Abstract

Lynch syndrome is the predisposition to visceral malignancies that are associated with deleterious germline mutations in DNA mismatch repair genes, including MLH1 , MSH2 , MSH6 , and PMS2 . Muir-Torre syndrome is a variant of Lynch syndrome that includes a predisposition to certain skin tumors. We determined the frequency of Muir-Torre syndrome among 50 Lynch syndrome families that were ascertained from a population-based series of cancer patients who were newly diagnosed with colorectal or endometrial carcinoma. Histories of Muir-Torre syndrome–associated skin tumors were documented during counseling of family members. Muir-Torre syndrome was observed in 14 (28%) of 50 families and in 14 (9.2%) of 152 individuals with Lynch syndrome. Four (44%) of nine families with MLH1 mutations had a member with Muir-Torre syndrome compared with 10 (42%) of 24 families with MSH2 mutations ( P = .302). Families who carried the c.942+3A>T MSH2 gene mutation had a higher frequency of Muir-Torre syndrome than families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026). Muir-Torre syndrome was not found in families with mutations in the MSH6 or PMS2 genes. Our results suggest that Muir-Torre syndrome is simply a variant of Lynch syndrome. Screening for Muir-Torre syndrome–associated skin lesions among patients with Lynch syndrome is recommended.

CONTEXT AND CAVEATS
Prior knowledge

Some individuals with Lynch syndrome—an inherited predisposition to develop colorectal and other specific cancers—also have a tendency to develop certain kinds of skin tumors (ie, Muir-Torre syndrome). Cancerous lesions associated with both syndromes are characterized by inherited deleterious mutations in DNA mismatch repair (MMR) genes, including MSH2 .

Study design

A cohort study to examine the frequency of Muir-Torre syndrome–related skin tumors among 50 Lynch syndrome families (confirmed by MMR gene mutation analysis) who were ascertained from a population-based series of patients newly diagnosed with colorectal or endometrial cancer.

Contribution

Muir-Torre syndrome was observed in 28% of the 50 families and in 9.2% of the 152 individuals with Lynch syndrome. The frequency of Muir-Torre syndrome was 75% among families who carried a specific deleterious mutation in the MSH2 gene vs 25% among families who carried other mutations in this gene.

Limitations

There was a preponderance of the Muir-Torre syndrome–associated deleterious MSH2 gene mutation in the study cohort. Histories of skin lesions may have been subject to recall bias.

Implications

Patients with Lynch syndrome should be screened for Muir-Torre syndrome–associated skin lesions.

Lynch syndrome (or hereditary nonpolyposis colorectal cancer) predisposes individuals to develop colorectal cancer and other visceral malignancies that are associated with germline mutations in the DNA mismatch repair (MMR) genes MLH1 , MSH2 , MSH6 , and PMS2 . Lynch syndrome–related cancers are characterized molecularly by microsatellite instability ( 1 ) and by deleterious mutations in the MMR genes ( 2 ).

Lynch syndrome also predisposes some individuals to develop cutaneous malignancies, including sebaceous gland tumors and keratoacanthomas of the skin, in addition to visceral malignancies ( 3 ). Individuals who develop these dermatologic tumors and one or more visceral malignancies associated with Lynch syndrome are considered to have Muir-Torre syndrome ( 4 ). Muir-Torre syndrome–associated skin lesions are characterized by microsatellite instability ( 5–7 ) and the absence of MMR protein expression as determined by immunohistochemical staining ( 8 , 9 ), suggesting that these tumors are molecularly similar to other Lynch syndrome–associated tumors ( 10–13 ).

The incidence of Muir-Torre syndrome is low: one of the largest reviews of the literature found that only 205 cases had been reported worldwide through 1999 ( 14 ). In one retrospective population-based analysis ( 15 ), 5.8% of individuals who presented with Muir-Torre syndrome–associated skin lesions (of whom 13.9% presented with sebaceous tumors and 2.4% presented with keratoacanthomas) were found to have a history of visceral malignancy on further chart review.

To our knowledge, only one study ( 16 ) has examined the incidence of Muir-Torre syndrome among families with Lynch syndrome. The authors reported that approximately 9% of their cohort of Lynch syndrome families had a family member who had Muir-Torre syndrome. Because the incidence of Muir-Torre syndrome was much larger than expected in this study, we examined the frequency of Muir-Torre syndrome–associated skin lesions in our cohort of families with Lynch syndrome (confirmed by MMR gene mutation analysis), which was ascertained from a population-based series of cancer patients.

Probands were identified from among all patients who were newly diagnosed with colorectal or endometrial adenocarcinoma at six hospitals in Columbus, Ohio, from April 1999 through September 2006. The six hospitals participating in the study were The Ohio State University Medical Center, Riverside Methodist Hospital, Grant Medical Center, Saint Ann’s Hospital, Mount Carmel East Hospital, and Mount Carmel West Hospital. The Ohio State University Medical Center is a university-based facility, and the other five hospitals represent two private health-care systems; these six institutions perform the vast majority of surgical procedures for colorectal and endometrial cancer in the Columbus, Ohio, metropolitan area (population = 1.5 million). The research protocol and consent form were approved by the institutional review board at each participating hospital, and all patients provided written informed consent.

Eligible patients were approached about participating in this study, and written informed consent was obtained. Each patient provided family history information and a 10- to 20-mL EDTA–blood sample and allowed us to obtain a paraffin-embedded sample of their colorectal or endometrial tumor from the pathology department of the treating institution. DNA and RNA were extracted from the blood sample by standard methods. The histology of the tumor was reevaluated, an area containing tumor cells was marked on the block, and the percentage of tumor cells was determined. Material from the tumor and adjacent normal tissue was obtained by microdissection of paraffin-embedded samples. All tumors underwent microsatellite instability testing, which involved genotyping five or six (the D17S250 marker was not run on all specimens) polymorphic markers (BAT25, BAT26, D2S123, D5S346, D18S69, and/or D17S250) in tumor and unaffected tissue (blood or colon). Microsatellite instability was scored positive when an allele was present in the tumor but not in unaffected tissue at two or more of the markers. To search for germline mutations, DNA (from blood or occasionally from normal colon tissue) was directly sequenced using oligonucleotide primers as previously described ( 17 ).

Those individuals who were found to have Lynch syndrome based on positive results of molecular testing for the presence of a germline mutation in an MMR gene were subsequently referred for genetic counseling. At-risk family members were referred for genetic counseling as well, and, when appropriate, they were also tested for germline mutations in Lynch syndrome–associated DNA MMR genes using EDTA-preserved blood samples. During genetic counseling sessions, individuals were questioned about their personal and family histories of sebaceous gland tumors and keratoacanthomas. No dermatologic exams were performed as part of the study.

Patients who had a deleterious germline mutation in an MMR gene and who reported a history of a sebaceous gland tumor and/or a keratoacanthoma were defined as having Muir-Torre syndrome, even if they had not been diagnosed with a visceral malignancy. We attempted to obtain the pathology reports confirming the diagnosis of the skin lesions and tissue samples for these patients. We obtained samples of skin tumors for two patients and performed immunohistochemistry to examine the expression of the MLH1, MSH2, MSH6, and PMS2 proteins on formalin-fixed, paraffin-embedded tissue, as previously described ( 18 ), using the following primary mouse monoclonal antibodies: MLH1 (1:10 dilution, BD Biosciences Pharmingen, San Diego, CA), MSH2 (1:200 dilution, EMD Biosciences, La Jolla, CA), MSH6/GTBP (1:300 dilution, BD Biosciences Pharmingen), and PMS2 (C20; 1:400 dilution, Santa Cruz Biotechnology, Santa Cruz, CA, or 1:50 dilution, BD Biosciences Pharmingen). Positive and negative controls (colorectal adenocarcinoma tissue from individuals with known deleterious germline mutations of MMR genes and normal colonic mucosa, respectively) stained appropriately, and any convincing nuclear staining was considered to be positive.

Fisher's exact test was used to compare the frequency of Muir-Torre syndrome among Lynch syndrome families with germline mutations in MLH1 , MSH2 , and/or MSH6 and between Lynch syndrome families with the c.942+3A>T mutation in MSH2 and Lynch syndrome families with other mutations in MSH2 . All statistical tests were two-sided.

Of the 50 Lynch syndrome families we identified, 14 (28%) had one family member who had a history of a Muir-Torre syndrome–related tumor. The overall frequency of Muir-Torre syndrome among the 152 Lynch syndrome family members who carried a deleterious mutation in one of the MMR genes was 9.2%.

Four (44%) of the nine families who were found to carry a deleterious germline mutation in the MLH1 gene had a family member with Muir-Torre syndrome ( Table 1 ). Two (50%) of the four individuals with Muir-Torre syndrome had been diagnosed with a skin malignancy before they were diagnosed with a visceral malignancy. Immunohistochemical analysis of skin tumor tissue that was available for proband 4 revealed the loss of expression of the MLH1 and PMS2 gene products (data not shown).

Table 1

MLH1 gene mutation–positive family members with Muir-Torre syndrome

Proband Relationship of mutation-positive family member to proband Sex of mutation-positive family member MLH1 gene mutation in family  Skin diagnosis (age, y) Visceral malignancy diagnosis (age, y) 
Maternal uncle Male c.1778_1779delCA Sebaceous carcinoma (61) Colorectal (43,55) 
Brother Male c.1852_1854delAAG Sebaceous adenoma (50s) Rectal (33), colon (43) 
Self Female Exon 16–19 deletion Sebaceous carcinoma (47) Colon (49) 
Self Female c.1489delC Keratoacanthoma (39),  sebaceous adenoma (39) Colon (46) 
Proband Relationship of mutation-positive family member to proband Sex of mutation-positive family member MLH1 gene mutation in family  Skin diagnosis (age, y) Visceral malignancy diagnosis (age, y) 
Maternal uncle Male c.1778_1779delCA Sebaceous carcinoma (61) Colorectal (43,55) 
Brother Male c.1852_1854delAAG Sebaceous adenoma (50s) Rectal (33), colon (43) 
Self Female Exon 16–19 deletion Sebaceous carcinoma (47) Colon (49) 
Self Female c.1489delC Keratoacanthoma (39),  sebaceous adenoma (39) Colon (46) 

Ten (42%) of 24 families who were found to carry deleterious germline MSH2 mutations had a family member with Muir-Torre syndrome ( Table 2 ). Four (40%) of the 10 individuals with Muir-Torre syndrome had been diagnosed with a skin malignancy before they were diagnosed with a visceral malignancy, and one individual was diagnosed concurrently with skin and visceral malignancies. Immunohistochemical analysis of skin tumor tissue that was available for proband 8 revealed a loss of expression of MSH2 gene products and decreased expression of the MSH6 gene product compared with the adjacent normal tissue (data not shown).

Table 2

MSH2 gene mutation–positive family members with Muir-Torre syndrome

Proband Relation ship of mutation-positive family member to proband Sex of mutation-positive family member MSH2 gene mutation in family  Skin diagnosis (age, y) Visceral malignancy diagnosis (age, y) 
Self Male c.1147C>T Sebaceous adenoma (55) Colon (51) 
Brother * Male c.2038C>T Sebaceous adenoma (53, 54) None in proband, brother— colon (57) 
Self Male c.587delC Sebaceous adenoma (49) Small bowel (33), colorectal (45) 
Father † Male c.942+3A>T Keratoacanthoma (57) None in proband, daughter—colon (63) 
Maternal great uncle † Male c.942+3A>T Keratoacanthoma (41) Colon (41) 
Brother Male c.942+3A>T Sebaceous adenoma (57) Ureter transitional cell (53) 
Sister Female c.942+3A>T Sebaceous adenoma (42) Uterine (43), colon (47) 
Self Female c.942+3A>T Keratoacanthoma (63) Endometrial (64), colon (71) 
Self Male c.942+3A>T Keratoacanthoma (56) Colon (58) 
10 Self Male Exon 1–6, deletion Keratoacanthoma (50) Colon (60) 
Proband Relation ship of mutation-positive family member to proband Sex of mutation-positive family member MSH2 gene mutation in family  Skin diagnosis (age, y) Visceral malignancy diagnosis (age, y) 
Self Male c.1147C>T Sebaceous adenoma (55) Colon (51) 
Brother * Male c.2038C>T Sebaceous adenoma (53, 54) None in proband, brother— colon (57) 
Self Male c.587delC Sebaceous adenoma (49) Small bowel (33), colorectal (45) 
Father † Male c.942+3A>T Keratoacanthoma (57) None in proband, daughter—colon (63) 
Maternal great uncle † Male c.942+3A>T Keratoacanthoma (41) Colon (41) 
Brother Male c.942+3A>T Sebaceous adenoma (57) Ureter transitional cell (53) 
Sister Female c.942+3A>T Sebaceous adenoma (42) Uterine (43), colon (47) 
Self Female c.942+3A>T Keratoacanthoma (63) Endometrial (64), colon (71) 
Self Male c.942+3A>T Keratoacanthoma (56) Colon (58) 
10 Self Male Exon 1–6, deletion Keratoacanthoma (50) Colon (60) 
*

Denotes presumed mutation carrier.

Denotes obligate mutation carrier.

Eight Lynch syndrome families in our cohort had the c.942+3A>T splice site mutation in the MSH2 gene. Six (75%) of these eight families had one family member with Muir-Torre syndrome. This splice site mutation was described previously in a family with Muir-Torre syndrome ( 19 ).

The frequency of Muir-Torre syndrome among Lynch syndrome families who carried MLH1 mutations was not statistically significantly different from that among Lynch syndrome families who carried MSH2 mutations (44% vs 42%; P = .302). The frequency of Muir-Torre syndrome among Lynch syndrome families who carried the c.942+3A>T MSH2 gene mutation was statistically significantly greater than that among Lynch syndrome families who carried other mutations in the MSH2 gene (75% vs 25%; P = .026).

We identified no individuals with Muir-Torre syndrome among Lynch syndrome families who carried mutations in either the MSH6 gene (13 families) or the PMS2 gene (four families). The frequency of Muir-Torre syndrome among families who carried MSH6 gene mutations was statistically significantly lower than that among families who carried MLH1 (0% vs 42%; P = .017) or MSH2 (0% vs 44%; P = .007) gene mutations.

To our knowledge, the incidence rates we present here are the highest reported for Muir-Torre syndrome among Lynch syndrome families. There are several reasons why such a high frequency has not been reported previously. First, the 50 Lynch syndrome families included in this study were ascertained from a population-based series of cancer patients and thus may be more representative of the typical Lynch syndrome family than Lynch syndrome families who are identified through high-risk clinics.

Second, histories of nonmelanoma skin cancers and benign skin pathology have not been rigorously pursued in cancer genetics clinic, and patients often do not list these lesions as part of their medical history. This inattention may have resulted in Muir-Torre–associated skin lesions being underrecognized in the past.

Finally, the higher incidence of Muir-Torre syndrome observed in our analysis compared with that previously reported (28% vs 9% of families) could be because we defined Muir-Torre syndrome on the basis of a molecular diagnosis rather than a clinical diagnosis. Previous studies ( 11 , 15 , 16 ) have used the strict clinical definition of Muir-Torre syndrome, which requires the presence of both a visceral malignancy and characteristic dermatologic tumors in a single individual and excludes patients who have only the dermatologic tumors. However, Muir-Torre syndrome was defined with clinical criteria before the discovery of the MMR genes, and subsequent evidence ( 6 , 8 , 9 , 15 ), such as the presence of microsatellite instability and the absence of MMR gene products in the visceral and skin tumors, suggested that Muir-Torre syndrome is simply a variant of Lynch syndrome. In this observational study, we included two individuals who we identified as having Muir-Torre syndrome who had skin neoplasms without a visceral malignancy and thus did not meet the strict clinical definition of Muir-Torre syndrome and thus would have been excluded from previous studies.

An important finding in our study is that 57% of individuals presented with dermatologic pathology before they were diagnosed with a visceral malignancy. A large percentage of patients presenting first with dermatopathology was also documented in a previous study ( 15 ) in which 60% of Muir-Torre syndrome patients were diagnosed with a skin lesion before their visceral malignancy was diagnosed. Because of the large number of Muir-Torre syndrome patients who present with skin lesions only, we agree with Ponti et al ( 16 ) that all individuals who are diagnosed with a Muir-Torre syndrome–related skin lesion should be screened for Lynch syndrome either by microsatellite instability testing or by immunohistochemistry for expression of the four MMR proteins. If the skin lesion has microsatellite instability or lacks staining for MMR gene products, further genetic testing to detect deleterious germline mutations of MMR genes may be warranted to determine if they have Lynch syndrome. Those who are found to have Lynch syndrome may benefit from intensive cancer surveillance in an attempt to prevent other Lynch syndrome–associated cancers or to diagnose those cancers at an earlier and potentially more treatable stage. If routine molecular testing of these skin lesions had been performed, two individuals who had skin malignancies diagnosed before their colorectal cancer diagnoses—proband 4 ( Table 1 ) and proband 8 ( Table 2 )—would have been identified as having Lynch syndrome and could have been monitored with high-risk cancer surveillance.

In this analysis, we also found that there was no statistically significant difference in the frequency of Muir-Torre syndrome–associated tumors between families with MLH1 mutations and those with MSH2 mutations. By contrast, a previous study ( 12 ) suggested a predominance of MSH2 mutations in patients with Muir-Torre syndrome. We also found statistically significantly fewer (ie, no) cases of Muir-Torre syndrome among MSH6 mutation carriers. However, a recent case report described a deleterious MSH6 gene mutation in a Muir-Torre family ( 20 ).

Six (43%) of the 14 Muir-Torre syndrome families in this study carried the c.942+3A>T mutation in the MSH2 gene. Lynch syndrome families who carried this mutation had a statistically significantly higher frequency of Muir-Torre syndrome than Lynch syndrome families who carried other mutations in the MSH2 gene. The c.942+3A>T mutation is a common mutation that accounts for 11% of all known pathogenic MSH2 gene mutations ( 21 ). If this mutation is truly associated with the Muir-Torre syndrome variant phenotype, then the overall frequency of Muir-Torre syndrome in our cohort may be falsely elevated because this mutation was disproportionally overrepresented in our cohort (33% of families with a deleterious germline mutation in the MSH2 gene and 16% of all Lynch syndrome families).

In addition to the preponderance of a single deleterious mutation of the MSH2 gene in our cohort, recall bias may have confounded our study. Patients often do not consider these lesions as a part of their medical history or do not remember the specific diagnosis. To offset this potential limitation, we obtained medical records on patients with any history of a skin lesion.

On the basis of our results, we suggest that Muir-Torre syndrome be defined as a variant of Lynch syndrome that is characterized by mutations in all MMR genes. We propose that Muir-Torre syndrome–associated skin lesions be included as a component tumor of the Lynch syndrome and screened for accordingly. There are currently no recommendations regarding screening for Muir-Torre syndrome–associated skin lesions among patients with Lynch syndrome. Given the high frequency of Muir-Torre syndrome–associated skin lesions among Lynch syndrome patients, an annual dermatologic examination is a reasonable strategy for the detection of these lesions and would provide an opportunity to discuss risk factor modification, such as minimizing sun exposure.

Funding

National Cancer Institute (CA67941 to A. d. l. C. and CA16058 to Michael Caliguiri, MD; State of Ohio Biomedical Research and Technology Transfer Commission (BRCP 06-20 to A. d. l. C.).

The study sponsors had no role in the design of the study; the collection, analysis, or interpretation of the data; the writing of the manuscript; or the decision to submit the manuscript for publication.

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Author notes

This publication was prepared under a grant from the State of Ohio Biomedical Research and Technology Transfer Commission. The content reflects the views of the Grantee and does not necessarily reflect the views of the State of Ohio Biomedical Research and Technology Transfer Commission. Ms Hampel had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.