Advancing Transcriptomics: An Insights into Lung Cancer

Next Generation Sequencing (NGS) is not just a standalone tool but part of a larger narrative. Originally designed to get over the Sanger sequencing constraints, the next generation sequencing (NGS) technology has now evolved significantly and is utilized in every aspect of genomic research of lung cancer.

When it comes to lung cancer, the sequencing of genetic material has paved the way for breakthroughs in diagnosis and treatment. This is particularly facilitated by Next-Generation Sequencing (NGS) technologies that enable a deeper understanding of the genetic alterations driving the disease, helping to steer personalized treatment strategies. The root causes of lung cancer lie in the genetic instability of cells, where abnormal cells grow uncontrolled due to accumulated somatic mutations. Traditional diagnostics may overlook these mutations, allowing the disease to thrive and often be detected at a later, more perilous stage. The multi-omics research and sequencing technologies promise a paradigm of personalized medicine or precision therapy, where treatment is tailored to an individual’s unique molecular profile rather than a one-size-fits-all approach ^[1].

Transcriptome Analysis of Mutations in Lung Adenocarcinomas

RNA Sequencing, a technique grounded in NGS, unveils the array of RNA in biological samples, offering a glimpse into the cellular dynamic RNA pool, crucial for understanding the molecular underpinnings of lung cancer. A comprehensive study used data from RNA-sequencing sourced from a public database and 281 patients, highlighting the important role of genetic expression of a protein called ASCL1 in certain types of lung cancers, especially lung adenocarcinomas. RNA-seq technique helped researchers to understand that there are two genes named TP53 and RB1 that are often mutated in other kinds of lung cancers, but not as much in these ASCL1-high adenocarcinomas. Another gene called KRAS was highlighted, where its mutation, along with high ASCL1, might indicate a different origin or growth pattern for some adenocarcinomas ^[2]​. These findings have unique clinical and molecular features with therapeutic implications.

The Implications of Advancement in Transcriptome and Epigenome Research for Small Cell Lung Cancer (SCLC)

Connecting transcriptome and epigenome data for a holistic view of subtype development of small cell lung cancer is forging a robust framework for lung cancer studies. A recent study has unveiled the epigenetic regulation of changes in small cell lung cancer (SCLC) types by a protein called KDM6A. Initially, SCLC was categorized into different subtypes, thinking they were distinct. However, this study showed that with changes in KDM6A, cells from one subtype can switch to another, specifically from ASCL1 to NEUROD1 subtype. Understanding this role of KDM6A can lead us to potentially halt or reverse this process ^[3].

Gene editing and sequencing techniques play a key role in this case study, as they provide the necessary data to analyze the transcriptome and epigenome, helping to identify such molecular mechanisms and targets for therapy. Sequencing tools such as RNA sequencing (RNA-seq), Assay for Transposase-Accessible Chromatin using sequencing (ATAC-seq), single cell sequencing and Chromatin Immunoprecipitation sequencing (ChIP–seq) were employed. The RNA-seq and ChIP–seq services were provided by Novogene ^[3]. This combined approach will offer a better understanding of cancer causes and its molecular root sources.

Another scientific research delved deeper into an examination of DNA methylation profiles. The study assessed 18 pairs of lung tumors and the normal tissues adjacent to them, all from patients with NSCLC. This was done using a technique known as Reduced Representation Bisulfite Sequencing (RRBS). By integrating the data on epigenomic (DNA methylation) and transcriptomic (gene activity) changes, a more detailed picture of lung cancer’s molecular landscape was depicted. The exploration led to the discovery of a significant number of hypermethylation events, where certain regions of the DNA are excessively methylated, acting as a hallmark of lung cancer ^[4]. Through an integrated analysis of the DNA methylation and gene activity data, eight new potential driver genes (like PCDH17 and IRX1) that were aberrantly methylated were identified ^[4]. These findings and further advancement in molecular and sequencing analysis provide the necessary data to analyze the transcriptome and epigenome, helping to identify molecular mechanisms and targets for therapy, thus accelerating the pace at which these insights are translated into tangible benefits in lung cancer treatment.

Conclusion

The journey across the epigenomic and transcriptome landscapes of lung cancer has revealed important molecular processes. Transcriptomics advances get us closer to tailored treatment approaches while also revealing the complex pattern of lung cancer. In the fight against lung cancer, the combination of transcriptome and epigenome data offers us an optimistic approach to better understand the triggers of lung cancer, the progression behavior and helps us to early diagnose and devise effective treatment interventions.

References

1. C. Cainap, O. Balacescu, S. S. Cainap, and L. A. Pop, “Next generation sequencing technology in lung cancer diagnosis,” Biology. 2021. doi: 10.3390/biology10090864.
2. N. Miyashita et al., “An Integrative Analysis of Transcriptome and Epigenome Features of ASCL1–Positive Lung Adenocarcinomas,” J. Thorac. Oncol., 2018, doi: 10.1016/j.jtho.2018.07.096.
3. L. Duplaquet et al., “KDM6A epigenetically regulates subtype plasticity in small cell lung cancer,” Nat. Cell Biol., 2023, doi: 10.1038/s41556-023-01210-z.
4. Sun X, Yi J, Yang J, et al. An integrated epigenomic-transcriptomic landscape of lung cancer reveals novel methylation driver genes of diagnostic and therapeutic relevance. Theranostics., 2021, doi:10.7150/thno.58385