Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma

Choi, Sukwoo; Kim, Hyeong Ryul; Sung, Chang‐Keun; Kim, Jong-Kyu; Kim, Suk-Jun; Ahn, Sung‐Min; Choi, Chang‐Min; Chun, Sung-Min; Choi, Eun Kyung; Kim, Yong Hee; Lee, Ji-Young; Song, Joon Seon; Kim, Deokhoon; Haq, Farhan; Lee, Sun Young; Lee, Jong-Eun; Jung, Woohyun; Jang, Hye Yoon; Yang, Eunho; Lee, Charles; Yu, Eunsil; Baek, Daehyun; Jang, Se Jin

doi:10.1158/1078-0432.ccr-14-0519

Cited by 14 publications

(8 citation statements)

References 42 publications

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“…There have been prior studies looking at the clinical correlation of RB1 in NSCLC with varying results, summarized in Table . The largest of these by Choi et al used DNA sequencing and identified RB1 mutant status to be associated with shorter disease‐free survival only in early stage adenocarcinoma . The incidence of RB1 mutation of 5.9% in their cohort is comparable to ours.…”

Section: Discussionsupporting

confidence: 76%

Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer

et al. 2019

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The retinoblastoma gene (RB1) encodes the retinoblastoma (RB) pocket protein that plays an important role in cell cycle progression. Here we determine the frequency and prognostic significance of RB1 mutation in non small cell lung cancer (NSCLC), restricting inclusion to Stage III and IV patients with linked genomic and clinical data. The primary outcome was median overall survival (OS). We identified RB1 mutation in 8.2% of NSCLC patients. The median OS for wild‐type (wt) RB1 was 28.3 months vs 8.3 months for mutant RB1 (Hazard Ratio = 2.59, P = 0.002). Of special interest, RB1 mutation also correlated with lack of response to immunotherapy. Our study focused on RB1 mutation in locally advanced and advanced non small cell lung cancer to better facilitate comparisons with small cell lung cancer (SCLC). In our SCLC cohort, RB1 mutation was identified in 75% of patients and wt RB1 was associated with significantly shorter OS (P = 0.002). The different outcomes of RB1 mutation observed among lung cancer subtypes suggest a more complicated mechanism than simple regulation of cell cycle or response to chemotherapy.

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Section: Discussionsupporting

confidence: 76%

Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer

et al. 2019

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“…TP53 was most prevalent among the somatically mutated genes detected in this IPF-LC cohort (22/35, 62.9%) irrespective of tumour subtype (P = 0.157), which is similar to the findings of prior studies conducted in the general LC population (55.5% Korean, Fisher's exact P = 0.533; 72.8% TCGA, P = 0.3) [16,17,36]. Ten somatic mutations in TP53 were located in a previously known recurrent hotspot [37], with the majority of them occurring in the p53 DNA-binding domain and the p53 tetramerization motif, except for four truncating mutations (Figure 2A).…”

Section: Significantly Mutated Genes In Ipf-lcsupporting

confidence: 87%

“…To compare gene mutation frequencies of IPF‐LC samples with those of the control group, clinical and genomic data were additionally obtained from the two previous studies conducted in Korean non‐small‐cell lung cancer (NSCLC) patients and The Cancer Genome Atlas (TCGA) Network. The number and the composition of tumour samples according to the histological subtype in the control group were determined on the basis of the proportion of each histological subtype among all of the IPF‐LC samples.…”

Section: Methodsmentioning

confidence: 99%

Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis

Hwang

Kim

Chun

et al. 2017

The Journal of Pathology

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Little is known about the pathogenesis or molecular profiles of idiopathic pulmonary fibrosis-associated lung cancer (IPF-LC). This study was performed to investigate the genomic profiles of IPF-LC and to explore the possibility of defining potential therapeutic targets in IPF-LC. We assessed genomic profiles of IPF-LC by using targeted exome sequencing (OncoPanel version 2) in 35 matched tumour/normal pairs surgically resected between 2004 and 2014. Germline and somatic variant calling was performed with GATK HaplotypeCaller and MuTect with GATK SomaticIndelocator, respectively. Copy number analysis was conducted with CNVkit, with focal events determined by Genomic Identification of Significant Targets in Cancer 2.0, and pathway analysis (KEGG) with DAVID. Germline mutations in TERT (rs2736100, n = 33) and CDKN1A (rs2395655, n = 27) associated with idiopathic pulmonary fibrosis risk were detected in most samples. A total of 410 somatic mutations were identified, with an average of 11.7 per tumour, including 69 synonymous, 177 missense, 17 nonsense, 1 nonstop and 11 splice-site mutations, and 135 small coding indels. Spectra of the somatic mutations revealed predominant C > T transitions despite an extensive smoking history in most patients, suggesting a potential association between APOBEC-related mutagenesis and the development of IPF-LC. TP53 (22/35, 62.9%) and BRAF (6/35, 17.1%) were found to be significantly mutated in IPF-LC. Recurrent focal amplifications in three chromosomal loci (3q26.33, 7q31.2, and 12q14.3) and 9p21.3 deletion were identified, and genes associated with the JAK-STAT signalling pathway were significantly amplified in IPF-LC (P = 0.012). This study demonstrates that IPF-LC is genetically characterized by the presence of somatic mutations reflecting a variety of environmental exposures on the background of specific germline mutations, and is associated with potentially targetable alterations such as BRAF mutations.

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“…Previous studies have demonstrated that CNV pattern in cfDNA could mirror the primary tumors of prostate and breast cancer 37 , 38 , suggesting CNV in cfDNA might act as a surrogate of primary tumor. Clinical application of cfDNA CNV has been extensively explored and most of the studies focused on the relationship between CNV of specific genes with clinicopathological features or prognosis in NSCLC 39 , 40 . Recently, Louise and colleagues examined the CNV in circulating tumor cells (CTC) from pretreatment blood samples of small cell lung cancer (SCLC) patients and reported that CNV-based classification could distinguish chemosensitive from chemorefractory cases with an accuracy of 83.3% 41 .…”

Section: Discussionmentioning

confidence: 99%

Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC

Jiang

Wang

et al. 2017

Theranostics

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Rationale To investigate whether the mutational landscape of circulating cell-free DNA (cfDNA) could predict and dynamically monitor the response to first-line platinum-based chemotherapy in patients with advanced non-small-cell lung cancer (NSCLC).Methods Eligible patients were included and blood samples were collected from a phase III trial. Both cfDNA fragments and fragmented genomic DNA were extracted for enrichment in a 1.15M size panel covering exon regions of 1,086 genes. Molecular mutational burden (MMB) was calculated to investigate the relationship between molecular features of cfDNA and response to chemotherapy.Results In total, 52 eligible cases were enrolled and their blood samples were prospectively collected at baseline, every cycle of chemotherapy and time of disease progression. At baseline, alterations of 17 genes were found. Patients with partial response (PR) had significantly lower baseline MMB of these genes than those patients with either stable disease (SD) (P = 0.0006) or progression disease (PD) (P = 0.0074). Further analysis revealed that the mutational landscape of cfDNA from pretreatment blood samples were distinctly different among patients with PR vs. SD/PD. For patients with baseline TP53 mutation, those with PR experienced a significant reduction in MMB whereas patients with SD or PD experienced an increase after two, three or four cycles of chemotherapy. Furthermore, patients with low MMB had superior response rate and significantly longer progression-free survival than those with high MMB.Conclusion This study indicated that the mutational landscape of cfDNA has potential clinical value to predict the therapeutic response to first-line platinum-based doublet chemotherapy in NSCLC patients. At the single gene level, dynamic change of molecular mutational burden of TP53 is valuable to monitor efficacy (and, therefore, might aid in early recognition of resistance and relapse) in patients harboring this mutation at baseline.

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Genomic Alterations in the RB Pathway Indicate Prognostic Outcomes of Early-Stage Lung Adenocarcinoma

Cited by 14 publications

References 42 publications

Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer

Retinoblastoma mutation predicts poor outcomes in advanced non small cell lung cancer

Genomic profiles of lung cancer associated with idiopathic pulmonary fibrosis

Mutational Landscape of cfDNA Identifies Distinct Molecular Features Associated With Therapeutic Response to First-Line Platinum-Based Doublet Chemotherapy in Patients with Advanced NSCLC

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