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Cancer genetics
Original article
Association between the Lynch syndrome gene MSH2 and breast cancer susceptibility in a Canadian familial cancer registry
  1. Mira Goldberg1,
  2. Kathleen Bell1,
  3. Melyssa Aronson2,
  4. Kara Semotiuk2,
  5. Greg Pond1,
  6. Steven Gallinger3,
  7. Kevin Zbuk1
  1. 1 Department of Oncology, McMaster University, Hamilton, Canada
  2. 2 Zane Cohen Centre for Digestive Diseases, Mount Sinai Hospital, Toronto, Canada
  3. 3 Division of Hepatobiliary and Pancreatic Surgical Oncology, Toronto General Hospital, Toronto, Canada
  1. Correspondence to Dr Mira Goldberg, Division of Radiation Oncology, Juravinski Cancer Centre, Hamilton L8V5C2, Canada; mirabgoldberg{at}gmail.com

Abstract

Background Previous studies assessing breast cancer risk in families with Lynch syndrome (LS) have yielded conflicting results. Furthermore, conclusions are limited by small sample size and few breast cancer outcomes. This study assesses breast cancer risk in a large prospectively followed LS cohort.

Methods Pedigrees of 325 unrelated families with LS within the Familial Gastrointestinal Cancer Registry in Canada were examined for breast cancer diagnoses. Standardised incidence ratios (SIR) and lifetime cumulative incidence calculations were used to compare the incidence of breast cancer in mutation carriers with the general population.

Results Forty-one mutation carriers diagnosed with breast cancer belonging to 34 unrelated families were identified. Mean age at diagnosis was 54 years. The mutation distribution among the LS patients with breast cancer was statistically different from those without breast cancer (p=0.015), reflecting the predominance of MSH2 mutations among affected patients (74%). Eighty-eight per cent of LS families with breast cancer met Amsterdam criteria, compared with 49% of LS families without breast cancer (p=0.03). Lifetime cumulative incidence of breast cancer in female MSH2 mutation carriers in our cohort was 22% (p<0.001). The SIR for breast cancer of female MSH2 mutation carriers in our cohort was 3.11 (95% CI 1.95 to 4.71).

Conclusions An increased risk of breast cancer in MSH2 mutation carriers was demonstrated in a Canadian familial cancer registry. Women with breast cancer often had a personal and family history of multiple LS-related malignancies. These results suggest a potential role for intensified breast cancer surveillance among women with LS.

  • lynch syndrome
  • breast cancer
  • hereditary nonpolyposis colorectal cancer
  • MSH2
  • mismatch repair mutation

https://doi.org/10.1136/jmedgenet-2017-104542

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    Introduction

    Initially described by Henry Lynch in 1966,1Lynch syndrome (LS) is an autosomal dominant cancer predisposition syndrome characterised by an increased lifetime risk of multiple malignancies at a young age. The principal germline mutations are in the DNA mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. These genes were identified in the early 1990s, shortly after the discovery of microsatellite instability (MSI) in colorectal tumours of families with LS. Subsequent to these developments, the spectrum of LS-related malignancies has expanded over the past two decades. Well-established associations have been demonstrated for colorectal, endometrial, ovarian, genitourinary, gastric, small intestine, hepatobiliary, sebaceous and central nervous system malignancies. However, the association of LS with breast cancer risk remains controversial, and as such breast cancer is currently not recognised as a LS-related malignancy. The results of studies examining the association between breast cancer and LS have yielded inconsistent results. Several retrospective reports have demonstrated no association,2–7 while other studies are suggestive of an association between breast cancer and LS.8–16 Much of this literature is composed of retrospective studies with small sample size, as well as case reports or small case series that are uncontrolled and lack statistical power.

    Two prospective studies exploring the association of LS with breast cancer demonstrated an increased risk in mutation carriers. However, these too are limited by few breast cancer events or short follow-up.17 18 Finally, a recent systematic review did report an increased risk of breast cancer associated with LS, ranging from 2-fold to 18-fold compared with non-mutation carriers, based on data from 8 of 21 studies.19

    Several studies have identified MSI, the molecular hallmark of LS-related malignancies, in breast tumours from known MMR mutation carriers.20–25 When all studies were combined, 51% (95% CI 42% to 60%) exhibited MSI.19 These molecular studies provide ancillary evidence that a subset of breast cancers in patients with LS may be directly related to deficient MMR gene function.

    Further clarification of the association between breast cancer and LS is critically important given the rapid uptake of multigene panel testing in clinical cancer genetics. Such panels very often include the MMR genes, and panel testing is used in individuals with diverse cancer histories, including those with a personal or family history of breast cancer. Panel testing has therefore increased the identification of MMR gene mutations in a subset of individuals who may not otherwise meet clinical criteria for LS based on their personal or family history of malignancy. As an illustration, of 145 patients identified to carry MMR gene mutations using multigene panel testing, 19.3% did not meet the National Comprehensive Cancer Network (NCCN) guidelines for LS testing.26 Further data demonstrating an association between breast cancer and LS will assist clinicians in the interpretation of ‘incidental’ MMR gene mutations discovered through panel testing.

    Finally, establishing a clear association between LS and breast cancer would likely result in recommendations for heightened breast cancer surveillance in MMR gene mutation carriers. Established surveillance strategies in families with LS, such as regular colonoscopic surveillance, have been associated with improved overall and cancer-specific survival.27 Similarly, effective screening and prevention strategies are available for managing breast cancer risk in high-risk populations such as those with BRCA1/2 mutations.28

    The current study explores the association between breast cancer and LS in a large familial colorectal cancer registry. Given the large number of breast cancer events in this study compared with other publications, this report contributes to an area of controversy within the literature where replication would be required to elucidate an association between breast cancer and LS. Furthermore, this analysis is the first to examine the association between breast cancer risk and family history of LS-related malignancies (Amsterdam criteria) in families with LS. The Familial Gastrointestinal Cancer Registry (FGICR), established in 1980 in Toronto, Ontario, is a pan-Canadian initiative dedicated to the prevention of inherited gastrointestinal cancers, patient education and research. The patient database used for this work was initiated in 1998.

    Methods

    The FGICR is a consolidated registry of Canadian families with LS and other gastrointestinal cancer predisposition syndromes. Patient enrolment in the FGICR and subsequent genetic testing is based on physician referral for genetic counselling. Eligibility for referral to the registry includes individuals from families with known MMR mutations, personal or family history of multiple cases of LS-related cancers (colorectal, endometrial, small bowel, ureter, kidney, stomach, ovarian, pancreatic, brain, hepatobiliary, sebaceous adenoma/carcinoma), with at least one relative with colorectal or endometrial cancer, or an individual diagnosed with colorectal cancer before age 35. After appropriate institutional review board approval, all pedigrees of unrelated families with LS within the FGICR database were screened retrospectively for breast cancer events. Our analysis was limited to carriers of MMR gene mutations, enrolled in the registry prior to study inception in January 2013. Clinic records and pedigrees of affected individuals were reviewed. Verbal reporting by family members of breast cancer diagnosis and birth or death dates were accepted; however, details were verified whenever possible with medical and pathology reports. BRCA1/2 mutation testing results were collected when available.

    Descriptive and χ2 statistics were used to investigate the potential association between all MMR mutation carriers and breast cancer. Pathogenic BRCA1/2 mutation carriers and their family members were excluded from all analyses to limit potential bias.

    The primary goal of this study was to investigate the incidence rate of breast cancer among known MSH2 mutation carriers (74% of mutation carriers with breast cancer in our cohort), and contrast that with non-carriers. Since the population of non-carriers could not be strictly defined, the comparator population used was the general Canadian population, of which non-carriers would make up the overwhelming majority.

    All known MSH2 carriers (both with and without breast cancer diagnoses) were included if they were alive and 20 years of age or older between 1997 (the year in which clinical testing for LS was first available) and December 2012 (the final full month before this project was initiated). Patients diagnosed with breast cancer prior to 1997 would have been unlikely to have had MMR testing at the time of this diagnosis, since testing was not yet readily available in Canada. However, the FGICR was established well before clinical or research testing for mutations in the MMR genes was available. A contemporary criterion for enrolment of families to the FGICR database is harbouring a known pathogenic variant in an MMR gene. Therefore, to control for heterogeneity within the composition of families recruited prior to and after the clinical availability of MMR gene testing, we limited the analysis to patients diagnosed with breast cancer after 1997.

    The incidence rate among this group was then calculated as the number of patients diagnosed with breast cancer within this time period, divided by the cumulative patient-years of follow-up for those patients with included events (until last known follow-up, death or the end of December 2012). The expected number of breast cancers from the general population was then calculated assuming a cohort of similar numbers and ages from the general Canadian population over the same time period. General population data from 1997 to 2010 (the last year with data available; for simplicity, 2011 and 2012 general population data was assumed to be the same as in 2010) were obtained from Statistics Canada.29 A standardised incidence ratio (SIR) was then calculated by taking the ratio of these two estimates (observed incidence rate/expected incidence rate). SIR calculations, p values and Confidence Intervals were performed following the methods of Kulkarni et al. 30

    As an exploratory analysis, we extended the dates of interest to 1992 (5 years prior to the availability of MMR gene mutation testing, where 1992 is the earliest date for which we were able to obtain general population data from Statistics Canada) and undertook a second SIR calculation (1992–2012).

    Results

    The study population consisted of 325 unrelated families with LS. Only families with confirmed deleterious MMR gene mutations were included in the analysis. Of these 325 families, 149 were MSH2 carriers (46%), 113 MLH1 (35%), 38 MSH6 (12%), 19 PMS2 (5%) and 6 EPCAM (2%) carriers.

    Forty-one female mutation carriers from 34 unrelated families, with a diagnosis of breast cancer, were included in our analysis (figure 1). No male breast cancers were identified. The mean and median age of breast cancer diagnosis was 54 (age range, 30–83), with 16 women (39%) diagnosed with breast cancer before the age of 50.

    Figure 1
    Figure 1

    Consort diagram of individual women included in descriptive and χ2 analyses. MMR, mismatch repair.

    The majority of families were of Caucasian descent (53%), and only two families were of Ashkenazi Jewish heritage. These two Ashkenazi Jewish families were confirmed BRCA1/2 negative. The specific mutation present in each individual/family is describedin the online supplementary table S1.

    Supplementary file 1

    p1

    SIR and cumulative breast cancer risk calculations were performed using only the MSH2 mutation carriers, given the paucity of non-MSH2 mutation carriers with breast cancer (n=10 for MLH1, MSH6 and PMS2 combined, figure 2). Twenty-two MSH2 mutation carrier females with a diagnosis of breast cancer, and 217 MSH2 mutation carrier females unaffected by breast cancer were eligible for a SIR analysis (figure 2). There was a cumulative 2883.36 years of follow-up between 1997 and 2012, which is an incidence rate of 7.63 diagnoses/1000 years of follow-up. In comparison, one would expect to observe 7.10 breast cancer events in a similar cohort of women during this time period in the general Canadian Population, resulting in an SIR of 3.11 (95% CI 1.95 to 4.71). A cumulative lifetime risk of breast cancer in our female MSH2 carriers was found to be 22% (95% CI 13% to 31%) (figure 3). Extending follow-up to 1992, the earliest date for which we could obtain general population data, allowed for an additional four breast cancer diagnoses to be observed over an additional 1052.2 years of follow-up. This results in an incidence rate of 6.6 diagnoses/1000 years of follow-up. In the general Canadian population, one would have expected 8.41 breast cancer events, resulting in an SIR of 3.09 (95% CI 2.02 to 4.53).

    Figure 2
    Figure 2

    Consort diagram of individual women included in SIR calculations for breast cancer. **Only 10 individual carriers of MLH1, PMS2 and MSH6 mutations who were affected by breast cancer were excluded from this SIR analysis. SIR, standardised incidence ratio.

    Figure 3
    Figure 3

    Cumulative lifetime risk of breast cancer in female MSH2 mutation carriers.

    We analysed all pedigrees to explore any potential influence of hereditary breast cancer risk arising from the side of the family unaffected by LS. Only 2 of 24 pedigrees were determined to have a family history of breast cancer in the lineage not affected by LS. These included one family with an MLH1 mutation, and the other with an MSH2 mutation. In the MLH1 carrier family, however, breast pathology confirmed an MSI high and MLH1/PMS2-deficient breast cancer. These findings suggest that hereditary influences, other than LS, were unlikely to contribute significantly to breast cancer risk in our patient cohort.

    When the mutation distribution among the families of LS patients with breast cancer was compared with the distribution among the remaining families in the registry using a χ2 test, the distributions were significantly different (p=0.015), reflecting the predominance of MSH2 mutations (25/34, 74%, 95% CI 56% to 87%) among patients with breast cancer in the study population (compared with 20% MLH1, 3% MSH6 and 3% PMS2 carrier families). Furthermore, 30 of 34 LS families with breast cancer met Amsterdam criteria (88%), compared with 143/291 (49%) of LS families without breast cancer within the registry (p=0.03).

    Seventy-one per cent (95% CI 54% to 84%) of women with breast cancer had an additional LS-related malignancy, with a mean of 1.6 (range 0–8) additional manifestations per patient. The number of women with each additional malignancy and the total number of each diagnosis among these women is shown in figure 4. Breast cancer was the initial diagnosis in 41% (n=17) of women. Of the pathology reports available for review, 50% (11/22) were high grade (grade 3). Of specimens with completed MSI testing, 60% (6/10) exhibited high MSI, including five of seven high grade tumours.

    Figure 4
    Figure 4

    Number of women with each Lynch syndrome-related malignancy and total number of each diagnosis, in patients affected by breast cancer.  CNS, central nervous system.

    Discussion

    The current study demonstrated an increased incidence of breast cancer in Canadian MSH2 mutation carriers compared with the general Canadian population (SIR: 3.11 (95% CI 1.95 to 4.71)). The SIR is similar to that demonstrated in a prospective cohort (SIR:3.95 (95% CI 1.59 to 8.13; p=0.001)), of which 50% were MSH2 mutation carriers.17 The cumulative risk of a female MSH2 mutation carrier developing breast cancer in her lifetime was found to be 22% in our study, double the quoted 11% lifetime risk in the general Canadian female population.31 A similar cumulative risk of breast cancer among mutation carriers was demonstrated by Engel et al.8 The American Cancer Society and NCCN guidelines recommend MRI screening for women whose lifetime risk of breast cancer is 20% or greater.32 33 Mean age of breast cancer diagnosis was also younger than cases in the general Canadian population, with 39% of the women diagnosed prior to age 50 in our study, compared with only 18% of cases diagnosed prior to age 50 in the general Canadian population.31 This suggests a possible role for initiation of intensified breast cancer screening at a younger age in patients with LS, similar to that recommended for other hereditary conditions with a confirmed increased risk of breast cancer.32 Further confirmatory studies are required before intensified breast cancer surveillance can be routinely recommended in patients with LS.

    We have demonstrated an over-representation of MSH2 mutation carriers in women affected by breast cancer in our study (p=0.015), which has similarly been demonstrated in two separate reports.10 21 Furthermore, MSH2 mutation carriers have been previously shown to have an increased lifetime risk of developing an LS-related malignancy at any site,34 compared with carriers of other MMR mutations. In contrast, several other publications have demonstrated an increased risk of breast cancer associated with MLH1 mutations carriers but not MSH2 mutation carriers.9 18 35 However, our study includes a greater number of MMR mutation carriers or breast cancer events in known mutation carriers, thus strengthening the statistical power. Furthermore, some studies included first-degree relatives with unknown mutation status,18 35 and mutation negative probands.9 It is therefore possible that interstudy heterogeneity with respect to MMR gene mutation distribution, coupled with small sample size, might account for the discordance in the literature with respect to gene-specific risk of breast cancer.2–16

    To the best of our knowledge, our study is the first to compare fulfilment of Amsterdam criteria among LS families with and without breast cancer. A greater proportion of women with breast cancer came from families that met Amsterdam criteria compared with the remaining registry population (p=0.03), suggesting that breast cancer is common among families with high penetrance for LS-related malignancies. That said, breast cancer was the incident cancer in 41% of patients in our series of MMR mutation carriers. Given the increased utilisation of multigene panel testing, this finding will become increasingly relevant, as a subset of patients will be found to have MMR gene mutations without the ‘classic’ phenotype of LS.26 36

    Our study is limited by a dataset that relied on patient reported cancer diagnoses when pathology and clinical records were unavailable. Furthermore, due to incomplete pathology records we are unable to make conclusions regarding the pathological features of breast cancer in MMR mutation carriers. Additional limitations of our study include its retrospective nature, the small number of breast cancer cases in LS carriers of genes other than MSH2 and a lack of data on wild-type family members to use as a comparator. However, as breast cancer is not an established LS-associated malignancy, women in the registry would not have qualified for intensified breast cancer screening, nor would they have been enrolled in the registry based on a personal or family history of breast cancer, thus limiting ascertainment bias within the FGICR. Furthermore, a review of the pedigrees for a family history of breast cancer on the lineage unaffected by LS demonstrated that possible hereditary influences, other than LS, were unlikely to contribute significantly to breast cancer risk in these families.

    Despite limitations, our finding of an increased risk of breast cancer in MSH2 mutation carriers adds to a growing body of literature to suggest breast cancer susceptibility as a component of LS. These findings suggest that female MSH2 mutation carriers should, at least, be encouraged to participate in population-based breast cancer screening programmes. Further prospective attempts to quantify the risks, benefits and cost-effectiveness of intensified breast cancer surveillance or preventative strategies in LS populations are required to inform future guidelines and recommendations.

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    Footnotes

    • Contributors MG contributed to the conception of study design, data acquisition and analysis, manuscript writing and manuscript submission. KB contributed to conception of study design, data acquisition and analysis, manuscript editing and final approval. MA and KS contributed to data acquisition and interpretation, as well as manuscript editing and final approval of the manuscript. GP contributed to data analysis and interpretation, manuscript writing and revisions, as well as finalising the submitted draft. SG contributed to the conception of the work and approving the final draft prior to submission. KZ contributed to the conception of study design, data acquisition and analysis, manuscript writing, revisions and approval for final submissions. MG and KZ are responsible for the overall content as guarantors.

    • Competing interests None declared

    • Patient consent Obtained.

    • Provenance and peer review Not commissioned; externally peer reviewed.