Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets

Veldore, Vidya Harini; Patil, Shekar; Satheesh, C T; H, Shashidhara; Tejaswi, R; Prabhudesai, Shilpa; Krishnamoorthy, Naveen; Hazarika, Diganta; Naik, Radheshyam; Rao, Raghavendra; Kumar, B S Ajai

doi:10.4103/0019-509x.175843

Cited by 11 publications

(10 citation statements)

References 2 publications

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“…Overall, this can mean that the KDR mutation leads to high expression of KDR protein. In addition, KDR gene mutation has been previously reported to play a therapeutic role using Regorafenib in metastatic colon cancer [14] as well as in Nonsmall cell lung cancer [27]. On the contrary, it has also been reported to occur as an adverse effect of Ramucirumab therapy [28] and may lead to side effects when used with FGFR inhibitors for treatment.…”

Section: Discussionmentioning

confidence: 94%

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

Jauhri¹,

Gupta²,

Shokeen³

et al. 2017

Next Generat Sequenc & Applic

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Aim: This study aims to find out the frequency of KDR mutation in colorectal cancer patients and if any correlation exists between KDR mutation and demographical features or with other common and uncommon gene mutations occurring in colon cancer.Methods: FFPE samples of 112 patients were analyzed using next generation sequencing.Results: KDR gene was found to be mutated most frequently (19.6%) as compared to other uncommon gene mutations occurring among patients. 21/22 patients had the p.Q472H type of KDR mutation. It was significantly associated with mutations in PTEN (p=0.003), KRAS (p=0.026), APC (p=0.033), EGFR (p=0.036), NOTCH1 (p=0.029) and ERBB4 (p=0.008) mutations. More number of males (22.06%) harbored KDR mutations than the number of females (15.9%). A higher number of KDR mutations in Stage III (31%) as compared to other stages -I-II (19.23%) and IV (7.31%) was reported. KDR mutations were found to be in greater number in patients with lymph node metastasis (27.3%) as compared to liver metastasis (8%). However, a statistically significant association of any clinical parameter was not found. Conclusion:Our results suggest that although KDR is a rare somatic mutation in CRC, it plays a pivotal role in the development of colon cancer via angiogenesis pathway.

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Section: Discussionmentioning

confidence: 94%

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

Jauhri¹,

Gupta²,

Shokeen³

et al. 2017

Next Generat Sequenc & Applic

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“…It is important that the new genomic findings of the current study, demonstrating the occurrence of rare but recurrent somatic KDR/VEGFR2 mutations across common cancers, should be considered separately from studies correlating angiogenic responses with VEGF/VEGFR germline polymorphisms (18,19,20) , as well as from the published genetic screening studies that inaccurately reported the two VEGFR2 variants V297I and Q472H as likely pathogenic/cancer-driven KDR mutations (21,22) . V297I (rs2305948) and Q472H (rs1870377) are not cancer-exclusive mutations but non-pathogenic germline polymorphisms with allele frequencies between 10% and 20% across noncancerous-enriched populations from the 10,000 genomes (10) and EXAC (23) databases ( Figure S26).…”

Section: #4: -Genomic Findings Of New Kdr Somatic/tumor-exclusive/nonmentioning

confidence: 99%

Whole-exome sequencing of plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and enables the discovery of mutatedKDR/VEGFR2 receptors as modulators of anti-angiogenic therapies

Toledo

Garralda

Mitsi

et al. 2017

Preprint

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The non-invasive detection of cancer mutations is a breakthrough in oncology. Here, we applied whole-exome sequencing of matched germline and basal plasma cell-free DNA samples (WES-cfDNA) on a RAS/BRAF/PIK3CA wild-type metastatic colorectal cancer patient with primary resistance to standard treatment regimens including VEGFR inhibitors. Using WES-cfDNA, we could detect 73% (54/74) of the somatic mutations uncovered by WES-tumor including a variety of mutation types: frameshift (indels), missense, noncoding (splicing), and nonsense mutations. Additionally, WES-cfDNA discovered 14 high-confidence somatic mutations not identified by WES-tumor. Importantly, in the absence of the tumor specimen, WES-cfDNA could identify 68 of the 88 (77.3%) total mutations that could be identified by both techniques. Of tumor biology relevance, we identified the novel KDR/VEGFR2 L840F somatic mutation, which we showed was a clonal mutation event in this tumor. Comprehensive in vitro and in vivo functional assays confirmed that L840F causes strong resistance to anti-angiogenic drugs, whereas the KDR/VEGFR2 hot-spot mutant R1032Q confers sensitivity to cabozantinib. Moreover, we found a 1-3% of recurrent KDR somatic mutations across large and non-overlapping cancer sequencing projects, and the majority of these mutations were located in protein residues frequently mutated in other cancer-relevant kinases, such as EGFR, ABL1, and ALK, suggesting a functional role.In summary, the current study highlights the capability of exomic sequencing of cfDNA from plasma of cancer patients as a powerful platform for somatic landscape analysis and discovery of resistance-associated cancer mutations. Because of its advantage to generate results highly concordant to those of tumor sequencing without the hurdle of conventional tumor biopsies, we anticipate that WES-cfDNA will become frequently used in oncology. Moreover, our study identified for the first-time KDR/VEGFR2 somatic mutations as potential genetic biomarkers of response to anti-angiogenic cancer therapies and will serve as reference for further studies on the topic.

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“…Mutations of the EGFR gene constitute about 43%–89% of NSCLC cases, depending on the case series, rendering the affected patients candidates for targeted treatment with EGFR ‐TKIs . Although screening for EGFR mutation‐status is performed routinely, little is known about possible coexisting carcinogenic mechanisms in the population of patients featuring EGFR mutation.…”

Section: Introductionmentioning

confidence: 99%

“…Although screening for EGFR mutation‐status is performed routinely, little is known about possible coexisting carcinogenic mechanisms in the population of patients featuring EGFR mutation. Therapeutic benefits by the supplemental use of other biologicals to further improve survival and quality of life have become evident according to clinical trials, and some targeted agents are already used as first‐line treatment for selected patients with EGFR mutations . Gefitinib, erlotinib and afatinib today constitute the standard of care drugs incorporated in routine clinical management of EGFR ‐mutated lung cancers.…”

Section: Introductionmentioning

confidence: 99%

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Oncogene addiction and tumor mutational burden in non‐small‐cell lung cancer: Clinical significance and limitations

2019

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Lung cancer incidence has increased worldwide over the past decades, with nonsmall cell lung cancer (NSCLC) accounting for the vast majority (85%) of lung cancer specimens. It is estimated that lung cancer causes about 1.7 million global deaths per year worldwide. Multiple trials have been carried out, with the aim of finding new effective treatment options. Lately, special focus has been placed on immune checkpoint (PD1/PD-L1) inhibitors which impact the tumor immune microenvironment. Tumor mutational burden (TMB) has been found to predict response to immune checkpoint inhibitors. Conversely, recent studies have weakened the significance of TMB as a predictor of response to therapy and survival. In this review article, we discuss the significance of TMB, as well as possible limitations. Furthermore, we give a concise overview of mutations frequently found in NSCLC, and discuss the significance of oncogene addiction in lung cancer as an essential driver of tumorigenesis and tumor progression. Key points1. Tumor mutational burden (TMB) predicts response to immune checkpoint inhibitors 2. Recent studies have shown, however, that TMB has significant limitations 3. Oncogene addicted cancers are driven by one predominant driver mutation 4. Targeted agents are used as first-line treatment in certain types of NSCLC

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Genomic profiling in a homogeneous molecular subtype of non-small cell lung cancer: An effort to explore new drug targets

Abstract: Results suggest, a potential role for PIK3CA, VEGFR2, RET and FGFR2 as therapeutic targets in EGFR non-mutated NSCLC that requires further clinical validation.

Cited by 11 publications

References 2 publications

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

Whole-exome sequencing of plasma cell-free DNA portrays the somatic mutation landscape of refractory metastatic colorectal cancer and enables the discovery of mutatedKDR/VEGFR2 receptors as modulators of anti-angiogenic therapies

Oncogene addiction and tumor mutational burden in non‐small‐cell lung cancer: Clinical significance and limitations

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