KMT2D Mutation Is Associated With Poor Prognosis in Non–Small-Cell Lung Cancer

Ardeshir‐Larijani, Fatemeh; Bhateja, Priyanka; Lipka, Mary Beth; Sharma, Neelesh; Fu, Pingfu; Dowlati, Afshin

doi:10.1016/j.cllc.2018.03.005

Cited by 38 publications

(31 citation statements)

References 36 publications

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“…STK11 is a tumor suppressor gene and the methylation of its promoter in renal cell carcinoma was reported as a risk factor for prognosis (56). The mutations of KMT2D and TERT have been reported to be associated with prognosis in different tumors (57)(58)(59). Histopathological grade is considered to be associated with the clinical characteristics of lymphovascular invasion, perineural invasion, tumor differentiation, lymph node and metastasis, as well as the prediction of prognosis (60,61).…”

Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profile of cholangiocarcinomas in China

Shi

Liu

et al. 2020

Oncol Lett

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Cholangiocarcinoma (CCA) is a primary malignancy, which is often diagnosed as locally advanced or metastatic. Previous studies have revealed genomic characteristics of CCA in Western patients, however comprehensive genomic features of CCA in Chinese patients have not been well understood. To explore the specific genomic characteristics of Chinese patients with CCA, a total of 66 patients with CCA, including 44 intrahepatic CCA (iCCA) and 22 extrahepatic CCA (exCCA) cases, were studied. The most commonly altered genes in CCAs were TP53 (62.12%, 41/66), KRAS (36.36%, 24/66), SMAD4 (24.24%, 16/66), TERT (21.21%, 14/66), ARID1A (19.70%, 13/66), CDKN2A (19.70%, 13/66), KMT2C (9.09%, 6/66) and RBM10 (9.09%, 6/66), ERBB2 (7.58%, 5/66) and BRAF (7.58%, 5/66). Many gene mutations, including STK11, CCND1 and FGF19, were only found in iCCA. RBM10 mutations were found to be significantly higher in exCCA. The gene mutations of neurofibromin 1, STK11, CCND1 and FBXW7 specifically occurred in males, whereas gene mutations of ERBB2, AXIN2 and CREBBP specifically occurred in females. ERBB2 mutations were significantly associated with the sex of patients with CCA. Mutations in PIK3CA, FGFR2 and ZNF750 were significantly associated with the age of patients with CCA and TERT mutations were significantly associated with tumor differentiation. Alterations in KMT2C, PBRM1, AXIN2, MAGI2, BRCA2 and SPTA1 were associated with tumor mutational burden. The findings of the present study suggest that targeted sequencing, using next-generation sequencing technology, provides comprehensive and accurate information on genomic alterations, which will provide novel potential biomarkers for the diagnosis of CCA and may guide precise therapeutic strategies for Chinese patients with CCA.

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Section: Discussionmentioning

confidence: 99%

Comprehensive genomic profile of cholangiocarcinomas in China

Shi

Liu

et al. 2020

Oncol Lett

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“…Although their variant frequencies were slightly higher than those documented by Tan et al and Tay et al (see supplementary material, Table S3), they provided an additional basis for FA tumourigenesis. KMT2D encodes for lysine (K)‐specific methyltransferase 2D, which is a histone methyltransferase that controls gene activity, normally acting as a tumour suppressor while its inactivating mutation had been described in solid tumours such as breast, lung, and prostate carcinomas . RARA encodes for the retinoic acid receptor alpha and functions as a transcription factor by regulating expression of its target genes in cellular differentiation and proliferation .…”

Section: Discussionmentioning

confidence: 99%

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Nasir

Rajasegaran

et al. 2019

The Journal of Pathology

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Fibroepithelial lesions (FELs) are a heterogeneous group of tumours comprising fibroadenomas (FAs) and phyllodes tumours (PTs). Here we used a 16-gene panel that was previously discovered to be implicated in pathogenesis and progression, to characterise a large international cohort of FELs via targeted sequencing. The study comprised 303 (38%) FAs and 493 (62%) PTs which were contributed by the International Fibroepithelial Consortium. There were 659 (83%) Asian and 109 (14%) non-Asian FELs, while the ethnicity of the rest was unknown. Genetic aberrations were significantly associated with increasing grade of PTs, and were detected more in PTs than FAs for MED12, TERT promoter, RARA, FLNA, SETD2, TP53, RB1, EGFR, and IGF1R. Most borderline and malignant PTs possessed ≥ 2 mutations, while there were more cases of FAs with ≤ 1 mutation compared to PTs. FELs with MED12 mutations had significantly higher rates of TERT promoter, RARA, SETD2, EGFR, ERBB4, MAP3K1, and IGF1R aberrations. However, FELs with wild-type MED12 were more likely to express TP53 and PIK3CA mutations. There were no significant differences observed between the mutational profiles of recurrent FAs, FAs with a history of subsequent ipsilateral recurrence or contralateral occurrence, and FAs without a history of subsequent events. We identified recurrent mutations which were more frequent in PTs than FAs, with borderline and malignant PTs harbouring cancer driver gene and multiple mutations. This study affirms the role of a set of genes in FELs, including its potential utility in classification based on mutational profiles.Conflict of interest statement: PHT, BTT, and PT jointly hold patent applications for PCT/SG2015/050107 (Breast fibroadenoma susceptibility mutations and use thereof) and PCT/SG2015/050368 (Method and kit for pathologic grading of breast neoplasms). The other authors declare no competing interests.

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“…But there are exceptions, e.g. in P2 potentially pathogenic mutation in KMT2D, a histone methyl-transferase implicated in non-small cell lung cancer (Ardeshir-Larijani et al, 2018), was only found in regions R2 and R3 but not in R1 region. Similarly, sample P3 harbors a potentially deleterious mutation in CASP9, a tumor suppressor, only in region R3.…”

Section: Landscape Of Genomic Changes In the Tumor Samplesmentioning

confidence: 99%

Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors

Sharma

Merritt

Cruz

et al. 2019

Preprint

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Impacts of genetic and non-genetic intra-tumor heterogeneity (ITH) on tumor phenotypes and evolvability remain debated. We analyzed ITH in lung squamous cell carcinoma (LUSC) at the levels of genome, transcriptome, tumor-immune interactions, and histopathological characteristics by multi-region profiling and using single-cell sequencing data. Overall, in LUSC genomic heterogeneity alone was a weak indicator of intra-tumor non-genetic heterogeneity at immune and transcriptomic levels that impacted multiple cancer-related pathways including those related to proliferation and inflammation, which in turn contributed to intra-tumor regional differences in histopathology and subtype classification. Genome, transcriptome, and immune-level heterogeneity influenced different aspects of tumor evolution. Tumor subclones had substantial differences in proliferation score, suggestive of non-neutral clonal dynamics. Scores for proliferation and other cancer-related pathways also showed intra-tumor regional differences, sometimes even within the same subclones. Neo-epitope burden negatively correlated with immune infiltration, indicating potential immune-mediated purifying selection on acquired mutations in these tumors. Taken together, our observations suggest that non-genetic heterogeneity is a major determinant of heterogeneity in histopathological characteristics and impacts evolutionary dynamics in lung cancer.

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KMT2D Mutation Is Associated With Poor Prognosis in Non–Small-Cell Lung Cancer

Cited by 38 publications

References 36 publications

Comprehensive genomic profile of cholangiocarcinomas in China

Comprehensive genomic profile of cholangiocarcinomas in China

Genomic characterisation of breast fibroepithelial lesions in an international cohort

Non-genetic intra-tumor heterogeneity is a major predictor of phenotypic heterogeneity and ongoing evolutionary dynamics in lung tumors

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