KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming

Na, Feifei; Pan, Xiangyu; Chen, Jingyao; Wang, Manli; Chi, Pengliang; You, Lei; Zhang, Lanxin; Zhong, Ailing; Zhao, Lei; Dai, Siqi; Zhang, Mengsha; Wang, Yiyun; Wang, Bo; Zheng, Jianan; Wang, Yuying; Xu, Jing; Wang, Jian; Wu, Baohong; Chen, Mei; Liu, Hongyu; Xue, Jianxin; Huang, Meijuan; Gong, Yanrong; Zhu, Jiang; Zhou, Lin; Zhang, Yan; Yu, Min; Tian, Panwen; Fan, Ming‐Yu; Lu, Zheng-Hao; Xue, Zhihong; Zhao, Yinglan; Yang, Huiling; Zhao, Chengjian; Wang, Zhongwang; Han, Junhong; Yang, Shengyong; Xie, Dan; Chen, Xuelan; Zhong, Qian; Zeng, Mu‐Sheng; Lowe, Scott W.; Lü, You; Yu, Liu; Wei, Yuquan; Chen, Chong

doi:10.1038/s43018-022-00361-6

Cited by 63 publications

(28 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In a subtractive copy number analysis, we also observed recurrence-specific deletions of KMT2C and MAD1L1, and frequent mutations across the cohort in KMT2C. Loss of KMT2C (MLL3) is associated with progression and metastatic disease in multiple cancer types, including BRCA1/2 mutated breast and ovarian cancers [66][67][68][69][70] . Mitotic arrest deficient-like 1 (MAD1L1) is a component of the mitotic spindle-assembly complex and repressor of TERT; its loss increases chromosomal instability and could allow telomere lengthening 71,72 .…”

Section: Breast Tumormentioning

confidence: 75%

Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers

et al. 2022

View full text Add to dashboard Cite

Recurrence is a major cause of death among BRCA1/2 mutation carriers with breast (BrCa) and ovarian cancers (OvCa). Herein we perform multi-omic sequencing on 67 paired primary and recurrent BrCa and OvCa from 27 BRCA1/2 mutation carriers to identify potential recurrence-specific drivers. PARP1 amplifications are identified in recurrences (False Discovery Rate q = 0.05), and PARP1 is significantly overexpressed across primary BrCa and recurrent BrCa and OvCa, independent of amplification status. RNA sequencing analysis finds two BRCA2 isoforms, BRCA2-201/Long and BRCA2-001/Short, respectively predicted to be sensitive and insensitive to nonsense-mediated decay. BRCA2-001/Short is expressed more frequently in recurrences and associated with reduced overall survival in breast cancer (87 vs. 121 months; Hazard Ratio = 2.5 [1.18–5.5]). Loss of heterozygosity (LOH) status is discordant in 25% of patient’s primary and recurrent tumors, with switching between both LOH and lack of LOH found. Our study reveals multiple potential drivers of recurrent disease in BRCA1/2 mutation-associated cancer, improving our understanding of tumor evolution and suggesting potential biomarkers.

show abstract

Section: Breast Tumormentioning

confidence: 75%

Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers

et al. 2022

View full text Add to dashboard Cite

show abstract

“…The second dataset revealed that despite their abundant expression in orthotopic SCLC cells, relatively high expression levels of IGF2R, ITGAV and THRA were also detected in liver metastases, whereas THRB was absent ( Fig. 5C and D ) ( 22 ). These results suggest that thyroid adenoma signals via IGF, the complement system, collagen system and thyroid hormones, and SCLC cells are well-prepared to receive these signals.…”

Section: Resultsmentioning

confidence: 99%

Clinical characteristics of second primary malignancies among first primary malignancy survivors: A single‑center study, 2005‑2020

Geng

Liu²,

Chen

et al. 2022

Oncol Lett

View full text Add to dashboard Cite

The cancer survivor population is growing due to advances in detection and treatment. For improved long-term patient management, it is critical to examine the clinical characteristics and outcomes of second primary malignancies (SPMs). An SPM is defined as a second distinct pathological diagnosis, with the same or different origin as the first primary malignancy (FPM). In the present retrospective study, categorical clinical variables were compared between subgroups and the impact on overall survival was evaluated. A total of 1,188 patients with an FPM were included, of which 102 experienced an SPM (8.59%). When compared with the patients who did not develop an SPM, patients with an SPM were significantly older at first diagnosis, had a higher pathological stage and higher rates of biliary tract disease and thyroid disease. In addition, patients with an SPM were more likely to have received postoperative chemotherapy (28.43 vs. 12.16%, P<0.0001) and to be long-term consumers of cigarettes and alcohol (25.00 vs. 8.95%, P<0.05). In addition, an increase in the number of regimens received but not in the number of courses of chemotherapy was associated with a reduction in the time interval to SPM development. Non-small cell lung cancer (NSCLC) was the most common type of FPM (18.27%). In patients with NSCLC the occurrence of SPMs was relatively low (5.07%) and the SPM-associated mortality rate was 2.30%. Breast cancer was the second common type of FPM (12.09%). Patients with breast cancer had a relatively high likelihood of developing an SPM (9.30%), for which family history of malignancy and postoperative chemotherapy were identified as potential risk factors. Patients with stomach cancer were the most vulnerable to SPM (17.95%) and patients with digestive tract cancer had the longest time interval between the FPM and SPM development. In addition, thyroid adenoma was identified as a potential risk factor for SCLC. The findings of the present study may provide valuable guidance for the short-and long-term monitoring of FPM survivors.

show abstract

“…Transformed organoids were then transplanted into the lungs of syngeneic mice, recapitulating the pathogenesis of human LUAD [ 68 ]. A model of tumorigenesis based on engineered mouse LCOs was recently employed to investigate the mechanisms of SCLC metastasis, finding that deficiency of the histone H3 lysine 4 methyltransferase KMT2C promoted extensive tumor metastasization [ 69 ]. Further insights in multi-step lung carcinogenesis were provided by Miura et al, showing that exogenous HER2 expression in iPSC-derived human lung organoids induced the formation of tumor-like structures and a transcriptional profile similar to LUAD with HER2 amplification [ 70 ].…”

Section: Preclinical Applications Of Lung Cancer Organoidsmentioning

confidence: 99%

Lung Cancer Organoids: The Rough Path to Personalized Medicine

Rossi

Angelis

Xhelili

et al. 2022

Cancers

View full text Add to dashboard Cite

Lung cancer is the leading cause of cancer death worldwide. Despite significant advances in research and therapy, a dismal 5-year survival rate of only 10–20% urges the development of reliable preclinical models and effective therapeutic tools. Lung cancer is characterized by a high degree of heterogeneity in its histology, a genomic landscape, and response to therapies that has been traditionally difficult to reproduce in preclinical models. However, the advent of three-dimensional culture technologies has opened new perspectives to recapitulate in vitro individualized tumor features and to anticipate treatment efficacy. The generation of lung cancer organoids (LCOs) has encountered greater challenges as compared to organoids derived from other tumors. In the last two years, many efforts have been dedicated to optimizing LCO-based platforms, resulting in improved rates of LCO production, purity, culture timing, and long-term expansion. However, due to the complexity of lung cancer, further advances are required in order to meet clinical needs. Here, we discuss the evolution of LCO technology and the use of LCOs in basic and translational lung cancer research. Although the field of LCOs is still in its infancy, its prospective development will likely lead to new strategies for drug testing and biomarker identification, thus allowing a more personalized therapeutic approach for lung cancer patients.

show abstract

KMT2C deficiency promotes small cell lung cancer metastasis through DNMT3A-mediated epigenetic reprogramming

Cited by 63 publications

References 46 publications

Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers

Analysis of matched primary and recurrent BRCA1/2 mutation-associated tumors identifies recurrence-specific drivers

Clinical characteristics of second primary malignancies among first primary malignancy survivors: A single‑center study, 2005‑2020

Lung Cancer Organoids: The Rough Path to Personalized Medicine

Contact Info

Product

Resources

About