New Target Genes in Endometrial Tumors Show a Role for the Estrogen-Receptor Pathway in Microsatellite-Unstable Cancers

Ferreira, Ana M.; Tuominen, Iina; Sousa, Sónia; Gerbens, Frans; Dijk-Bos, Krista van; Osinga, Jan; Kooi, Krista; Sanjabi, Bahram; Esendam, Chris; Oliveira, Carla; Terpstra, Peter; Hardonk, Menno; Sluis, Tineke van der; Zazula, Monika; Stachura, Jerzy; Zee, Ate Gj van der; Hollema, H; Sijmons, Rolf H.; Aaltonen, Lauri A.; Seruca, Raquel; Hofstra, Robert; Westers, Helga

doi:10.1002/humu.22700

Cited by 10 publications

(11 citation statements)

References 45 publications

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“…The overall JAK1 mutation frequency of 28% in our large series of MSI endometrial cancers is in line with findings from two recent smaller studies [4, 5]. Both studies also showed that JAK1 frameshift mutations in MSI tumors are tissue specific and significantly less important in colorectal cancers as compared with endometrial cancers.…”

Section: Discussionsupporting

confidence: 91%

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Microsatellite instability derivedJAK1frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer

et al. 2016

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JAK1 frameshift mutations may promote cancer cell immune evasion by impeding upregulation of the antigen presentation pathway in microsatellite unstable endometrial cancers (ECs). This study investigated the JAK1 mutation frequency, its functional implication in immune evasion and its prognostic significance in microsatellite unstable EC. Microsatellite instability and three microsatellite repeats within JAK1 were analyzed in 181 ECs. Sixty-two (34%) ECs showed microsatellite instability, of which 22 (35%) had a JAK1 mutation. LMP7, TAP1 and HLA class I protein expression and the presence of CD8-positive T-cells were analyzed in the microsatellite unstable ECs. JAK1 mutant microsatellite unstable ECs showed impaired upregulation of LMP7 (P=0.074) and HLA class I (P<0.001), validated using RNAseq data of the TCGA. TAP1 expression and presence of CD8-positive T-cells were not related to JAK1 mutations. In 198 additional microsatellite unstable ECs, the JAK1 mutation frequency was confirmed but no prognostic significance was found. For, JAK1 wildtype (n=135, 72%) and mutant (n=52, 28%) ECs, 10-year recurrence free rates were 84% and 77% (P=0.301). These observations show that JAK1 mutations are highly frequent in microsatellite unstable EC, not associated with survival, but are associated with impaired upregulation of LMP7 and HLA class I and may therefore facilitate immune escape.

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Section: Discussionsupporting

confidence: 91%

“…colorectal- and ovarian cancer), whereas others, such as JAK1 , have a very restricted occurrence in MSI endometrial cancers [3–6]. MSI endometrial cancers show a remarkably high number of JAK1 frameshift mutations that may have clinical implications [4, 5]. …”

Section: Introductionmentioning

confidence: 99%

Microsatellite instability derivedJAK1frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer

et al. 2016

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“…Therefore, specific tumorigenesis pathways associated to a specific type of tissue might have been missed using this strategy. That was the reason why we performed an unbiased screen for target gene mutations in endometrial carcinomas [9] .…”

Section: Reviewmentioning

confidence: 99%

“…Doing so we identified 44 possible target genes of which seven are highly mutated (>15%). Some candidates were also found mutated in colorectal and gastric tumors [9] .…”

Section: Target Genes In Endometrial Carcinomasmentioning

confidence: 99%

“…Also the RAR pathway was one of the networks showing a deregulation of many of its members due to NRIP1 knock-down. On forehand we expected that the inactivation of NRIP1 would interfere with the process of co-repression of the ER complex and lead to differences in the expression of estrogen-dependent genes; indeed that's what the Ingenuity Pathway analysis (IPA) showed us [9] . From literature it is known that there is an important correlation between NRIP1 and the RAR pathways, and that the RAR pathway is implicated in many types of cancer, including endometrial cancer and other hormone-dependent cancers [14][15][16][17] .…”

Section: Nrip1 Silencing In Endometrial Cancermentioning

confidence: 99%

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Estrogen pathway mutations and cancer

Ferreira¹,

Hofstra²,

Westers³

2015

Receptor Clin Invest

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Cancer is caused by an accumulation of mutations in a stem cell. A defective mismatch repair (MMR) systemcan lead to such an accumulation of mutations. MMR defects are found in a cancer syndrome called Lynch Syndrome, and tumors of this syndrome are indeed characterized by such an accumulation of mutations, particularly in short repetitive DNA sequences, called microsatellites. When such mutated microsatellites are located in the coding sequences of genes with essential roles for tumorigenesis, we speak of 'target genes'. Many such target genes have been found and in this review we focus the possible involvement of target genes involved in the estrogen-receptor pathway (ER). We recently identified NRIP1, encoding the nuclear receptor-interacting protein 1, as the most frequently mutated gene in microsatellite instable (MSI) endometrial cancer (EC). NRIP1 is a known corepressor of the ER pathway, the pathway essential in regulating the concentrations of estrogens, a hormone for which the endometrium is highly responsive. This in combination with the fact that high exposure to estrogens is currently considered the major risk factor for EC -approximately 80% of all sporadic EC tumors are estrogen dependent carcinomas -make NRIP1 the perfect target gene for EC. Interestingly, mutations in NRIP1 were also detected in MSI colorectal carcinoma (CRC) samples. Finding mutations in an estrogen receptor signaling protein in colorectal tissue might not be that expected, as colon is not typically associated with being responsive to estrogens. However, evidence is accumulating to better understand this finding. For instance, it was shown that NRIP1, in colon tissue, stimulates APC gene transcription and inhibits β-catenin activation. Moreover, some studies suggested that estrogens can increase the expression of MLH1 in colon cancer cells, highlighting the implications of estrogen protecting against colon cancer, by regulating the MMR system. All in all we conclude that genes involved in the estrogen pathway are the perfect candidates to be studied in MMR-deficient tumors, especially those developing in hormonal responsive tissues. Mismatch repair (MMR) and endometrial carcinomasGenetic inactivation of mismatch repair (MMR) genes, by mutations or epigenetic alterations, eventually leads to the accumulation of mutations that otherwise would be corrected. These mutations are easily visualized by analyzing short repetitive DNA sequences, called microsatellites. An accumulation of mutations in such microsatellites is known as microsatellite instability or MSI. MSI, caused by defects in the MMR system, is the hallmark of Lynch syndrome, a hereditary disease, characterized by the development of hereditary carcinomas, such as colorectal-, endometrial-, and gastric carcinomas. Moreover MSI is also observed in a percentage (15-25%) of sporadic tumors [1][2][3][4][5].

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Next-Generation Sequencing

Gallo

Lozy

Bell

2016

Advances in Experimental Medicine and Biology

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Endometrial cancers are the most frequently diagnosed gynecological malignancy and were expected to be the seventh leading cause of cancer death among American women in 2015. The majority of endometrial cancers are of serous or endometrioid histology. Most human tumors, including endometrial tumors, are driven by the acquisition of pathogenic mutations in cancer genes. Thus, the identification of somatic mutations within tumor genomes is an entry point toward cancer gene discovery. However, efforts to pinpoint somatic mutations in human cancers have, until recently, relied on high-throughput sequencing of single genes or gene families using Sanger sequencing. Although this approach has been fruitful, the cost and throughput of Sanger sequencing generally prohibits systematic sequencing of the ~22,000 genes that make up the exome. The recent development of next-generation sequencing technologies changed this paradigm by providing the capability to rapidly sequence exomes, transcriptomes, and genomes at relatively low cost. Remarkably, the application of this technology to catalog the mutational landscapes of endometrial tumor exomes, transcriptomes, and genomes has revealed, for the first time, that serous and endometrioid endometrial cancers can be classified into four distinct molecular subgroups. In this chapter, we overview the characteristic genomic features of each subgroup and discuss the known and putative cancer genes that have emerged from next-generation sequencing of endometrial carcinomas.

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New Target Genes in Endometrial Tumors Show a Role for the Estrogen-Receptor Pathway in Microsatellite-Unstable Cancers

Cited by 10 publications

References 45 publications

Microsatellite instability derivedJAK1frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer

Microsatellite instability derivedJAK1frameshift mutations are associated with tumor immune evasion in endometrioid endometrial cancer

Estrogen pathway mutations and cancer

Next-Generation Sequencing

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