Loss of fragile histidine triad (FHIT) expression and microsatellite instability in periocular sebaceous gland carcinoma in patients with Muir-Torre syndrome

Holbach, Leonard M.; Moller, Alexander von; Decker, Carsten; Jünemann, Anselm; Rummelt-Hofmann, Carmen; Ballhausen, Wolfgang G.

doi:10.1016/s0002-9394(02)01434-4

Cited by 30 publications

(25 citation statements)

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“…The index patients either had presented with a visceral malignancy themselves, or an affected first degree relative had developed an internal malignancy [Conway et al, 2004;Holbach et al, 2002]. Biopsy specimens of the lower or upper eyelids were obtained by full-thickness excision and were histopathologically proven to be SGCs.…”

Section: Materials and Methods Patientsmentioning

confidence: 99%

“…In a previous study we presented preliminary data indicating that SGCs derived from MTS patients can be divided into tumors with positivity for FHIT polypeptide chains or tumors with a loss of FHIT protein staining [Conway et al, 2004;Holbach et al, 2002]. The present study was intended not only to add novel cases to our study, but also to exemplify mutational mechanisms associated with the development of FHIT-negative periocular SGC of presumed MTS patients (see Table 1).…”

Section: Expression Of Fhit In Sgcmentioning

confidence: 97%

“…The AEC substrate-chromogen system (DakoCytomation) was used for peroxidase-based immunohistochemical staining. Sections were counterstained with hematoxylin, mounted with an aqueous-based mounting medium, and analyzed with a Zeiss Axiophot microscope (Zeiss, Oberkochen, Germany) following digital documentation [Holbach et al, 2002].…”

Section: Immunohistochemistrymentioning

confidence: 99%

“…Based on our initial data we proposed that two different pathogenetic factors may lead to the development of SGC in patients with MTS [Holbach et al, 2002]. One mechanism would include functional deletion of MMR genes resulting in microsatellite instability (MSI).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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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.

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Section: Materials and Methods Patientsmentioning

confidence: 99%

Section: Expression Of Fhit In Sgcmentioning

confidence: 97%

Section: Immunohistochemistrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2006

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“…Interestingly, in a study of biopsies of periocular sebaceous gland carcinomas, of patients with Muir -Torre syndrome, Holbach et al (2002) determined that Fhit was detectable in the one sebaceous gland carcinoma with microsatellite instability but not in the five sebaceous carcinomas without microsatellite instability. These authors made the intriguing suggestion that loss of either Fhit or mismatch repair could contribute to the development of sebaceous gland carcinoma in MTS.…”

Section: Consistently With This Idea Several Reports Of Increased Fhmentioning

confidence: 99%

Cancer and the FRA3B/FHIT fragile locus: it's a HIT

2003

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The FHIT gene encompassing the most active common human chromosomal fragile region, FRA3B, was discovered in 1996 and proposed as a tumour suppressor gene for important human cancers. Seven years and more than 350 reports later, early questions concerning its tumour suppressor role have been answered. Recent studies on the role of Fhit loss in major types of human cancers report association with high proliferative and low apoptotic indices, node positivity, loss of mismatch repair protein, likelihood of progression and reduced survival.

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