UvA-DARE (Digital Academic Repository) Molecular genetic alterations in gastrointestinal polyposis syndromes: with emphasis on the Peutz-Jeghers syndrome

Sebaceous gland carcinomas (SGCs) are rare malignant skin tumors occurring sporadically or as a phenotypic feature of the Muir-Torre syndrome (MTS). A subset of patients with MTS have a variant of the hereditary nonpolyposis colorectal cancer syndrome caused by mutations in mismatch repair (MMR) genes, which lead to microsatellite instability (MSI). We evaluated the value of MSI and loss of expression of the MMR genes, hMLH-1 and hMSH-2, as a marker to identify and distinguish MTS from sporadic SGC. Using a nationwide pathology report database system, we identified patients with the MTS phenotype. SGCs from 10 MTS patients and the colorectal carcinomas from 3 additional MTS patients were collected. In addition, SGCs from eight patients without a history of visceral neoplasm were collected. MSI was detected in 9 of 13 MTS-associated tumors (69%) versus 0 of 8 sporadic SGCs (P = 0.002). Except for the age of onset of colorectal carcinoma [58 years in the MSI-positive group versus 69.8 years in the MSInegative group (P = 0.17)], no differences were seen between the MSI-negative and the MSI-positive MTS patients. Loss of expression of hMLH-1 (n = 4) or hMSH-2 (n = 4) was found in MSI-positive patients only. MSI and loss of expression of MMR genes can be used as markers for MTS in patients with SGC. Consequently, MSI and loss of MMR gene expression in a patient presenting with SGC as the initial malignancy have important consequences for the patient and family. There are at least two variants of MTS with different molecular genetic mechReceived 11/15/99; revised 2/4/00; accepted 2/7/00. 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 in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 Supported by the Netherlands Digestive Disease Foundation (Grant WS 97-75). 2 To whom requests for reprints should be addressed, at Academic Medical Center, Department of Pathology. Meibergdreef 9. 1105 AZ Amsterdam, the Netherlands. Phone: 31-20-5665635: Fax: 31-206960389; E-mail: g.j.offerhaus@amc.uva. nl. anisms because 31 % of the patients with the MTS phenotype had no MSI. I N T R O D U C T I O N In 1967, Muir (1) and Torre (2) described independently a patient with both sebaceous gland tumors and intestinal malignancies. Since then, >150 patients have been reported with the MTS (3. 4). MTS is defined as the presence of: (a) a sebaceous gland adenoma, epithelioma, or carcinoma; and (b) an internal malignancy. Internal malignancies that are most often seen in MTS patients are CRCs and genitourinary tract neoplasms predominantly originating from the bladder, uterus, renal pelvis, or ovaries, which together account for —75% of the observed internal malignancies in MTS. Furthermore, breast, hematological, head and neck, and small intestinal malignancies have been described in combination with sebaceous gland tumors (3, 4). Also, the diagnosis MTS is appropriate for a patient with multiple KAs in combination with more than one visceral malignancy and a positive family history of the MTS (4). Because a subset of patients fulfilling these criteria appeared to have HNPCC, a relation between HNPCC and MTS was first suggested by Lynch in 1981 (5). HNPCC {Lynch syndrome) is characterized by an autosomal dominantly inherited predisposition to the development of CRC or specific extracolonic cancers, such as endometrial or gastric carcinomas. CRCs in HNPCC patients present at a young age (—44 years) and have a favorable prognosis compared to sporadic malignancies. HNPCC can be diagnosed on clinical grounds if all three Amsterdam criteria are fulfilled: (a) three or more relatives with histologically verified CRC, one of whom is a first degree relative of the other two; (b) CRC involving at least two generations; and (c) one or more CRC cases diagnosed before age 50 (6). HNPCC is caused by an inherited germ-line mutation in one allele of MMR genes. When a somatic loss-of-function alteration of the remaining wild-type allele occurs, MMR deficiency develops. The MMR system repairs small errors in repeat sequences of the DNA (microsatellites). which occur during replication. Consequently, MMR deficiency results in accumulating mutations of these microsatellites, which is termed MSI. Carcinomas of HNPCC patients show MSI (7). Presently, defects in six genes have been described leading to the HNPCC phenotype: hMLHl , hMSH2, hPMSl, hPMS2, hMSH6. and the 3 The abbreviations used are: MTS, Muir-Torre syndrome; SGC. sebaceous gland carcinoma; MMR, mismatch repair; HNPCC. hereditary nonpolyposis colorectal cancer; MSI. microsatellite instability: CRC, colorectal carcinoma; KA, keratoacanthoma: IHC, immunohistochemistry.