Lung cancer is still the most common and deadly cancer in the world. Small cell lung cancer (SCLC) is the deadliest type of lung cancer, accounting for about 15% of all lung cancer cases. SCLC is an aggressive high-grade neuroendocrine tumor characterized by short doubling time, rapid growth, and early metastasis and spread. Most SCLC patients develop resistance rapidly, and their 5-year survival rate is very low (5-6%), even when the initial response to standard chemotherapy is good. The addition of immune checkpoint inhibitors to conventional chemotherapy for small cell lung cancer is promising; however, their absolute long-term benefits are moderate. The complex mechanisms of widespread SCLC metastasis and recurrence need to be clarified to expand the long-lasting benefits of chemotherapy and immunotherapy to more patients.
M6A is the most abundant and common RNA modification in eukaryotic RNA, and it is an important part of tumor biology. Similar to other epigenetic modifications, M6A modification is a dynamic and reversible process regulated by methyltransferase, RNA binding protein and demethylase. More and more evidences strongly indicate that m6A modification is a new determinant of tumor metastasis, recurrence and treatment resistance, especially anti-pd-1/PD-L1 single-drug resistance. A variety of epigenetic abnormalities have been confirmed to be closely related to the cancer phenotype and aggressiveness of SCLC. However, as the most common RNA epigenetic modification, m6A has never been thought to be involved in the progression of SCLC.
This is the first description of m6A regulatory factors, including its molecular characteristics, immuno-oncology characteristics and clinical relevance. This data emphasizes the importance of m6A regulatory factors in tumor pathogenesis and the formation of tumor immune microenvironment (TIME), and lays a reasonable foundation and support for formulating treatment strategies for m6A modification in SCLC patients. The researchers planned a catalog of 30 m6A regulators, including 11 writers, two erasers and 17 readers. In 110 cases of SCLC samples, 30 cases of somatic mutations of m6A regulatory factors were detected. M6A regulatory factor mutations occurred in 28 samples, with a mutation frequency of 25.5. Among all regulatory factors, the mutation frequency of the reader is relatively high, and the mutation frequency of FMR1 is the highest.
In contrast, no erasers showed mutations. The researchers also noticed simultaneous mutations between metttl3 and YTHDC2 and between IGF2BP2 and YTHDC2. Then, they studied the copy number variation of these regulatory factors in 53 SCLC cell lines from the Encyclopedia of Cancer Cell Lines.
Because genetic changes in m6A regulatory factors are common in SCLC, researchers should determine whether these changes affect expression patterns. Principal component analysis was used to evaluate the overall expression of m6A regulatory factors in normal lung and SCLC samples, and it was found that their distribution patterns were significantly different. Almost all writers and readers are significantly up-regulated in SCLC; however, erasers expression tends to decrease, indicating that SCLC is associated with abundant m6A modifications. IGF2BP3 is significantly elevated in a variety of solid tumors, and this study extends this phenomenon to SCLC for the first time. Combining the results of CNV and the expression pattern of m6A regulators, the author speculates that CNV changes may be one of the reasons for the disorder of m6A regulator expression.
This study describes for the first time the abnormal expression pattern of m6A regulatory factors in SCLC, specific immune tumor characteristics and clinical relevance. A comprehensive evaluation of m6A regulatory factors in SCLC will help people deepen their understanding of tumorigenesis and remodeling TIME, and provide more effective chemotherapy and immunotherapy options.