Gene Summary

Gene:MLH1; mutL homolog 1
Aliases: FCC2, COCA2, HNPCC, hMLH1, HNPCC2
Summary:The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]
Databases:OMIM, HGNC, Ensembl, GeneCard, Gene
Protein:DNA mismatch repair protein Mlh1
Source:NCBIAccessed: 01 September, 2019


What does this gene/protein do?
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Pathways:What pathways are this gene/protein implicaed in?
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Cancer Overview

Research Indicators

Publications Per Year (1994-2019)
Graph generated 01 September 2019 using data from PubMed using criteria.

Literature Analysis

Mouse over the terms for more detail; many indicate links which you can click for dedicated pages about the topic.

Tag cloud generated 01 September, 2019 using data from PubMed, MeSH and CancerIndex

Specific Cancers (3)

Data table showing topics related to specific cancers and associated disorders. Scope includes mutations and abnormal protein expression.

Entity Topic PubMed Papers
Hereditary Nonpolyposis Colorectal Cancer MLH1 and Lynch Syndrome
See: More details below...
View Publications1369
Turcot SyndromeMLH1 mutations in Turcot Syndrome View Publications56
Lynch Syndrome IILynch Syndrome II
Hereditary nonpolyposis colorectal neoplasms associated with other malignancies, more commonly of ovarian or uterine origin. When also associated with SEBACEOUS GLAND NEOPLASMS, it is called MUIR-TORRE SYNDROME. (Source: MeSH)
See: More details below...
View Publications50

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

MLH1 and Lynch Syndrome

See also: Colorectal (Bowel) Cancer - Clinical and Research information

Latest Publications

Lynch Syndrome II

Hereditary nonpolyposis colorectal neoplasms associated with other malignancies, more commonly of ovarian or uterine origin. When also associated with SEBACEOUS GLAND NEOPLASMS, it is called MUIR-TORRE SYNDROME. (Source: MeSH)

Latest Publications

Torre K, Ricketts J, Dadras SS
Muir-Torre Syndrome: A Case Report in a Woman Without Personal Cancer History.
Am J Dermatopathol. 2019; 41(1):55-59 [PubMed] Related Publications
We report a case of a 68-year-old white woman presenting with 5 sebaceous neoplasms, ranging from sebaceous adenoma to sebaceoma on histopathology. Despite the lack of a personal cancer history, her multiple sebaceous neoplasms and a paternal history of colon cancer prompted testing her sebaceous adenomas for microsatellite instability (MSI) by immunohistochemistry. The results showed retained nuclear expressions of MLH1 and PMS2 while MSH2 and MSH6 proteins were absent. The tumor infiltrating lymphocytes expressed both MSH2 and MSH6, providing reliable internal positive controls. Having a high probability for MSI, she was found to be heterozygous for a germline point mutation in MSH2 gene, where a pathologic variant, c.1165C > T (p.Arg389*), determined by sequencing confirmed Muir-Torre syndrome (MTS). On further genetic counseling recommendations, one of her 2 sons was found to have colon cancer in the context of his MTS. In this article, we highlight and review the implications of MSI testing by both immunohistochemistry and sequencing as they relate to confirming the diagnosis of a suspected case of MTS.

Yokoyama T, Takehara K, Sugimoto N, et al.
Lynch syndrome-associated endometrial carcinoma with MLH1 germline mutation and MLH1 promoter hypermethylation: a case report and literature review.
BMC Cancer. 2018; 18(1):576 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Lynch syndrome is an autosomal dominant inherited disease caused by germline mutations in mismatch repair genes. Analysis for microsatellite instability (MSI) and immunohistochemistry (IHC) of protein expressions of disease-associated genes is used to screen for Lynch syndrome in endometrial cancer patients. When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.
CASE PRESENTATION: Here we report a woman who developed endometrial cancer at the age of 49 years. She had a family history of colorectal cancer (first-degree relative aged 52 years) and stomach cancer (second-degree relative with the age of onset unknown). No other family history was present, and she failed to meet the Amsterdam II criteria for the diagnosis of Lynch syndrome. Losses of MLH1 and PMS2, but not MSH2 and MSH6, proteins were observed by IHC in endometrial cancer tissues. Because MLH1 promoter hypermethylation was detected in endometrial cancer tissue samples, the epigenetic silencing of MLH1 was suspected as the cause of the protein loss. However, because of the early onset of endometrial cancer and the positive family history, a diagnosis of Lynch syndrome was also suspected. Therefore, we provided her with genetic counseling. After obtaining her consent, MLH1 promoter methylation testing and genetic testing of peripheral blood were performed. MLH1 promoter methylation was not observed in peripheral blood. However, genetic testing revealed a large deletion of exon 5 in MLH1; thus, we diagnosed the presence of Lynch syndrome.
CONCLUSIONS: Both MLH1 germline mutation and MLH1 promoter hypermethylation may be observed in endometrial cancer. Therefore, even if MLH1 promoter hypermethylation is detected, a diagnosis of Lynch syndrome cannot be excluded.

Jockenhöfer F, Schimming TT, Schaller J, et al.
Sebaceous tumours: more than skin deep.
Gut. 2018; 67(11):1957 [PubMed] Related Publications
CLINICAL PRESENTATION: A 77-year-old man presented to our skin cancer centre with various cutaneous tumours occurring in 2006-2017. Histopathology showed a 'hidradenocarcinoma' on the left upper back (2006) and a sebaceous adenoma (figure 1) on the left shoulder (2011). In 2017, he developed a sebaceous carcinoma on the middle upper back, which manifested as a slowly enlarging, asymptomatic nodule. Medical history was significant for curative resection of colorectal cancer in 1988.gutjnl;67/11/1957/F1F1F1Figure 1Clinical appearance of the sebaceous adenoma on the patient's left shoulder in 2011.The most recent lesion was subjected to extensive immunohistochemical assessment. The neoplastic cells were positive for cytokeratin 5/6, cytokeratin 7, cluster of differentiation antigen 10, adipophilin, androgen receptor, epithelial membrane antigen, KI67 antigen, MLH1 and PMS2, but stained negative for gross cystic disease fluid protein 15, prostate-specific antigen, carbohydrate antigen 19/9, CDX2 protein, hepatocyte-specific antigen, carcinoembryonic antigen, cluster of differentiation antigen 117 and cytokeratin 19. Given the variety of histological manifestations of the patient's skin neoplasms, further studies were performed. They revealed positive nuclear expression signals for MLH1, MSH6 and PMS2, whereas MSH2 expression was absent in almost all tumour cells (figure 2). Positron emission tomography (PET)/CT and colonoscopy did not detect any pathological findings. However, molecular genetic analysis of peripheral blood showed a heterozygous deletion of exon 7 of the
QUESTION: What is your diagnosis?
DIAGNOSIS: Muir-Torre syndrome (MTS).

Pollinger TH, Kieliszak CR, Logemann N, Gratrix ML
Analysis of Sebaceous Neoplasms for DNA Mismatch Repair Proteins in Muir-Torre Syndrome.
Skinmed. 2017; 15(4):259-264 [PubMed] Related Publications
Muir-Torre syndrome is a rare genodermatosis inherited most frequently in an autosomal dominant fashion. Current criteria for its diagnosis include at least one sebaceous tumor and an underlying visceral malignancy. Muir-Torre syndrome is strongly associated with a germline mutation in DNA mismatch repair genes. We report two patients with a history of colorectal carcinoma who presented with sebaceous neoplasms on the face and trunk. Immunohistochemical staining of the sebaceous neoplasms demonstrated absence of mismatch repair proteins MSH2 and MSH6. Genetic studies confirmed deletions in the

Lee JB, Litzner BR, Vidal CI
Review of the current medical literature and assessment of current utilization patterns regarding mismatch repair protein immunohistochemistry in cutaneous Muir-Torre syndrome-associated neoplasms.
J Cutan Pathol. 2017; 44(11):931-937 [PubMed] Related Publications
Muir-Torre syndrome is a clinical variant of Lynch syndrome defined by the synchronous or metachronous occurrence of at least one sebaceous neoplasm and at least one Lynch syndrome-related internal cancer. Although screening guidelines for patients with colorectal carcinomas have been established, screening guidelines for cutaneous Muir-Torre associated neoplasms are not currently available. As such, we reviewed the current evidence for the use of MLH1, MSH2, MSH6 and PMS2 immunohistochemistry when cutaneous Muir-Torre associated neoplasms are encountered. We identified weak to moderate support overall for the global use of these assays, with some evidence suggesting a tailored approach using clinical parameters as an adjunct. We also assessed the current utilization patterns of attendees of the American Society of Dermatopathology Annual Meeting (Chicago, 2016). We found that 91% of respondents utilize mismatch repair immunohistochemistry, with the majority utilizing these tests only when requested by the submitting clinician.

Mahalingam M
MSH6, Past and Present and Muir-Torre Syndrome-Connecting the Dots.
Am J Dermatopathol. 2017; 39(4):239-249 [PubMed] Related Publications
Sebaceous neoplasms such as adenoma, sebaceoma, and carcinoma, although sporadic in their occurrence, are clinically significant because of their association with Muir-Torre syndrome (MTS). MTS is a rare autosomal dominant genodermatosis characterized by the occurrence of sebaceous neoplasms and/or keratoacanthomas and visceral malignancies. MTS is usually the result of germline mutations in the DNA mismatch repair genes MSH2 and, albeit less commonly, MLH1. Although less know, MSH6 is yet another key player. Evidence from Lynch syndrome indicates that pathogenic germline mutations in MSH6 are typically microsatellite stable and have a clinical presentation that differs from that associated with germline mutations in MSH2 and/or MLH1. Given this unique mutator phenotype of MSH6, the primary aim of this review was to underscore the clinical manifestations associated with pathogenic mutations in MSH6 in patients with MTS. As the current clinical and laboratory work-up of MTS is geared toward patients harboring a germline mutation in MSH2 and/or MLH1, an additional aim was to provide a scaffolding for the work-up of a patient presenting with an isolated germline mutation in MSH6.

Němejcová K, Dundr P, Rosmusová J, Tučková I
Sebaceous adenoma arising in mature cystic teratoma of the ovary. Case report.
Cesk Patol. Winter 2017; 53(1):35-37 [PubMed] Related Publications
We report the case of a 44-year-old female with sebaceous adenoma arising in mature cystic teratoma of the ovary. The patient had a tumor in the left ovary; 125 x 90 x 70 mm. Microscopically, the tumor consisted of structures typical of dermoid cysts. However, large areas of sebaceous proliferation were found. These areas were comprised of sebaceous nodules with features similar to a sebaceous adenoma of the skin. Immunohistochemically, the tumor showed "wild-type" expression of p53 and low proliferative activity (Ki-67 index < 5%). To verify the possibility of Muir-Torre syndrome we performed immunohistochemical examination of DNA mismatch repair proteins expression. However, all four proteins examined (MSH2, MSH6, MLH1, PMS2) were positive. Sebaceous adenoma arising in mature teratoma of the ovary is rare. To the best of our knowledge, only six cases have been reported in the literature to date.

Hoss E, Nelson SA, Sharma A
Sebaceous carcinoma in solid organ transplant recipients.
Int J Dermatol. 2017; 56(7):746-749 [PubMed] Related Publications
BACKGROUND: Though a rare tumor, sebaceous carcinoma is relatively well-described in immunocompetent patients, in whom it often occurs in a periorbital distribution where it has an overall poor prognosis with a high metastasis rate. The effect of transplant-related immunosuppression on the development of sebaceous carcinoma and its outcomes has not been characterized.
METHODS: We collected 9 cases from a single institution of patients developing sebaceous carcinoma after solid organ transplantation. We analyzed clinicopathologic features.
RESULTS: We estimate the prevalence of sebaceous carcinoma post-solid organ transplantation to be 0.09%. The mean age at diagnosis was 66.1 years (std 7.0 years). The mean time between transplantation and sebaceous carcinoma diagnosis was 7.1 years (std 5.1 years). All tumors occurred in extra-ocular distribution. Two patients likely had Muir-Torre syndrome, of whom 1 died from metastatic sebaceous carcinoma. No other patients developed metastatic disease or had disease-related death. Mohs micrographic surgery and wide local excision were equally effective and there were no recurrences with either procedure.
CONCLUSIONS: Our study found that sebaceous carcinoma in solid organ transplant recipients occurs in in an extraorbital distribution with only 1 patient developing metastatic disease. Both Mohs micrographic surgery and wide local excision are acceptable treatment modalities for sebaceous carcinoma in transplant recipients.

Shiki M, Hida T, Sugano K, et al.
Muir-Torre syndrome caused by exonic deletion of MLH1 due to homologous recombination.
Eur J Dermatol. 2017; 27(1):54-58 [PubMed] Related Publications
BACKGROUND: Muir-Torre syndrome (MTS) is characterized by sebaceous neoplasms with internal malignancies and regarded as a variant of hereditary nonpolyposis colorectal cancer (HNPCC). Pathogenic variations of MTS have been identified in the MSH2, MLH1, and MSH6 genes, with the majority of variations located in MSH2.
OBJECTIVES: To present an MTS patient who was the only individual with skin malignancies within a cancer-prone pedigree and to show the usefulness of RNA-based genetic analysis in the investigation of MTS.
MATERIALS & METHODS: A 77-year-old man who had operated X-ray equipment at his workplace in his twenties was clinically diagnosed with MTS and investigated by RNA-based analysis, multiplex ligation-dependent probe amplification, and genomic DNA sequencing.
RESULTS: The patient had suffered from sebaceous tumours, squamous cell carcinomas of the skin, and colon cancer. The patient's family history was remarkable for visceral malignant diseases. Genetic analysis revealed homologous recombination between two Alu elements within intron 4 and 5 of the MLH1 gene. The rearrangement caused a 1,222-bp deletion, including the entire exon 5. Deletion of exon 5 has previously been reported only in two patients with HNPCC, and not in patients with MTS.
CONCLUSION: For the genetic analysis of MTS, the possibility of rare copy number variations of MLH1, as well as MSH2 variations, should be considered. RNA-based screening using puromycin is recommended in order to identify such variations. It remains unclear why only the proband among the pedigree had skin malignancies, however, the skin carcinogenesis might have been related to occupational radiation exposure.

Kacerovska D, Drlik L, Slezakova L, et al.
Cutaneous Sebaceous Lesions in a Patient With MUTYH-Associated Polyposis Mimicking Muir-Torre Syndrome.
Am J Dermatopathol. 2016; 38(12):915-923 [PubMed] Related Publications
A 76-year-old white male with a history of adenocarcinoma of the rectosigmoideum and multiple colonic polyps removed at the age of 38 and 39 years by an abdominoperitoneal amputation and total colectomy, respectively, presented with multiple whitish and yellowish papules on the face and a verrucous lesion on the trunk. The lesions were surgically removed during the next 3 years and a total of 13 lesions were investigated histologically. The diagnoses included 11 sebaceous adenomas, 1 low-grade sebaceous carcinoma, and 1 squamous cell carcinoma. In some sebaceous lesions, squamous metaplasia, intratumoral heterogeneity, mucinous changes, and peritumoral lymphocytes as sometimes seen in sebaceous lesions in Muir-Torre syndrome were noted. Mutation analysis of the peripheral blood revealed a germline mutation c.692G>A,p.(Arg231His) in exon 9 and c.1145G>A, p.(Gly382Asp) in exon 13 of the MUTYH gene. A KRAS mutation G12C (c.34G>T, p.Gly12Cys) was detected in 1 sebaceous adenoma and a NRAS mutation Q61K (c.181C>A, p.Gln61Lys) was found in 2 other sebaceous adenomas. No germline mutations in MLH1, MSH2, MSH6 and PMS2 genes, no microsatellite instability, no aberrant methylation of MLH1 promoter, and no somatic mutations in MSH2 and MSH6 were found. An identical MUTYH germline mutation was found in the patient's daughter. Despite striking clinicopathological similarities with Muir-Torre syndrome, the molecular biologic testing confirmed the final diagnosis of MUTYH-associated polyposis.

Goverde A, Spaander MC, van Doorn HC, et al.
Cost-effectiveness of routine screening for Lynch syndrome in endometrial cancer patients up to 70years of age.
Gynecol Oncol. 2016; 143(3):453-459 [PubMed] Related Publications
PURPOSE: To assess cost-effectiveness of routine screening for Lynch Syndrome (LS) in endometrial cancer (EC) patients ≤70years of age.
METHODS: Consecutive EC patients ≤70years of age were screened for LS by analysis of microsatellite instability, immunohistochemistry and MLH1 hypermethylation. Costs and health benefit in life years gained (LYG) included surveillance for LS carriers among EC patients and relatives. We calculated incremental cost-effectiveness ratios (ICERs) comparing LS screening among EC patients ≤70years with ≤50years and the revised Bethesda guidelines.
RESULTS: Screening for LS in 179 EC patients identified 7 LS carriers; 1 was ≤50 and 6 were 51-70years. Per age category 18 and 9 relatives were identified as LS carrier. Screening resulted in 74,7 LYG (45,4 and 29,3 LYG per age category). The ICER for LS screening in EC patients ≤70 compared with ≤50years was €5,252/LYG. The revised Bethesda guidelines missed 4/7 (57%) LS carriers among EC patients. The ICER for LS screening in EC patients ≤70years of age compared with the revised Bethesda guidelines was €6,668/LYG. Both ICERs remained <€16,000/LYG in sensitivity analyses.
CONCLUSION: Routine LS screening in EC patients ≤70years is a cost-effective strategy, allowing colorectal cancer prevention in EC patients and their relatives.

Djordjevic B, Broaddus RR
Laboratory Assays in Evaluation of Lynch Syndrome in Patients with Endometrial Carcinoma.
Surg Pathol Clin. 2016; 9(2):289-99 [PubMed] Free Access to Full Article Related Publications
This article reviews the main tissue testing modalities for Lynch Syndrome in the pathology laboratory, such as immunohistochemistry and PCR based analyses, and discusses their routine application, interpretation pitfalls, and troubleshooting of common technical performance issues. Discrepancies between laboratory and genetic testing may arise, and are examined in the context of the complexity of molecular abnormalities associated with Lynch Syndrome. The merits of targeted versus universal screening in a changing healthcare climate are addressed. In the absence of comprehensive screening programs, specific tumor topography and histological features that may prompt pathologist-initiated molecular tumor testing are outlined.

Mills AM, Longacre TA
Lynch Syndrome: Female Genital Tract Cancer Diagnosis and Screening.
Surg Pathol Clin. 2016; 9(2):201-14 [PubMed] Related Publications
Lynch syndrome is responsible for approximately 5% of endometrial cancers and 1% of ovarian cancers. The molecular basis for Lynch syndrome is a heritable functional deficiency in the DNA mismatch repair system, typically due to a germline mutation. This review discusses the rationales and relative merits of current Lynch syndrome screening tests for endometrial and ovarian cancers and provides pathologists with an informed algorithmic approach to Lynch syndrome testing in gynecologic cancers. Pitfalls in test interpretation and strategies to resolve discordant test results are presented. The potential role for next-generation sequencing panels in future screening efforts is discussed.

Jessup CJ, Redston M, Tilton E, Reimann JD
Importance of universal mismatch repair protein immunohistochemistry in patients with sebaceous neoplasia as an initial screening tool for Muir-Torre syndrome.
Hum Pathol. 2016; 49:1-9 [PubMed] Related Publications
Muir-Torre syndrome, a Lynch syndrome variant, is characterized by sebaceous neoplasia plus one or more malignancies, typically colon cancer. The significance of DNA mismatch repair (MMR) deficiency detection by immunohistochemistry (IHC) in colorectal carcinomas is well established and is recommended as a screening tool for Lynch syndrome in newly diagnosed colorectal carcinomas. In comparison, literature on IHC application to detect MMR proteins (MLH1, MSH2, MSH6, and PMS2) in sebaceous neoplasia has been less studied and has been derived almost exclusively from tertiary care centers. Herein we describe the largest series to date characterizing MMR deficiency in sebaceous neoplasms, as well as the relative frequencies of each deficiency. Two hundred sixteen consecutive sebaceous neoplasms (216 patients) were analyzed from a community practice setting (133 sebaceous adenomas, 68 sebaceomas, 15 sebaceous carcinomas). One hundred forty-three were MMR deficient (66%), of which 90 were MSH2/MSH6 deficient (63%), 27 MLH1/PMS2 deficient (19%), 22 MSH6 deficient (15%), and 4 PMS2 deficient (3%). MMR deficiency was significantly associated with site, with tumors off of the head and neck more likely to be MMR deficient (specificity 96%). In contrast to prior reports, no significant trend in MMR-deficient versus -nondeficient tumors was seen in age at presentation (median age, 68 versus 66), tumor-infiltrating lymphocytes, or tumor type. Given the low sensitivity of age < 60 years (30%), location off of the head and neck (41%), or presence of tumor-infiltrating lymphocytes (29%) in MMR deficiency detection, IHC screening programs should test all sebaceous neoplasms for MMR deficiency, regardless of their clinicopathological features.

Hung CT, Wang WM
JAAD Grand Rounds quiz: A subcutaneous nodule on the right shoulder.
J Am Acad Dermatol. 2015; 73(5):889-91 [PubMed] Related Publications
LEARNING OBJECTIVES: At the conclusion of this learning activity, physician participants should be able to assess their own diagnostic and patient management skills and use the results of this exercise to help determine personal learning needs. Instructions: In answering each question, refer to the specific directions provided. Because it is often necessary to provide information occurring later in a series that give away answers to earlier questions, please answer the questions in each series in sequence.

Oliveira CM, Campos JG, Maia MR, et al.
The role of immunohistochemistry in the Muir-Torre Syndrome.
An Bras Dermatol. 2015 May-Jun; 90(3 Suppl 1):168-70 [PubMed] Free Access to Full Article Related Publications
Muir-Torre Syndrome is defined by the coexistence of sebaceous skin tumors and internal malignancies. Mutations in the DNA mismatch repair genes are found in the inherited form of the disease, resulting in the absence of crucial enzymes involved with DNA replication process. This case describes a patient with sebaceous adenoma and colorectal carcinoma, meeting the criteria for Muir-Torre Syndrome. The immunohistochemical analysis of the skin lesion was an important tool to confirm the diagnosis, as it revealed nuclear negativity for MSH2 and MSH6.

Ponti G, Manfredini M, Tomasi A, Pellacani G
Muir-Torre Syndrome and founder mismatch repair gene mutations: A long gone historical genetic challenge.
Gene. 2016; 589(2):127-32 [PubMed] Related Publications
A "cancer predisposing syndrome" later labeled as Hereditary Non-Polyposis Colorectal Cancer (HNPCC) or Lynch Syndrome, was firstly described by Warthin, about one century ago. An increased predisposition to the development of multiple familial tumors is described as characteristic of this syndrome where visceral and cutaneous malignancies may appear at an early age namely endometrial, gastric, small bowel, ureteral and renal pelvis, ovarian, hepatobiliary tract, pancreatic, brain (Turcot Syndrome) and sebaceous glands (Muir-Torre Syndrome). The latter, a variant of Lynch Syndrome, is characterized by the presence of sebaceous skin adenomas, carcinomas and/or keratoacanthomas associated with visceral malignancies. Both Lynch Syndrome and Muir-Torre Syndrome have been recognized due to germline mutations in mismatch repair genes MLH1, MSH2 and MSH6. To date, 56 Lynch Syndrome founder mutations dependent on MLH1, MSH2 and, although less frequently found, MSH6 and PMS2 are described. Some of these founder mutations, principally of MSH2 gene, have been described to cause Muir-Torre phenotype and have been traced in large and outbreed Muir-Torre Syndrome families living in different US and European territories. Due to the evidences of highly specific Muir-Torre phenotypes related to the presence of widespread MSH2 founder mutations, preliminary search for these MSH2 common mutations in individuals carrying sebaceous tumors and/or keratoacanthomas, at early age or in association to visceral and familial tumors, permits cost-effective and time-saving diagnostic strategies for Lynch/Muir-Torre Syndromes.

Lamba AR, Moore AY, Moore T, et al.
Defective DNA mismatch repair activity is common in sebaceous neoplasms, and may be an ineffective approach to screen for Lynch syndrome.
Fam Cancer. 2015; 14(2):259-64 [PubMed] Related Publications
A subset of individuals with Lynch syndrome (LS) has a variant called Muir-Torre syndrome (MTS) where patients develop multiple sebaceous neoplasms. Absence of gene expression and microsatellite instability (MSI) have been welldocumented in LS neoplasms. It is unclear whether the presence of these abnormalities in isolated sebaceous neoplasms would indicate the likely presence of otherwise unsuspected LS or MTS. 164 specimens of sporadic cutaneous sebaceous neoplasms were obtained. IHC was performed for expression of the DNA mismatch repair (MMR) genes MSH2 and MLH1. A 5-marker mononucleotide repeat microsatellite panel was analyzed to detect MSI, and two or more mutated markers were required for MSI. 164 sebaceous neoplasms were obtained from 162 patients. IHC data was successfully obtained from 162 samples and MSI data was obtained from 138 samples. 50/162 (31%) had abnormal IHC with loss of staining for either MSH2 (37/162, 23%), MLH1 (9/162, 5%) or both (4/162, 2%). 37% (52/138) of the tumors had MSI. 82% (111/136) of those with both IHC and MSI results correlated as expected. 18% (25/136) showed discordance between IHC and MSI. 69/163 (42%) had either abnormal IHC or MSI, indicating deficient DNA MMR activity. Given the substantial proportion of DNA MMR deficiency in these sebaceous neoplasms, screening for DNA MMR defects in sebaceous neoplasms would not appear to be an effective way to distinguish patients with LS or MTS from those with sporadic skin lesions and an ordinary risk of cancer.

Jagan L, Zoroquiain P, Bravo-Filho V, et al.
Sebaceous adenomas of the eyelid and Muir-Torre Syndrome.
Br J Ophthalmol. 2015; 99(7):909-13 [PubMed] Related Publications
BACKGROUND/AIMS: Sebaceous adenomas (SAs) are rare, benign sebaceous gland tumours of the eyelid. SAs may be associated with primary internal malignancies. This association is known as Muir-Torre Syndrome (MTS). The purpose of this study was to approximate the prevalence of SAs, to determine the reliability of the clinical diagnosis of SAs and to demonstrate immunohistochemical staining of DNA mismatch repair proteins mutL homologue 1 (MLH1) and mutS homologue 2 (MSH2) for a case of MTS.
METHODS: We reviewed the histopathology reports from all eyelid specimens collected between 1993 and 2013 at the Henry C Witelson Ocular Pathology Laboratory to determine the proportion of SAs. For the SAs identified on histopathology, we looked at patient charts to see what diagnosis was originally suspected on clinical examination. Immunohistochemical staining for MLH1 and MSH2 was performed on all SAs to screen for MTS.
RESULTS: Of the 5884 eyelid specimens collected, 9 were SAs (6 women, 3 men; 42-72 years old). The diagnosis of SA was suspected clinically in only one of the nine cases based on the gross appearance of the eyelid lesion. Immunohistochemistry revealed one SA case with positive MLH1 expression and negative MSH2 expression. These findings prompted systemic work-up and this patient was diagnosed with MTS after discovery of a colon adenocarcinoma T2M0N0.
CONCLUSIONS: The diagnosis of eyelid SA is rare. The importance of this benign eyelid tumour stems from its association with internal malignancies in MTS. Immunohistochemical staining of mismatch repair proteins MLH1 and MSH2 is a valid and accessible strategy for investigating MTS in patients with SAs.

Joly MO, Attignon V, Saurin JC, et al.
Somatic MMR gene mutations as a cause for MSI-H sebaceous neoplasms in Muir-Torre syndrome-like patients.
Hum Mutat. 2015; 36(3):292-5 [PubMed] Related Publications
Sebaceous neoplasms are a major clinical feature of Muir-Torre syndrome (MTS) associated with visceral malignancies, especially colorectal and endometrial tumors. The diagnosis of MTS relies largely on the microsatellite instability (MSI) phenotype in tumors, suggesting germline mutations in DNA mismatch repair (MMR) genes responsible for the inherited disease. We hypothesized that in some MSI-H sebaceous tumors, acquired rather than inherited mutations in MMR genes could be involved. Using next-generation sequencing, we screened MMR gene mutations in 18 MSI-H sebaceous tumors. We found mutations in 17 samples (94%). Indeed, 12/17 (71%) were shown to carry acquired somatic mutations and among 12 samples, seven were shown to be associated with additional somatic alterations like loss of heterozygosity or multiple mutations, suggesting somatic second hits. Our findings strongly suggest that somatic MMR deficiency is responsible for a proportion of MSI-H sebaceous tumors.

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