Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation

Pinheiro, Manuela; Pinto, Carla; Peixoto, Ana; Veiga, Isabel; Lopes, Paula; Henrique, Rui; Baldaia, Helena; Carneiro, Fátima; Seruca, Raquel; Tomlinson, Ian; Kováč, Michal; Heinimann, Karl; Teixeira, Manuel R.

doi:10.1038/bjc.2015.281

Cited by 32 publications

(18 citation statements)

References 31 publications

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“…S1), indicating a potential role of this mutation in colorectal cancer. In addition, it was recently reported that 35% of Lynch syndrome colorectal cancers had the same mutation seen in this study (29). Similarly, the frameshift InDel seen here in 72% of MSI tumors in SETD1B (H8fs) has been reported as a confirmed somatic mutation in colorectal cancer, albeit at a mutation rate of $6% (7).…”

Section: Discussionsupporting

confidence: 82%

Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer

et al. 2017

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The contribution of somatic mutations to metastasis of colorectal cancers is currently unknown. To find mutations involved in the colorectal cancer metastatic process, we performed deep mutational analysis of 676 genes in 107 stages II to IV primary colorectal cancer, of which half had metastasized. The mutation prevalence in the ephrin (EPH) family of tyrosine kinase receptors was 10-fold higher in primary tumors of metastatic colorectal than in nonmetastatic cases and preferentially occurred in stage III and IV tumors. Mutational analyses in situ confirmed expression of mutant EPH receptors. To enable functional studies of EPHB1 mutations, we demonstrated that DLD-1 colorectal cancer cells expressing EPHB1 form aggregates upon coculture with ephrin B1 expressing cells. When mutations in the fibronectin type III and kinase domains of EPHB1 were compared with wild-type EPHB1 in DLD-1 colorectal cancer cells, they decreased ephrin B1-induced compartmentalization. These observations provide a mechanistic link between EPHB receptor mutations and metastasis in colorectal cancer.

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Section: Discussionsupporting

confidence: 82%

Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer

et al. 2017

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“…DNA MMR deficiency is known to underlie MSI and hypermutability in LS and sporadic tumors, but the mutational landscapes may differ depending on the mechanism of MMR gene inactivation [ 7 , 15 ]. Even in LS mutation carriers, MSI is not invariably present but shows tumor type-specific variation, likely reflecting different patterns of clonal growth [ 6 ].…”

Section: Discussionmentioning

confidence: 99%

Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

et al. 2017

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Genomic instability and epigenetic aberrations are important classifiers of human tumors, yet, their interrelations are poorly understood. We used Lynch syndrome (LS) to address such relationships. Forty-five tumors (11 colorectal adenomas, 18 colorectal carcinomas, and 16 ovarian carcinomas) were profiled for CpG Island Methylator Phenotype (CIMP) and somatic mutations. All tumors showed high-degree microsatellite instability. Panel sequencing of 578 cancer-relevant genes revealed the average number of 1433, 1124, and 657 non-synonymous somatic mutations per colorectal adenoma, colorectal carcinoma, and ovarian carcinoma, respectively. Genes harboring mutations with allele frequency 25 % or higher in at least 31 % of tumors were regarded to be possible drivers. Among 72 and 10 such genes identified in colorectal and ovarian tumors, respectively, the most frequently mutated genes BRD4 and MLL2 (62 % of colorectal tumors) and ARID1A (50 % of ovarian carcinomas) are involved in epigenetic regulation. The total number of somatic mutations or mutant genes per tumor were significantly associated with CIMP. Our results suggest that even in an inherited disease, tumor type-specific epigenetic changes are significant and may result from regulatory changes (CIMP) or structural events (mutations of epigenetic regulatory genes). The findings are clinically relevant since many of the affected pathways can be therapeutically targeted.

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“…5 Mutations were common in the genes that coding TGF-b signaling proteins. 15 Specially, those mutations major effected TGFBRII and SMAD4. 16,17 TGFBRII mutations were detected nearly 74% of CRC patients with microsatellite instability (MSI) and did not associated with the patients outcome.…”

Section: Discussionmentioning

confidence: 99%

Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer

Yang

Liu

Tan

et al. 2017

Cancer Biology & Therapy

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Advances in multiplex immunohistochemistry (IHC) techniques and digital pathology platforms allow quantification of multiple proteins at same tissue section and produce continuous data. TGF-β signaling plays crucial and complex roles in colorectal cancer (CRC). We here aimed to investigate clinical pathological relevant of proteins involved in TGF-β signaling at CRC tissues. Multiplex fluorescent IHC was used to quantitative analysis. The levels of eight proteins (TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD2/3, p-SMAD2/3, SMAD1/5/9, and p-SMAD1/5/9) were determined in TMA sections. Quantitative analysis was carried out by a scoring system by InForm software. It revealed that TGF-β signaling was hyper active. The levels of TGF-β1, TGFBRI, TGFBRII, SMAD4, SMAD1/5/9 and p-SMAD2/3 were significantly increased in cancer tissues when compared their levels in normal tissues. Furthermore, the levels of eight proteins in stroma were significantly lower than the levels that in cancer tissues. Clinical pathological relevant analysis exhibited that TGF-β signaling inclined to suppress the progression of tumor. SMAD1/5/9, TGFBRII, SMAD2/3 were confirmed as significant predictors for overall survival. In conclusion, we established a method based on multispectral imaging to extensively explore the clinical relevant of TGF-β signaling proteins. These results provided an opportunity to consider the novel application for proteins involving TGF-β signaling that used as diagnostic or prognostic biomarkers to conduct tumor therapy.

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Target gene mutational pattern in Lynch syndrome colorectal carcinomas according to tumour location and germline mutation

Cited by 32 publications

References 31 publications

Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer

Somatic Ephrin Receptor Mutations Are Associated with Metastasis in Primary Colorectal Cancer

Sequencing of Lynch syndrome tumors reveals the importance of epigenetic alterations

Multispectral imaging reveals hyper active TGF-β signaling in colorectal cancer

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