Germ‐line and somatic mutations of the APC gene in patients with turcot syndrome and analysis of APC mutations in brain tumors

Mori, Takahiro; Nagase, Hiroki; Horii, Akira; Miyoshi, Yasuo; Nakatsuru, Shuichi; Aoki, Takahira; Arakawa, Hirofumi; Nakamura, Yusuke; Shimano, Takashi; Yanagisawa, Akio; Ushio, Yukitaka; Takano, Sadamu; Ogawa, Michio; Nakamura, Masato; Shibuya, Masabumi; Nishikawa, Ryo; Matsutani, Masao; Hayashi, Yasuhide; Takahashi, Hitoshi; Ikuta, Fusahiro; Nishihira, Tetsuro; Mori, Satoshi

doi:10.1002/gcc.2870090304

Cited by 108 publications

(48 citation statements)

References 25 publications

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“…In embryonic brain, APC mRNA was particularly abundant in cortical, cerebellar, and retinal layers containing newly formed, post-mitotic neurons, suggesting that APC may contribute to suppressing neuronal proliferation (Bhat et al, 1994). The role of APC isoforms in brain may be signi®cant in that germline mutation of APC is associated with central nervous system tumors in some families (Groden, 1995;Mori et al, 1994;Hamilton et al, 1995). The in situ probes used by Bhat and colleagues (1994), however, did not allow determination of the temporal expression and distribution of transcripts likely to encode BS proteins, i.e., transcripts in which BS is spliced to exon 2 vs conventional exon 1-containing APC splice-forms.…”

Section: Discussionmentioning

confidence: 99%

Novel protein isoforms of the APC tumor suppressor in neural tissue

et al. 1998

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Section: Discussionmentioning

confidence: 99%

Novel protein isoforms of the APC tumor suppressor in neural tissue

et al. 1998

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“…In two reports, totaling 49 patients, there was no loss of heterozygosity at the APC allele (Yong et al, 1995;Vortmeyer et al, 1999). Another report failed to reveal any somatic mutations in 49 MBs regardless of whether or not MB was associated with Turcot syndrome (Mori et al, 1994). Two groups have found missense mutations of APC in the 4/143 tumors analysed, but there was no loss of the wild-type allele (Huang et al, 2000;Koch et al, 2001).…”

Section: Introductionmentioning

confidence: 98%

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

et al. 2004

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Germline mutations of APC in patients with Turcot syndrome (colon cancer and medulloblastoma), was well as somatic mutations of APC, b-catenin, and Axin in sporadic medulloblastomas (MBs) have shown the importance of WNT signaling in the pathogenesis of MB. A subset of children with MB have germline mutations of SUFU, a known inhibitor of Hedgehog signal transduction. A recent report suggested that murine Sufu can bind b-catenin, export it from the nucleus, and thereby repress b-catenin/T-cell factor (Tcf)-mediated transcription. We show that an MB-derived mutant of SUFU has lost the ability to decrease nuclear levels of b-catenin, and cannot inhibit b-catenin/Tcf-mediated transcription as compared to wild type SUFU. Our results suggest that loss of function of SUFU results in overactivity of both the Sonic Hedgehog, and the WNT signaling pathways, leading to excessive proliferation and failure to differentiate resulting in MB.

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“…Mutations in PMS2 or MLH1 have been noted in glioblastomas of two Turcot syndrome cases, whereas MSH2 mutations were identified in three Turcot syndrome cases studied by another group (12 -14). Ninety-five percent of hereditary nonpolyposis colorectal cancer cases show microsatellite instability caused by errors in DNA mismatch repair, as compared with only 15% of unselected colon cancers showing microsatellite instability (15). Microsatellite instability has also been exhibited by gliomas in Turcot syndrome.…”

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A Homozygous Mutation in MSH6 Causes Turcot Syndrome

Hegde

Chong

Blazo

et al. 2005

Clinical Cancer Research

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Heterozygous mutations in one of the DNA mismatch repair genes cause hereditary nonpolyposis colorectal cancer (MIM114500). Turcot syndrome (MIM276300) has been described as the association of central nervous system malignant tumors and familial colorectal cancer and has been reported to be both a dominant and recessive disorder. Homozygous and compound heterozygous mutations in APC, MLH1, MSH2, and PMS2 genes have been reported in five families. Here we describe a nonconsanguineous Pakistani family, including a son with lymphoma and colorectal cancer diagnosed at ages 5 and 8, respectively, and an 8-year-old daughter with glioblastoma multiforme. Both children had features of neurofibromatosis type 1 including atypical cafe¤ au lait spots and axillary freckling without a family history consistent with neurofibromatosis type 1, familial adenomatous polyposis, or hereditary nonpolyposis colorectal cancer. Mutational analysis was done for MLH1, MSH2, and MSH6 using denaturing highperformance liquid chromatography and sequencing of a blood sample from the daughter. A novel homozygous single base insertion mutation was identified (3634insT) resulting in a premature stop at codon 1,223 in exon 7 of the MSH6 gene. Both parents were found to be heterozygous for the 3634insT mutation. Microsatellite instability testing showed instability in the glioblastoma sample. We report here the first identification of a homozygous mutation in MSH6 in a family with childhood-onset brain tumor, lymphoma, colorectal cancer, and neurofibromatosis type 1 phenotype. Our findings support a role for MSH6 in Turcot syndrome and are consistent with an autosomal recessive mode of inheritance.

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Germ‐line and somatic mutations of the APC gene in patients with turcot syndrome and analysis of APC mutations in brain tumors

Cited by 108 publications

References 25 publications

Novel protein isoforms of the APC tumor suppressor in neural tissue

Novel protein isoforms of the APC tumor suppressor in neural tissue

Failure of a medulloblastoma-derived mutant of SUFU to suppress WNT signaling

A Homozygous Mutation in MSH6 Causes Turcot Syndrome

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