4601

MXI1

MAD2|MXD2|MXI|bHLHc11;MAX interactor 1, dimerization protein;MXI1;MAX interactor 1, dimerization protein

MAX dimerization protein 2|Max-related transcription factor|class C basic helix-loop-helix protein 11|max-interacting protein 1

10q24-q25

protein-coding

Melanoma development and progression is thought to be the result of a multi-step accumulation of genetic damage, with loss of heterozygosity in chromosome 9p (MTS1) frequently described. In addition, chromosome 10q allelic loss has been reported, implicating the tumor suppressor gene PTEN/MMAC1 on 10q23.3. The MXI1 gene at 10q24-25 is another candidate tumor suppressor that has only rarely been studied in melanomas, with conflicting results. We used microdissection-based genotyping to investigate 29 melanomas from 20 patients for loss of heterozygosity in intragenic and flanking microsatellite markers for this latter gene. Concurrently, the MTS1 gene was similarly studied using two flanking microsatellites. Fifty-four percent (15 of 28) of the informative cases showed loss of heterozygosity for one or both MXI1 markers, as compared with 67% (16 of 24) of the informative cases for MTS1. MXI1 allelic loss was seen more frequently in recurrent/metastatic tumors (59%), as compared with in primary (33%) lesions. Eighty percent of the primary tumors showed loss of heterozygosity for MTS1, as well as 63% of recurrent/metastatic ones. We studied more than one tumor in eight patients, with those from three patients showing discordant genetic patterns. One patient showed a metastatic tumor with allelic loss for MXI1 that was not identified in the primary melanoma or a local recurrence. The other two patients showed clonal heterogeneity in MXI1 at synchronous and metachronous metastatic foci. These findings support MXI1 as a putative tumor suppressor gene involved in conventional melanoma progression. genetic heterogeneity seen in different metastases from the same primary suggests a nonlinear pattern of chromosomal damage, with the development of multiple clones within the primary tumor, each acquiring its own metastatic potential.

OBJECTIVE: To detect the status of loss of heterozygosity (LOH) on chromosome 10 in prostate carcinoma and high grade prostatic intraepithelial neoplasia (PIN). METHODS: Pure DNA was obtained from prostate neoplasms and normal tissues by tissue microdissection. LOH of chromosome 10 was detected by PCR based microsatellite polymorphism analysis technique using 20 pairs of microsatellite primers in 16 samples of prostate carcinoma and 14 samples of high grade PIN. RESULTS: There were different frequencies of LOH in different loci on chromosome 10, varying from 0 to 46.2%, mainly located at 10q23 and 10q24-q25 regions. Seven samples of high grade PIN had LOH detected on chromosome 10. CONCLUSION: There were high frequency of LOH regions on chromosome 10 of prostate carcinoma. The rate of LOH in high grade PIN was much lower than that in prostate carcinoma. PTEN and MXI1 were two candidate tumor suppressor genes on 10q23 and 10q24-q25. They may be potentially involved in the initiation and progression of prostate carcinoma.

Abnormalities of chromosome 10 are frequently observed in the development of medulloblastoma, the most common malignant brain tumor of childhood. To identify critical genetic loci involved, we performed detailed physical mapping of regions of allelic loss on this chromosome. 18% of cases (5/32 primary tumors, 2/8 cell lines) harbored allelic losses on 10q. Refined mapping identified a 21.7Mb common interval, affecting the region 10q23.3-10q25.3. This region contains three genes, MXI1, SUFU and BTRC, which represent putative medulloblastoma tumor suppressor (TS) genes on the basis of either (i) negative regulation of critical medulloblastoma pathways, or (ii) mutation in other cancer types. We therefore sought evidence of their genetic inactivation in 46 cases, by mutational analysis of their entire coding regions. A MXI1 mutation was identified which abolishes its translation initiation site (A1G; MET1VAL), however no further tumor-specific sequence variations were detected. We next identified and characterised CpG islands associated with 5 regions of the MXI1, SUFU and BTRC genes; analysis of these regions for evidence of DNA hypermethylation, alongside expression analysis of their respective transcripts, revealed no evidence to support epigenetic inactivation of any gene. These findings implicate the inactivation of critical TS loci at 10q23.3-25.3 in medulloblastoma, however comprehensive analysis of SUFU, BTRC and MXI1 indicates they are unlikely to represent major targets of these allelic losses. MXI1 mutation appears to play a role in the pathogenesis of a small subset of cases, and suggests an alternative mechanism to MYC amplification for disruption of the MYC/MAD/MAX network in medulloblastoma.

MXI1, a member of the MYC family of transcription factors, is thought to negatively regulate MYC function and may therefore be a potential tumor suppressor gene. Using detailed restriction mapping and partial DNA sequencing analysis, we have determined the genomic organization of the human MXI1 gene to facilitate a search for mutations that affect MXI1 function. The gene spans a region of approximately 60 kb on chromosome 10q24-q25 and comprises six exons. The correspondence of these exons to previously identified Mxi1 functional domains suggests that alternatively spliced transcripts may regulate Mxi1 functional activity. The presence of a cryptic ATG start codon in exon 2 suggests that a functional protein missing the SIN3-interacting domain (exon 1) may be generated by alternative splicing. Finally, we have identified two polymorphic regions within the MXI1 locus: a polymorphic CA repeat in the third intron and an AAAAC polymorphism in the noncoding region of exon 6. These findings will facilitate the analysis of tumors for the presence of inactivating mutations in MXI1 coding and regulatory sequences.