Different genetic pathways in the development of periocular sebaceous gland carcinomas in presumptive Muir-Torre syndrome patients

Abstract

Periocular sebaceous gland carcinomas (SGCs) occur in the eyelids either sporadically or as a phenotypic feature of Muir-Torre syndrome (MTS). In knockout mice mismatch-repair (MMR) defects or inactivation of the fragile histidine triad (FHIT) gene are associated with MTS-like signs, including SGC. To dissect the genetic alterations associated with microsatellite instability (MSI) and inactivation of the FHIT gene, we studied nine periocular SGC specimens from MTS patients. Immunohistochemistry was performed for FHIT, MSH2, MLH1, and MSH6. We assessed MSI as well as loss of heterozygosity (LOH) at the FHIT locus with polymorphic markers and genomic multiplex PCR. Epigenetic silencing was detected by methylation-specific PCR (MSP) and combined bisulfite restriction analysis (COBRA). Our analyses identified two SGCs with FHIT positivity and high-grade MSI, and seven cases with loss of FHIT and microsatellite stability (MSS). MSI correlated with loss of MSH2 and MLH1 immunostaining. Loss-of-function mechanisms affecting the FHIT gene were identified as intragenic deletions eliminating the coding exons 5 and 6 on one hand, and complete biallelic methylation of the FHIT transcription regulatory region on the other hand. Germinal FHIT mutations as a predisposing factor for MTS were excluded in two index patients with cancer in three generations, including an FHIT-negative SGC. Our data suggest that either somatic inactivation of the FHIT gene associated with MSS or inactivation of the MMR system resulting in MSI contribute to the development of periocular SGCs in presumptive MTS.

Identification of Fhit as a post-transcriptional effector of Thymidine Kinase 1 expression

“…Recent reports from our laboratory have established a role for Fhit loss in the initiation of genome instability [22–24, 32], and have unambiguously characterized Fhit as a ‘genome caretaker’, a role intimated by the discovery that Fhit knockout mice develop sebaceous tumors [10], similar to those caused by loss of DNA mismatch repair enzymes [33]. Such sebaceous carcinomas in humans can also be caused either by loss of Fhit or loss of mismatch repair enzymes [34, 35]. …”

p53 Staining Correlates With Tumor Type and Location in Sebaceous Neoplasms

“…It is well established that a subset of sebaceous lesions harbor microsatellite instability and mutations in proteins encoding DNA mismatch repair enzymes 8, 11, 12, 35, 36. However, the presence of mismatch repair deficiency has been shown to occur less frequently in carcinomas than in benign sebaceous lesions and is seen more commonly in tumors occurring outside of the head and neck region 11, 12.…”

“…Interestingly, a recent study specifically examined periocular sebaceous carcinomas in patients with concurrent visceral malignancy (a Muir-Torre syndrome phenotype) and found that the fragile histadine triad gene ( FHIT ) was disrupted in a subset of cases with confirmed microsatellite stability 35. The authors suggested that mutations in FHIT provided another mechanism for sebaceous carcinoma formation.…”

The significance of DNA mismatch repair genes in the diagnosis and management of periocular sebaceous cell carcinoma and Muir-Torre syndrome

“…However, it is important to remember that an MSH6 defect was once thought to occur only in association with an MSH2 defect but has since been shown to occur independently 30. Goldberg et al 31 have described microsatellite-stable MTS associated with inactivation of the fragile histidine triad gene. However, they were unable to show a germline defect linking the sebaceous gland carcinoma and the visceral malignancy.…”