Mutation of TCF1 encoding hepatocyte nuclear factor 1α in gynecological cancer

Rebouissou, Sandra; Rosty, Christophe; Lécuru, Fabrice; Boisselier, Sophie; Bui, Hung; Frere-Belfa, Marie-Aude Le; Sastre, Xavier; Laurent‐Puig, Pierre; Zucman‐Rossi, Jessica

doi:10.1038/sj.onc.1207989

Cited by 21 publications

(16 citation statements)

References 18 publications

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“…Of interest, over half of these regions (9/14, 64%) included genes that are of known significance in cancer such as the DHFR gene, whose product may confer methotrexate resistance, and the PCBD2 gene, which is a co-factor for TCF1 [39], [40].…”

Section: Resultsmentioning

confidence: 99%

Second Generation Sequencing of the Mesothelioma Tumor Genome

et al. 2010

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The current paradigm for elucidating the molecular etiology of cancers relies on the interrogation of small numbers of genes, which limits the scope of investigation. Emerging second-generation massively parallel DNA sequencing technologies have enabled more precise definition of the cancer genome on a global scale. We examined the genome of a human primary malignant pleural mesothelioma (MPM) tumor and matched normal tissue by using a combination of sequencing-by-synthesis and pyrosequencing methodologies to a 9.6X depth of coverage. Read density analysis uncovered significant aneuploidy and numerous rearrangements. Method-dependent informatics rules, which combined the results of different sequencing platforms, were developed to identify and validate candidate mutations of multiple types. Many more tumor-specific rearrangements than point mutations were uncovered at this depth of sequencing, resulting in novel, large-scale, inter- and intra-chromosomal deletions, inversions, and translocations. Nearly all candidate point mutations appeared to be previously unknown SNPs. Thirty tumor-specific fusions/translocations were independently validated with PCR and Sanger sequencing. Of these, 15 represented disrupted gene-encoding regions, including kinases, transcription factors, and growth factors. One large deletion in DPP10 resulted in altered transcription and expression of DPP10 transcripts in a set of 53 additional MPM tumors correlated with survival. Additionally, three point mutations were observed in the coding regions of NKX6-2, a transcription regulator, and NFRKB, a DNA-binding protein involved in modulating NFKB1. Several regions containing genes such as PCBD2 and DHFR, which are involved in growth factor signaling and nucleotide synthesis, respectively, were selectively amplified in the tumor. Second-generation sequencing uncovered all types of mutations in this MPM tumor, with DNA rearrangements representing the dominant type.

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Section: Resultsmentioning

confidence: 99%

Second Generation Sequencing of the Mesothelioma Tumor Genome

et al. 2010

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“…14 Furthermore, among the benign hepatocellular tumors, HNF1␣ mutations occur specifically in adenomas as no mutations were identified either in typical FNH or TFNH cases, 12 in contrast to rare mutations observed in endometrial, colon, and renal carcinomas. [15][16][17] Recently, activation of the ␤-catenin pathway was also found in HA. [18][19][20] Conversely, activating mutations of ␤-catenin are found in 20% to 34% of hepatocellular carcinomas, [21][22][23][24] suggesting that ␤-catenin is the most frequently activated oncogene in HCC.…”

Section: (Omim#142330)mentioning

confidence: 99%

Genotype–phenotype correlation in hepatocellular adenoma: New classification and relationship with HCC

et al. 2006

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Hepatocellular adenomas are benign tumors that can be difficult to diagnose. To refine their classification, we performed a comprehensive analysis of their genetic, pathological, and clinical features. A multicentric series of 96 liver tumors with a firm or possible diagnosis of hepatocellular adenoma was reviewed by liver pathologists. In all cases, the genes coding for hepatocyte nuclear factor 1␣ (HNF1␣) and ␤-catenin were sequenced. No tumors were mutated in both HNF1␣ and ␤-catenin enabling tumors to be classified into 3 groups, according to genotype. Tumors with HNF1␣ mutations formed the most important group of adenomas (44 cases). They were phenotypically characterized by marked steatosis (P < 10 ؊4 ), lack of cytological abnormalities (P < 10 ؊6 ), and no inflammatory infiltrates (P < 10 ؊4 ). In contrast, the group of tumors defined by ␤-catenin activation included 13 lesions with frequent cytological abnormalities and pseudo-glandular formation (P < 10 ؊5 ). The third group of tumors without mutation was divided into two subgroups based on the presence of inflammatory infiltrates. The subgroup of tumors consisting of 17 inflammatory lesions, resembled telangiectatic focal nodular hyperplasias, with frequent cytological abnormalities (P ‫؍‬ 10 ؊3 ), ductular reaction (P < 10 ؊2 ), and dystrophic vessels (P ‫؍‬ .02). In this classification, hepatocellular carcinoma associated with adenoma or borderline lesions between carcinoma and adenoma is found in 46% of the ␤-catenin-mutated tumors whereas they are never observed in inflammatory lesions and are rarely found in HNF1␣ mutated tumors (P ‫؍‬ .004). In conclusion, the molecular and pathological classification of hepatocellular adenomas permits the identification of strong genotype-phenotype correlations and suggests that adenomas with ␤-catenin activation have a higher risk of malignant transformation. (

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“…The mutations were predicted to inactivate the protein as they included mainly nonsense and frame-shift mutations within the N-terminal portion of the protein, or mutations leading to amino-acid substitutions within the homeodomain (80)(81)(82). Mutations of HNF1α or HNF1ß have also been identified in rare cases of colon, renal, breast and endometrial cancers (83)(84)(85)(86).…”

Section: A-hnf1α Inactivationmentioning

confidence: 99%