Frequent Alteration of MLL3 Frameshift Mutations in Microsatellite Deficient Colorectal Cancer

Watanabe, Yoshiyuki; Castoro, Ryan; Kim, Hyun Soo; North, Brittany; Oikawa, Ritsuko; Hiraishi, Tetsuya; Ahmed, Saira; Chung, Woonbok; Cho, Mee Yon; Toyota, Minoru; Itoh, Fumio; Estécio, Marcos R.H.; Shen, Lanlan; Jelı́nek, Jaroslav; Issa, Jean–Pierre J.

doi:10.1371/journal.pone.0023320

Cited by 67 publications

(59 citation statements)

References 20 publications

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“…We found also frameshift mutation in the other repeat of MLL3 (c.8525insA). We found MLL3 frameshift mutations in 7.5% of CRC with MSI, which were in contrast with other study where the mutations had been detected in 24.5% of CRC [18] (Fisher's exact test, p = 0.024). By contrast, the incidence in GC was not statistically different (Fisher's exact test, p > 0.05).…”

Section: Discussioncontrasting

confidence: 99%

“…An earlier study documented that CRC with MSI-H harbored a type of MLL3 frameshift mutation (c.8390delA) in 24.5% of the cases [18]. In our study, we found MLL3 frameshift mutations in GC with MSI that had not been reported yet.…”

Section: Discussionsupporting

confidence: 57%

“…Somatic mutations of the MLL2 gene have also been identified in medulloblastomas and lymphomas [16,17]. Somatic mutations of MLL3 gene have been found in colorectal cancers (CRC) [18,19]. An earlier study found missense mutations of MLL3, while another study reported absence of MLL3 missense mutation in CRC [19,20].…”

Section: Mixed Lineage Leukemia (Mll) Genes Include Mll Mll2 Mll3 mentioning

confidence: 99%

“…It is possible that frameshift mutations of the MLL-encoding genes could cause alterations of MLL functions and contribute to cancer pathogenesis in the cancers with MSI. However, frameshift mutations among these genes are known only in the MLL3 in CRC [18]. In this study, we used tumors that had already been evaluated their MSI status by a well developed criteria.…”

Section: Mixed Lineage Leukemia (Mll) Genes Include Mll Mll2 Mll3 mentioning

confidence: 99%

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Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Je¹,

Yoo²,

LEE³

2012

neo

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MLL genes encode histone methyltransferases that are required for proper expression of a variety of genes. The pathologic implications of MLL genes have been studied not only in leukemias, but also in some solid cancers. We found in a public database that MLL, MLL2, MLL3, MLL4 and MLL5 genes had mononucleotide repeats that might be mutated in cancers with microsatellite instability (MSI). Frameshift mutations in a repeat of MLL3 have been found in colorectal cancers (CRC), but there is no frameshift mutation data of the other genes. In this study, we analyzed these repeats in 32 gastric cancers (GC) with high MSI (MSI-H), 59 GC with low MSI (MSI-L)/stable MSI (MSS), 40 CRC with MSI-H and 59 CRC with MSI-L/MSS by single-strand conformation polymorphism and DNA sequencing. We also analyzed MLL3 expression in GC and CRC tissues using immunohistochemistry. We found MLL, MLL2, MLL3 and MLL5 frameshift mutations in two (one GC and one CRC), three (one GC and two CRC), 17 (14 GC and three CRC) and six (four GC and two CRC) cancers, respectively. They were detected exclusively in MSI-H cancers, but not in MSI-L/MSS cancers. All of the cancers with MLL3 mutations showed loss of MLL3 expression, and their values were significantly lower than in those without MLL3 mutation (50.9%). Of note, the GC with MSI-H had significantly higher incidences in both MLL mutations and MLL3 expression loss than the CRC with MSI-H. Our data indicate that frameshift mutations of MLL genes and loss of expression of MLL3 protein are common in GC and CRC with MSI-H.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionsupporting

confidence: 57%

Section: Mixed Lineage Leukemia (Mll) Genes Include Mll Mll2 Mll3 mentioning

confidence: 99%

Section: Mixed Lineage Leukemia (Mll) Genes Include Mll Mll2 Mll3 mentioning

confidence: 99%

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Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Je¹,

Yoo²,

LEE³

2012

neo

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“…MLL3 is located on chromosome 7q36.1 and has been associated with different types of cancers. MLL3 presents inactivating mutations in medulloblastoma (26) and colorectal cancer (27). Moreover, it shows reduced expression in primary breast tumor samples (28) and radioresistant esophageal cancer cell lines (29).…”

Section: Discussionmentioning

confidence: 99%

Assessment of MLL methyltransferase gene expression in larynx carcinoma

et al. 2015

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Abstract. Larynx cancer is the second most common type of cancer among all head and neck cancers. Deregulation of epigenetic effectors, including altered expression of histone methyltransferases from the MLL (mixed lineage leukemia) family, have been reported in many cancer types, yet little is known concerning their involvement in larynx cancer. Our objective was to determine the expression profile of MLL genes in larynx carcinoma and normal adjacent tissues and correlate this profile to tumor characteristics. We analyzed the expression profile of 5 MLL genes in 13 cases of larynx carcinoma and their adjacent non-tumor tissues using quantitative real-time PCR. MLL3 was significantly downregulated in tumor samples compared to their normal counterparts, and all MLL genes showed decreased expression in advanced tumors compared to tumors in the initial stage. Altered expression in a single MLL gene was associated with a similar alteration in the other MLL genes, revealing a strong correlation of expression in each individual patient. In conclusion, MLL genes may have similar transcriptional control, and decreased expression of these genes may contribute to larynx cancer progression. IntroductionLarynx cancer is the second most common among all head and neck cancers, representing 2% of all malignant diseases worldwide, with 140,000 cases occurring every year (1). In Brazil alone, there is an estimated risk of 7 cases for every 100,000 men. Usually, affected men are over the age of 40 years. The registered incidence of this cancer in women is very low, accounting for less than 1 case for every 100,000 women. The disease can cause hoarseness, dysphagia, odynophagia, pain and other symptoms, according to the affected site (supraglottis, glottis, subglottis). Early detection leads to a better prognosis, enabling a cure in the majority of the cases, while patients with advanced tumors usually succumb to the disease (2). Tobacco is the main associated risk factor, with a positive correlation of duration and intensity of smoking and increased risk for larynx cancer. Other risk factors include alcohol consumption, occupational exposures and various dietary habits. Moreover, the risk for larynx cancer increases with the combined effect of smoking and alcohol consumption (2). Studies concerning the association of human papillomavirus (HPV) infection with larynx cancer are heterogeneous and inconclusive, yet HPV infection appears to be associated with the risk of larynx cancer, particularly with the high-risk type HPV16 (3).Almost all cancers occurring in the head and neck are squamous cell carcinomas. Although they have the same histological characteristics, they appear to have genetic and epigenetic differences, depending on the site. Allelic loss leading to the loss of function of tumor-suppressor genes are an important alteration in larynx tumors, such as the loss of heterozygosity (LOH) at 9p21, a region harboring the cell cycle regulator p16 gene (4). LOH at 8p was also found to be common in larynx and oral squamous cell...

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Enhancer deregulation in cancer and other diseases

Herz

2016

BioEssays

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Summary Mutations in enhancer-associated chromatin-modifying components and genomic alterations in non-coding regions of the genome occur frequently in cancer and other diseases pointing to the importance of enhancer fidelity to ensure proper tissue homeostasis. In this review, I will use specific examples to discuss how mutations in chromatin-modifying factors might affect enhancer activity of disease-relevant genes. I will then consider direct evidence from single nucleotide polymorphisms, small insertions or deletions but also larger genomic rearrangements such as duplications, deletions, translocations and inversions of specific enhancers to demonstrate how they have the ability to impact enhancer activity of disease genes including oncogenes and tumor suppressor genes. Considering that the scientific community only fairly recently has begun to focus its attention on “enhancer malfunction” in disease, I propose that multiple new enhancer-regulated and disease-relevant processes will be uncovered in the near future that will constitute the mechanistic basis for novel therapeutic avenues.

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Frequent Alteration of MLL3 Frameshift Mutations in Microsatellite Deficient Colorectal Cancer

Cited by 67 publications

References 20 publications

Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Mutational and expressional analysis of MLL genes in gastric and colorectal cancers with microsatellite instability

Assessment of MLL methyltransferase gene expression in larynx carcinoma

Enhancer deregulation in cancer and other diseases

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