tumor margin, confluent necrosis, calcification, presence of tumor-infiltrating and peritumoral lymphocytes, presence of in situ carcinoma and atypical ductal hyperplasia and axillary lymph node status. Although note was also made of the steroid hormone receptor status as originally reported, these markers were re assessed by immunohistochemistry in our laboratory owing to the large number of incomplete reports. HER2/neu status was extracted, where available, from original laboratory reports.

Immunohistochemistry

Immunohistochemistry for DNA MMR proteins was done as previously described (26). A subset of tumors was stained for estrogen receptor (ER), progesterone receptor (PR), and p53. Paraffin sections (4 μm) were subjected to heat-induced epitope retrieval in High pH Target Retrieval Solution (Dako Corporation) for ER and PR, and Reveal Decloaker Solution (BioCare Medical) for p53. Sections were stained with rabbit monoclonal anti-human ER (clone SP1) or rabbit monoclonal anti-human PR (clone SP2) at 1:2,500 or mouse monoclonal anti-p53 antibody at 1:100 followed by the EnVision Plus Mouse HRP detection system (Dako) for p53, or MACH3 Rabbit HRP polymer kit (BioCare Medical) for ER and PR. The proportion of positive cancer cell staining was graded as follows: 0 (negative), <10% (1+), 11% to 25% (2+), 26% to 50% (3+), 51% to 75% (4+), and >75% (5+). Tumors were scored as positive when there was strong expression in >10% tumor cells. Histologically normal breast epithelium present within tumor blocks served as the positive control for ER and PR, and sections from known p53-overexpressing colorectal cancers were used as positive controls when staining for p53 in breast cancers.

Assessment of tumors for MSI and MLH1 methylation

Tumors were assessed for MSI using a panel of 10 microsatellite markers and classified as MSI-high if ≥30% of the markers showed instability, MSI-low if one or more markers but <30% of all markers showed instability, and microsatellite stable if no marker exhibited instability, as has been previously reported (17). Only cases with five or more evaluable markers were considered. Methylation of the MLH1 promoter was detected using the MethyLight Assay as has been recently described (27).

BRAF V600E allele-specific PCR assay

The somatic T>A mutation at nucleotide 1799 causing the V600E mutation in the BRAF gene was determined using a fluorescent allele-specific PCR assay. Briefly, 20 to 50 ng of DNA, extracted from formalin-fixed, paraffin-embedded tumor tissue, was amplified in a 25 μL reaction containing 100 nmol/L each of allele-specific primers tagged with differing fluorophores [mutant primer (F1): 6-Fam, 5′-CAGTGATTTTGGTCTAGCTTCAGA-3′; wild-type primer (F2): NED, 5′-TGATTTTGGTCTAGCTACAGT-3′; and a common reverse primer (REV), 5′-CTCAATTCTTACCATCCACAAAATG-3′], together with 2.5 units of Taq polymerase (Eppendorf), 1× buffer, and 200 μmol/L of deoxynucleotide triphosphates. The cycling conditions consisted of an initial denaturation at 95°C for 2 min followed by 35 cycles at 94°C for 30 s, 59°C for 30 s, and 65°C for 30 s then a final extension at 65°C for 10 min. After amplification, 1 μL of the PCR product was added to an 8.7-μL mix of HiDi formamide and ROX Genescan 500 size marker (Applied Biosystems). The mutant allele (A1799) primer generated a PCR product of 97 bp, 3 bp larger than the wild-type PCR product after separation on an ABI 3100 genetic analyzer. GeneMarker (SoftGenetics) software was used to identify the different size and fluorescent allele PCR products. Positive and negative controls were run in each experiment and 10% of samples were replicated with 100% concordance.

Mutation testing

DNA (10 ng) was amplified in 25 μL reactions using HotMaster Taq and buffer (Eppendorf) with 20 pmol of each primer. Cycling protocols were applied according to previously established conditions for each primer set and amplicon, verified to selectively amplify the target amplicon only. PCR products were cleaned using Millipore Montage PCR96 Cleanup Plates (Millipore). Cleaned PCR product (1 μL) was used in a 12 μL sequencing reaction utilizing the BigDye Terminator v3.1 reagents and protocol (Applied Biosystems) and 2 pmol of primer. Sequencing product was cleaned with the DyeEx 96 Kit (Qiagen) using the recommended protocol. The product was dried, resuspended in HiDi Formamide (Applied Biosystems), and analyzed on an ABI PRISM 3100 (Applied Biosystems). Bidirectional sequencing was done throughout. Results were compared with reference sequence NC_000003.10 (genomic) and NM_000249.2 (cDNA) for MLH1, and NC_000002.10 (genomic) and NM_000251.1 (cDNA) for MSH2, NC_000002.11 (genomic) and NM_000179.2 (cDNA) for MSH6, and NC_000007.13 (genomic) and NM_000535.3 (cDNA) for PMS2. Multiplex ligation-dependent probe amplification (MLPA) was used to detect large exonic deletions and duplications in the four MMR genes, using the Salsa MLPA P003 and P248 kits for MLH1 and MSH2, and the P008 kit for MSH6 and PMS2 (MRC-Holland) according to the protocols of the manufacturer.

Statistical analysis

Statistical analysis was carried out using Statistical Package for Social Sciences (version 17.0). Contingency tables were assessed using χ2 or Fisher's exact test as appropriate. Differences between means were assessed using a t test to ensure equality of the variance in groups using probability plots and an F test. P < 0.05 was considered significant. Sensitivity and specificity calculations were done using VassarStats.23

Results

Of 90 families with breast and colorectal cancer, 53 families (59%) were classified as Lynch syndrome on the basis of a germ line mutation (n = 52) or multiple MSH2/MSH6-deficient tumors within the family (n = 1). Table 1 shows the distribution of families among the four causative MMR genes (MLH1, MSH2, MSH6, and PMS2). In the 37 remaining families, Lynch syndrome could be excluded as no evidence of MMR deficiency from immunohistochemistry or MSI testing was found, nor were any MMR mutations identified where tested. In 30 families, Lynch syndrome was excluded on the basis of immunohistochemistry and MSI testing of several family members with no evidence of MMR deficiency. The remaining seven families showed multiple MLH1-deficient colorectal and/or endometrial cancers associated with MLH1 methylation and/or somatic BRAF mutation (colorectal cancer only) with no evidence of germ line mutations in MLH1 either by direct sequencing or MLPA. Only one of these seven families met modified ACII. None of the 61 breast cancers in this study, which could be analyzed, showed the V600E activating mutation in BRAF.

View this table:
  • View inline
  • View popup
Table 1.

Characteristics of families related to mutation in a particular MMR gene

Abnormal immunostaining for MMR protein was observed for 18 of 107 breast cancers (17%; Fig. 1; Supplementary Figs. S1 and S2). In 12 cases, tumors showed loss of MSH2 and MSH6 proteins, in five cases, MLH1 and PMS2 were absent, and in one case, only MSH6 was absent. MSI testing was done for 89 breast cancers and was concordant with immunohistochemistry results in 85 cases (96%). All but one of the MMR-deficient breast cancers arose in families meeting ACII. Of the 18 participants whose breast cancers showed loss of one or more MMR proteins on immunohistochemistry, 16 tested positive for germ line mutations in the DNA MMR genes MLH1, MSH2, or MSH6 consistent with both their tumor immunodeficiency as well as their respective family mutation, while another individual who was deceased was found to be an obligate carrier of her family mutation (Table 2). The remaining case demonstrating immunohistochemical loss of MSH2 and MSH6 arose in a family in which no MSH2 mutation has been identified to date but which has three affected kindred members wherein their tumors show commensurate loss of MMR proteins.

Figure 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
Figure 1.

A poorly differentiated ductal carcinoma showing retention of MLH1 (A) and PMS2 (D) expression but loss of MSH2 (B) and MSH6 (C) staining in tumor cells.

View this table:
  • View inline
  • View popup
Table 2.

Mutation status of individuals with MMR deficient breast cancers

Overall, 18 of 35 known MMR mutation carriers with breast cancer (51%) produced a breast cancer that was MMR deficient. Of the 89 breast cancers with normal immunohistochemistry, 13 arose in individuals from families in which MLH1 mutations were identified, 20 in individuals with a family MSH2 mutation, 5 with MSH6 mutations, and 3 with PMS2. Of these 41, 17 individuals tested carried the family mutation, suggesting that only a proportion of breast cancers in mutation carriers are associated with MMR deficiency.

Ten of the 18 individuals showing loss of one or more MMR proteins in their breast cancers had other primary tumors as summarized in Table 3. In 3 of the 10 cases, breast cancer was the first diagnosed malignancy, preceding the second cancer by between 2 and 27 years. In the other patients, the breast cancers were diagnosed between 1 and 42 years after the first cancer. In all cases but one (a meningioma), the non–breast cancers tested showed the same pattern of MMR protein deficiency as the breast tumors, a finding which supports the premise of this report, i.e., that the breast cancers in mutation carriers that are MMR deficient are likely to have developed in association with the germ line mutation carried. Importantly, in eight cases of breast cancer in a proven mutation carrier, breast cancer was the only cancer documented.

View this table:
  • View inline
  • View popup
Table 3.

Multiple MMR-deficient tumors in MMR-deficient breast cancer patients

There was no statistical difference in age of presentation between the MMR-deficient breast cancers (mean, 57.5 ± 8.1 years; range, 43.4-75.0 years) and MMR-intact breast cancers (mean, 55.8 ± 11.9 years; range, 36.1-86.7 years; P = 0.56), nor between the MMR-deficient breast cancer group and MMR-intact known mutation carriers (57.1 ± 12.0 years; range, 36.1-80.5 years; P = 0.90). Similarly, no difference in mean age of presentation was observed between the five breast cancer cases which were MMR-deficient in MLH1 germ line mutation carriers and the 12 cases occurring in MSH2 carriers (58.0 versus 57.5 years; P = 0.90). The average age of the 11 individuals with the primary or only cancer being a breast cancer with MMR deficiency was 53.7 ± 6.0 years.

In 104 breast cancers that underwent pathology review, only histologic differences for invasive breast cancers were compared, with 12 cases of ductal carcinoma in situ excluded from analysis. Specifically, MMR-deficient invasive breast cancers (n = 16) were more likely to be ER- and PR-negative (P = 0.031 and P = 0.022, respectively), have peritumoral lymphocytes (P = 0.015), have confluent necrosis (P = 0.002), have growth in solid sheets (P < 0.001), and to have a higher mitotic rate (P = 0.002) when compared with MMR-proficient breast cancers (n = 79). In addition, MMR-deficient breast cancers less frequently had contiguous in situ disease (P = 0.038). No statistically significant association was seen between MMR status and tumor type, size, lymphovascular invasion, node status, prominent eosinophilic nucleoli, or tumoral calcification (Table 4; Supplementary Table S1). No statistical differences were observed for clinicopathologic features between the MMR-proficient invasive breast tumors arising in known carriers of germ line MMR gene mutations and tumors from the non–Lynch syndrome group (data not shown), and therefore, all MMR-intact tumors were considered together as the reference group for comparison with MMR-deficient invasive cancers. There were, however, significant differences in growth in solid sheets (P = 0.002), and the presence of pushing margins (P = 0.042), and confluent necrosis (P = 0.017) and residual carcinoma in situ (P = 0.004) between MMR-deficient and -intact invasive cancers among proven carriers of MMR gene germ line mutations (Table 5).

View this table:
  • View inline
  • View popup
Table 4.

Histologic features in MMR-deficient vs MMR-proficient invasive breast cancers

View this table:
  • View inline
  • View popup
Table 5.

Histologic features in MMR-deficient vs MMR-proficient invasive breast cancers from MMR germ line mutation carriers

Four tumors displayed typical BRCA1 histologic phenotype (characterized by high grade, high mitotic index, pushing margin, growth in solid sheets, and the presence of lymphocytic infiltrate and tumor necrosis; ref. 28), and two of these tumors (50%) showed loss of MSH2 and MSH6.

The two cases of ductal carcinoma in situ which exhibited loss of MMR expression were both of solid type, but there was no significant difference overall between DCIS type (cribriform, solid, papillary, or clinging) and MMR expression when including in situ disease accompanied by an invasive component (P = 0.45; data not shown). Lobular carcinoma in situ was present in eight cases accompanying invasive disease. There was no statistically significant difference between MMR-deficient and -proficient breast cancers and overexpression of p53 (P = 0.39).

There was a trend for individuals with a MMR-deficient breast cancer to have also developed an early-onset colorectal cancer, or was a first-degree relative of someone so affected (n = 15) when compared with individuals with a MMR-proficient breast cancer having more distantly related cases of early-onset colorectal cancer (n = 3; P = 0.11, 21% versus 9%, respectively). Of the 13 cases in which the same individual had both early-onset colorectal cancer and breast cancer, 5 (39%) showed MMR deficiency. There was no statistical difference between degree of kinship between the breast and early-onset colorectal cancer patients within individual families and whether the pedigree satisfied the modified ACII (P = 0.17).

Discussion

In the present study, we have examined the incidence of MMR deficiency occurring in breast cancers from families with a history of early-onset (<50 years) colorectal cancer and breast cancer occurring at any age. Of the 104 individuals investigated, 35 were found to harbor deleterious mutations in one of the DNA MMR genes, and of these, 18 individuals (51%) were found to have loss of MMR expression consistent with their respective germ line mutations. This study follows previous reports in which several groups have examined breast cancers with varying panels of markers to assess the extent of instability in tumors from this site. Many, however, have yielded disappointing results in which little or no instability could be detected in the majority of tumors (22, 29–32), although these studies were not specifically designed to detect Lynch syndrome. In 1996, Risinger and colleagues described breast cancer occurring in Lynch syndrome kindreds that showed high-level MSI. On the basis of this, it was suggested that breast cancer might be included in the tumor spectrum of Lynch syndrome II (21). A subsequent study failed to show an increased risk for breast cancer in Lynch syndrome, and further suggested that sporadic breast cancer with MMR deficiency may be exceedingly rare (8). However, reports of breast cancer with MMR-deficient phenotypes continued to be presented (9, 10, 33), with more targeted studies subsequently demonstrating that MSI is indeed a common feature of breast cancers occurring in known mutation carriers, being found in up to 60% of cases (10, 34, 35). In our study, in which MSI and immunohistochemistry results were highly correlated, we returned a figure of 51% for the proportion of breast cancers (which included a male breast cancer) arising in MMR mutation carriers that showed MMR deficiency, commensurate with this previously reported figure.

A study by Vasen and coworkers of 200 putative Lynch syndrome families has shown that although breast cancer occurs at an early age in Lynch syndrome, there is no elevated risk per se (9). This suggested that MMR deficiency may accelerate tumorigenesis in breast cancers which occur in Lynch syndrome mutation carriers but is unlikely to be the initiating event (10). We found no significant difference between MMR-proficient and MMR-deficient breast cancers when age of onset was analyzed. The mean age at diagnosis was 57 years in our study. Vasen et al. reported a mean age of 46 years for seven cases of breast cancer arising in mutation carriers (9), or 50 years as reported by both Stupart et al., who examined the incidence of breast cancers in women carrying in common a single mutation in MLH1 (c. C1528T; ref. 36), and Jensen et al., for a series of breast cancers arising in 20 mutation carriers reported recently (35). The numbers of cases in all studies were, however, small, and recruitment biases in different studies might account for any differences.

Medullary carcinomas of the breast show morphologic similarities to the MSI-high colorectal tumors (poor differentiation and lymphocytic infiltrate) and a proportion of these are MSI-high (37). Many of the studies to date investigating the issue of breast carcinomas arising in the setting of Lynch syndrome have been anecdotal case reports of one or two patients who have shown loss of appropriate MMR proteins by immunohistochemistry and/or high levels of MSI in tumors arising in proven mutation carriers (19, 38, 39). With such small numbers in any given study, it has been difficult to determine whether there is an “MSI” phenotype associated with such cancers, although Yee et al. described higher levels of MSI in lobular carcinomas (39%) than in infiltrating ductal cancers (13.5%; ref. 40). The issue has been made all the more difficult in that, whereas some breast cancers in mutation carriers have appropriate MMR protein loss with resultant MSI, there are a commensurate number of reports of breast tumors arising in proven carriers which have competent MMR (8, 39, 41). In this report, we found that breast cancers with proven MMR deficiency are significantly more likely than those with proficient MMR to show hormone receptor negativity, poor differentiation, a solid growth pattern, lymphocytic infiltrate, high mitotic rate, confluent necrosis, and vesicular tumor nuclei. In common with the study by Jensen et al., we found that ductal carcinoma not otherwise specified (NOS) was the predominant histotype (35), with no evidence of overrepresentation of specific types such as medullary or invasive lobular carcinoma.

Several of these features, including poor differentiation and lymphocytic infiltration, are also reported features of Lynch syndrome colorectal cancers (42, 43), and a dense lymphocytic infiltrate has been previously shown in a breast cancer case arising in a Lynch syndrome mutation carrier (14), and more recently, in a larger series of MMR-deficient breast cancers arising in mutation carriers in which three of the six tumors were reported to have both tumor-infiltrating lymphocytes and peritumoral lymphocytes (35).

The presence of breast cancer in Lynch syndrome has been reported to be overrepresented in Lynch syndrome families with MLH1 mutations (11, 15). Rarer causes of Lynch syndrome such as germ line mutations in MSH6 have also been associated with synchronous breast and colon cancers (44). However, due to our limited study design, we are unable to offer any comments regarding whether or not the risk of breast cancer is increased in Lynch syndrome mutation carriers.

Familial aggregation of cancers from different anatomic sites has been previously documented (45–47). Such clustering may arise from shared environmental risk factors common to the cancers, inherited defects in cancer susceptibility genes or interaction between the two. A series of large studies using the Swedish Family-Cancer Database, concluded that in the absence of known, strong environmental risk factors, most of the familial aggregation that is observed is likely due to genetic factors that increase the risk of cancer at more than one site (48). In addition, it has become increasingly apparent that most inherited cancer susceptibilities confer a risk for cancer at a range of sites, suggesting that mechanisms of carcinogenesis are shared by different tissues. This is true of Lynch syndrome, in which a defect in DNA MMR clearly confers an increased risk for cancers of the colorectum, endometrium, ovary, stomach, bladder and renal pelvis. As described in multiple previous reports, we found gene-appropriate MMR deficiency to be also readily demonstrable in approximately half of the breast cancers arising in Lynch syndrome mutation carriers using MMR protein immunohistochemistry, thereby confirming breast cancer tissue as a valid screening option for Lynch syndrome diagnosis. A caveat to testing breast cancers for Lynch syndrome however is that, although in this study we showed that loss of MMR by immunohistochemistry is 100% specific for Lynch syndrome, the sensitivity for detecting a mutation carrier is only 51.4%. This compares with a much higher sensitivity for colorectal cancers in which MMR-proficient phenocopies are relatively rare in mutation carriers.

Furthermore, we found that MMR-deficient tumors show certain histologic features significantly more often than would be expected thus increasing confidence in the selection and use of particular breast cancers for this purpose. It is worth noting that, of four cancers that displayed the “BRCA1” histologic phenotype, two showed loss of MMR proteins, suggesting that screening of such cases for Lynch syndrome might be considered where BRCA1 mutation testing proved fruitless. The finding that breast carcinoma was the only malignancy reported for half of the women with MMR-deficient breast cancers is consistent with the findings of Jensen et al., who reported no other cancer types in three of seven such cases (35).

Disclosure of Potential Conflicts of Interest

No potential conflicts of interest were disclosed.

Acknowledgments

The authors are grateful to the many pathology laboratories involved for the supply of extra archived breast tissue for analysis. Thanks are due to Erika Pavluk, Judi Maskiell, Leanne Prior, and Maggie Angelakos for data and pedigree retrieval, as well as to the members of the families who gave significant time and effort to the contribution of data. Joanne Young is a Cancer Council Queensland Senior Research Fellow.

Grant Support: National Cancer Institute, NIH under RFA no. CA-95-011, and through cooperative agreements with the Australasian Colorectal Cancer Family Registry (U01 CA097735) and the Mayo Clinic Cooperative Family Registry for Colon Cancer Studies (U01 CA074800).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement inaccordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Footnotes

  • Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/).

  • A subset of this work, namely, the pathology features of 94 breast cancers, was presented as a poster at the XXVII Congress of the International Academy of Pathology, Athens, Greece, 2008 [DNA Mismatch Repair Deficiency in Breast Cancers Arising in Breast/Colon Families. Walsh M, Cummings M, Buchanan D, Arnold S, McKeone D, Walters R, Jass J, Hopper J, Jenkins M, Spurdle A, McGuckin M, and Young J. Histopathology (2008) 53 (Suppl. 1):71.].

  • The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the U.S. Government or the CFR. A portion of archival tissue for this project was obtained from The Jeremy Jass Memorial Pathology Bank.

  • ↵22http://epi.grants.cancer.gov/CFR

  • ↵23http://faculty.vassar.edu/lowry/VassarStats.html

    • Received November 23, 2009.
    • Revision received February 4, 2010.
    • Accepted February 4, 2010.

References

  1. ↵
    1. Anonymous
    . Familial breast cancer: collaborative reanalysis of individual data from 52 epidemiological studies including 58,209 women with breast cancer and 101,986 women without the disease. Lancet 2001;358:1389–99.
    OpenUrlCrossRefPubMed
  2. ↵
    1. Claus EB,
    2. Schildkraut JM,
    3. Thompson WD,
    4. Risch NJ
    . The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318–24.
    OpenUrlCrossRefPubMed
  3. ↵
    1. Foulkes WD
    . Inherited susceptibility to common cancers. N Engl J Med 2008;359:2143–53.
    OpenUrlCrossRefPubMed
  4. ↵
    1. Tan DS,
    2. Marchio C,
    3. Reis-Filho JS
    . Hereditary breast cancer: from molecular pathology to tailored therapies. J Clin Pathol 2008;61:1073–82.
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Claus EB,
    2. Risch NJ,
    3. Thompson WD
    . Age at onset as an indicator of familial risk of breast cancer. Am J Epidemiol 1990;131:961–72.
    OpenUrlAbstract/FREE Full Text
  6. ↵
    1. Jass JR
    . Hereditary non-polyposis colorectal cancer: the rise and fall of a confusing term. World J Gastroenterol 2006;12:4943–50.
    OpenUrlPubMed
  7. ↵
    1. Woods MO,
    2. Williams P,
    3. Careen A,
    4. et al
    . A new variant database for mismatch repair genes associated with Lynch syndrome. Hum Mutat 2007;28:669–73.
    OpenUrlCrossRefPubMed
  8. ↵
    1. Müller A,
    2. Edmonston TB,
    3. Corao DA,
    4. et al
    . Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res 2002;62:1014–9.
    OpenUrlAbstract/FREE Full Text
  9. ↵
    1. Vasen HF,
    2. Morreau H,
    3. Nortier JW
    . Is breast cancer part of the tumor spectrum of hereditary nonpolyposis colorectal cancer? Am J Hum Genet 2001;68:1533–5.
    OpenUrlCrossRefPubMed
  10. ↵
    1. de Leeuw WJ,
    2. van Puijenbroek M,
    3. Tollenaar RA,
    4. Cornelisse CJ,
    5. Vasen HF,
    6. Morreau H
    . Correspondence re: A. Müller et al., Exclusion of breast cancer as an integral tumor of hereditary nonpolyposis colorectal cancer. Cancer Res, 62:1014-1019, 2002. Cancer Res 2003;63:1148–9.
    OpenUrlFREE Full Text
  11. ↵
    1. Scott RJ,
    2. McPhillips M,
    3. Meldrum CJ,
    4. et al
    . Hereditary nonpolyposis colorectal cancer in 95 families: differences and similarities between mutation-positive and mutation-negative kindreds. Am J Hum Genet 2001;68:118–27.
    OpenUrlCrossRefPubMed
  12. ↵
    1. Oliveira Ferreira F,
    2. Napoli Ferreira CC,
    3. Rossi BM,
    4. et al
    . Frequency of extra-colonic tumors in hereditary nonpolyposis colorectal cancer (HNPCC) and familial colorectal cancer (FCC) Brazilian families: an analysis by a Brazilian Hereditary Colorectal Cancer Institutional Registry. Fam Cancer 2004;3:41–7.
    OpenUrlCrossRefPubMed
  13. ↵
    1. Shanley S,
    2. Fung C,
    3. Milliken J,
    4. et al
    . Breast cancer immunohistochemistry can be useful in triage of some HNPCC families. Fam Cancer 2009;8:251–5.
    OpenUrlCrossRefPubMed
  14. ↵
    1. Westenend PJ,
    2. Schutte R,
    3. Hoogmans MM,
    4. Wagner A,
    5. Dinjens WN
    . Breast cancer in an MSH2 gene mutation carrier. Hum Pathol 2005;36:1322–6.
    OpenUrlCrossRefPubMed
  15. ↵
    1. Barrow E,
    2. Robinson L,
    3. Alduaij W,
    4. et al
    . Cumulative lifetime incidence of extracolonic cancers in Lynch syndrome: a report of 121 families with proven mutations. Clin Genet 2009;75:141–9.
    OpenUrlCrossRefPubMed
  16. ↵
    1. Geary J,
    2. Sasieni P,
    3. Houlston R,
    4. et al
    . Gene-related cancer spectrum in families with hereditary non-polyposis colorectal cancer (HNPCC). Fam Cancer 2008;7:163–72.
    OpenUrlCrossRefPubMed
  17. ↵
    1. Lindor NM,
    2. Burgart LJ,
    3. Leontovich O,
    4. et al
    . Immunohistochemistry versus microsatellite instability testing in phenotyping colorectal tumors. J Clin Oncol 2002;20:1043–8.
    OpenUrlAbstract/FREE Full Text
  18. ↵
    1. Bergthorsson JT,
    2. Egilsson V,
    3. Gudmundsson J,
    4. Arason A,
    5. Ingvarsson S
    . Identification of a breast tumor with microsatellite instability in a potential carrier of the hereditary non-polyposis colon cancer trait. Clin Genet 1995;47:305–10.
    OpenUrlPubMed
  19. ↵
    1. Boyd J,
    2. Rhei E,
    3. Federici MG,
    4. et al
    . Male breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 1999;53:87–91.
    OpenUrlCrossRefPubMed
    1. Caluseriu O,
    2. Cordisco EL,
    3. Viel A,
    4. et al
    . Four novel MSH2 and MLH1 frameshift mutations and occurrence of a breast cancer phenocopy in hereditary nonpolyposis colorectal cancer. Hum Mutat 2001;17:521–5.
    OpenUrlPubMed
  20. ↵
    1. Risinger JI,
    2. Barrett JC,
    3. Watson P,
    4. Lynch HT,
    5. Boyd J
    . Molecular genetic evidence of the occurrence of breast cancer as an integral tumor in patients with the hereditary nonpolyposis colorectal carcinoma syndrome. Cancer 1996;77:1836–43.
    OpenUrlCrossRefPubMed
  21. ↵
    1. Siah SP,
    2. Quinn DM,
    3. Bennett GD,
    4. et al
    . Microsatellite instability markers in breast cancer: a review and study showing MSI was not detected at ‘BAT 25’ and ‘BAT 26’ microsatellite markers in early-onset breast cancer. Breast Cancer Res Treat 2000;60:135–42.
    OpenUrlCrossRefPubMed
  22. ↵
    1. Spagnoletti I,
    2. Pizzi C,
    3. Galietta A,
    4. et al
    . Loss of hMSH2 expression in primary breast cancer with p53 alterations. Oncol Rep 2004;11:845–51.
    OpenUrlPubMed
  23. ↵
    1. Newcomb PA,
    2. Baron J,
    3. Cotterchio M,
    4. et al
    . Colon Cancer Family Registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev 2007;16:2331–243.
    OpenUrlAbstract/FREE Full Text
  24. ↵
    1. Elston CW
    . The assessment of histological differentiation in breast cancer. Aust N Z J Surg 1984;54:11–5.
    OpenUrlCrossRefPubMed
  25. ↵
    1. Walsh MD,
    2. Cummings MC,
    3. Buchanan DD,
    4. et al
    . Molecular, pathologic, and clinical features of early-onset endometrial cancer: identifying presumptive Lynch syndrome patients. Clin Cancer Res 2008;14:1692–700.
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Poynter JN,
    2. Siegmund KD,
    3. Weisenberger DJ,
    4. et al
    . Molecular characterization of MSI-H colorectal cancer by MLHI promoter methylation, immunohistochemistry, and mismatch repair germline mutation screening. Cancer Epidemiol Biomarkers Prev 2008;17:3208–15.
    OpenUrlAbstract/FREE Full Text
  27. ↵
    1. Lakhani SR,
    2. Jacquemier J,
    3. Sloane JP,
    4. et al
    . Multifactorial analysis of differences between sporadic breast cancers and cancers involving BRCA1 and BRCA2 mutations. J Natl Cancer Inst 1998;90:1138–45.
    OpenUrlAbstract/FREE Full Text
  28. ↵
    1. Jönsson M,
    2. Johannsson O,
    3. Borg Å
    . Infrequent occurrence of microsatellite instability in sporadic and familial breast cancer. Eur J Cancer 1995;31A:2330–4.
    OpenUrlPubMed
    1. Lee SC,
    2. Berg KD,
    3. Sherman ME,
    4. Griffin CA,
    5. Eshleman JR
    . Microsatellite instability is infrequent in medullary breast cancer. Am J Clin Pathol 2001;115:823–7.
    OpenUrlAbstract/FREE Full Text
    1. Özer E,
    2. Yuksel E,
    3. Kizildag S,
    4. et al
    . Microsatellite instability in early-onset breast cancer. Pathol Res Pract 2002;198:525–30.
    OpenUrlCrossRefPubMed
  29. ↵
    1. Zhou XP,
    2. Hoang JM,
    3. Li YJ,
    4. et al
    . Determination of the replication error phenotype in human tumors without the requirement for matching normal DNA by analysis of mononucleotide repeat microsatellites. Genes Chromosomes Cancer 1998;21:101–7.
    OpenUrlCrossRefPubMed
  30. ↵
    1. Walsh T,
    2. Chappell SA,
    3. Shaw JA,
    4. Walker RA
    . Microsatellite instability in ductal carcinoma in situ of the breast. J Pathol 1998;185:18–24.
    OpenUrlCrossRefPubMed
  31. ↵
    1. Jeon HM,
    2. Lynch PM,
    3. Howard L,
    4. Ajani J,
    5. Levin B,
    6. Frazier ML
    . Mutation of the hMSH2 gene in two families with hereditary nonpolyposis colorectal cancer. Hum Mutat 1996;7:327–33.
    OpenUrlCrossRefPubMed
  32. ↵
    1. Jensen UB,
    2. Sunde L,
    3. Timshel S,
    4. et al
    . Mismatch repair defective breast cancer in the hereditary nonpolyposis colorectal cancer syndrome. Breast Cancer Res Treat 2009; Jul 3 [Epub ahead of print].
  33. ↵
    1. Stupart DA,
    2. Goldberg PA,
    3. Algar U,
    4. Ramesar R
    . Cancer risk in a cohort of subjects carrying a single mismatch repair gene mutation. Fam Cancer 2009;8:519–23.
    OpenUrlCrossRefPubMed
  34. ↵
    1. Schmitt FC,
    2. Soares R,
    3. Gobbi H,
    4. et al
    . Microsatellite instability in medullary breast carcinomas. Int J Cancer 1999;82:644–7.
    OpenUrlCrossRefPubMed
  35. ↵
    1. González-Aguilera JJ,
    2. Nejda N,
    3. Fernández FJ,
    4. et al
    . Genetic alterations and MSI status in primary, synchronous, and metachronous tumors in a family with hereditary nonpolyposis colorectal cancer (HNPCC). Am J Clin Oncol 2003;26:386–91.
    OpenUrlCrossRefPubMed
  36. ↵
    1. Müller A,
    2. Beyser K,
    3. Arps H,
    4. Bolander S,
    5. Becker H,
    6. Rüschhoff J
    . Genotype and phenotype of a new 2-bp deletion of hMSH2 at codon 233. Virchows Arch 2001;439:191–5.
    OpenUrlCrossRefPubMed
  37. ↵
    1. Yee CJ,
    2. Roodi N,
    3. Verrier CS,
    4. Parl FF
    . Microsatellite instability and loss of heterozygosity in breast cancer. Cancer Res 1994;54:1641–4.
    OpenUrlAbstract/FREE Full Text
  38. ↵
    1. Cederquist K,
    2. Emanuelsson M,
    3. Wiklund F,
    4. Golovleva I,
    5. Palmqvist R,
    6. Grönberg H
    . Two Swedish founder MSH6 mutations, one nonsense and one missense, conferring high cumulative risk of Lynch syndrome. Clin Genet 2005;68:533–41.
    OpenUrlPubMed
  39. ↵
    1. Jenkins MA,
    2. Hayashi S,
    3. O'Shea AM,
    4. et al
    . Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007;133:48–56.
    OpenUrlCrossRefPubMed
  40. ↵
    1. Young J,
    2. Simms LA,
    3. Biden KG,
    4. et al
    . Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 2001;159:2107–16.
    OpenUrlCrossRefPubMed
  41. ↵
    1. Plaschke J,
    2. Kruppa C,
    3. Tischler R,
    4. et al
    . Sequence analysis of the mismatch repair gene hMSH6 in the germline of patients with familial and sporadic colorectal cancer. Int J Cancer 2000;85:606–13.
    OpenUrlCrossRefPubMed
  42. ↵
    1. Ford D,
    2. Easton DF,
    3. Bishop DT,
    4. Narod SA,
    5. Goldgar DE
    . Risks of cancer in BRCA1-mutation carriers. Breast Cancer Linkage Consortium. Lancet 1994;343:692–5.
    OpenUrlCrossRefPubMed
    1. Cannon-Albright LA,
    2. Thomas A,
    3. Goldgar DE,
    4. et al
    . Familiality of cancer in Utah. Cancer Res 1994;54:2378–85.
    OpenUrlAbstract/FREE Full Text
  43. ↵
    1. Hemminki K,
    2. Vaittinen P
    . Familial risks in in situ cancers from the Family-Cancer Database. Cancer Epidemiol Biomarkers Prev 1998;7:865–8.
    OpenUrlAbstract
  44. ↵
    1. Dong C,
    2. Hemminki K
    . Second primary neoplasms in 633,964 cancer patients in Sweden, 1958-1996. Int J Cancer 2001;93:155–61.
    OpenUrlCrossRefPubMed
PreviousNext
Back to top
Clinical Cancer Research: 16 (7)
April 2010
Volume 16, Issue 7
  • Table of Contents
  • Table of Contents (PDF)
  • About the Cover

Sign up for alerts

View this article with LENS

Open full page PDF
Article Alerts
Sign In to Email Alerts with your Email Address
Email Article

Thank you for sharing this Clinical Cancer Research article.

NOTE: We request your email address only to inform the recipient that it was you who recommended this article, and that it is not junk mail. We do not retain these email addresses.

Enter multiple addresses on separate lines or separate them with commas.
Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry
(Your Name) has forwarded a page to you from Clinical Cancer Research
(Your Name) thought you would be interested in this article in Clinical Cancer Research.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
Citation Tools
Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry
Michael D. Walsh, Daniel D. Buchanan, Margaret C. Cummings, Sally-Ann Pearson, Sven T. Arnold, Mark Clendenning, Rhiannon Walters, Diane M. McKeone, Amanda B. Spurdle, John L. Hopper, Mark A. Jenkins, Kerry D. Phillips, Graeme K. Suthers, Jill George, Jack Goldblatt, Amanda Muir, Kathy Tucker, Elise Pelzer, Michael R. Gattas, Sonja Woodall, Susan Parry, Finlay A. Macrae, Robert W. Haile, John A. Baron, John D. Potter, Loic Le Marchand, Bharati Bapat, Stephen N. Thibodeau, Noralane M. Lindor, Michael A. McGuckin and Joanne P. Young
Clin Cancer Res April 1 2010 (16) (7) 2214-2224; DOI: 10.1158/1078-0432.CCR-09-3058

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Lynch Syndrome–Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry
Michael D. Walsh, Daniel D. Buchanan, Margaret C. Cummings, Sally-Ann Pearson, Sven T. Arnold, Mark Clendenning, Rhiannon Walters, Diane M. McKeone, Amanda B. Spurdle, John L. Hopper, Mark A. Jenkins, Kerry D. Phillips, Graeme K. Suthers, Jill George, Jack Goldblatt, Amanda Muir, Kathy Tucker, Elise Pelzer, Michael R. Gattas, Sonja Woodall, Susan Parry, Finlay A. Macrae, Robert W. Haile, John A. Baron, John D. Potter, Loic Le Marchand, Bharati Bapat, Stephen N. Thibodeau, Noralane M. Lindor, Michael A. McGuckin and Joanne P. Young
Clin Cancer Res April 1 2010 (16) (7) 2214-2224; DOI: 10.1158/1078-0432.CCR-09-3058
del.icio.us logo Digg logo Reddit logo Twitter logo CiteULike logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Abstract
    • Patients and Methods
    • Results
    • Discussion
    • Disclosure of Potential Conflicts of Interest
    • Acknowledgments
    • Footnotes
    • References
  • Figures & Data
  • Info & Metrics
  • PDF
Advertisement

Related Articles

Cited By...

More in this TOC Section

  • BRCA1/2 Aberrant Splicing in Breast/Ovarian Cancer
  • Mesalazine and MSI in TGFBR2
Show more Susceptibility and Prevention
  • Home
  • Alerts
  • Feedback
  • Privacy Policy
Facebook  Twitter  LinkedIn  YouTube  RSS

Articles

  • Online First
  • Current Issue
  • Past Issues
  • CCR Focus Archive
  • Meeting Abstracts

Info for

  • Authors
  • Subscribers
  • Advertisers
  • Librarians

About Clinical Cancer Research

  • About the Journal
  • Editorial Board
  • Permissions
  • Submit a Manuscript
AACR logo

Copyright © 2021 by the American Association for Cancer Research.

Clinical Cancer Research
eISSN: 1557-3265
ISSN: 1078-0432

Advertisement