1805P - PKD1L1 mutations in small cell lung cancer: A genomic signature for poor prognosis and drug susceptibility

Background

Managing small cell lung cancer (SCLC) is a significant challenge for medical professionals, as current treatment methods have limited effects on improving patient longevity. A key obstacle in enhancing treatment for SCLC patients is the absence of an in-depth understanding of the disease at the molecular level. Recent extensive real-world data has provided a genomic profile primarily of Caucasian SCLC patients. However, there is a scarcity of information regarding the genomic characteristics of Chinese SCLC patients.

Methods

Here, we analyzed whole-exome sequencing (WES) data based on 178 Chinese SCLC patients to understand the genomic characteristics of Chinese patients and compared them with those of Caucasian patients. Univariate Cox regression analysis was performed to figure out the correlation between gene mutation and prognosis. The Cancer Cell Line Encyclopedia (CCLE) was utilized to forecast the responses of SCLC cells to various treatments, based on their distinct genetic mutations.

Results

The top ten genes most frequently mutated in Chinese patients with SCLC were as follows: TP53, TTN, RB1, MUC16, USH2A, FSIP2, ZFHX4, SYNE1, CSMD3, and OBSCN. Additionally, the top ten genes exhibiting copy number variations, specifically amplifications or deletions, were SDHA, NKX2-1, PSIP1, SRSF2, CALR, PTPN6, SUZ16, PABPC1, MAP2K4, and MSI2. Significantly, mutations in the PKD1L1 gene have been linked to poorer prognoses in SCLC patients across both Chinese and Caucasian populations (p < 0.01, respectively). Further analysis of the CCLE dataset revealed that SCLC cell lines harboring PKD1L1 mutations demonstrate increased sensitivity to small molecule inhibitors that target the MYC and mTOR signaling pathways.

Conclusions

Compared with Caucasian, the genetic alterations of Chinese SCLC patients presented distinct patterns. Notably, a shared gene, PKD1L1, has been identified as a prognostic marker associated with unfavorable outcomes across diverse patient populations. This gene's predictive potential extends to its possible utility as a biomarker for the sensitivity to drugs that target the MYC and mTOR signaling pathways.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Chin: Financial Interests, Institutional, Full or part-time Employment: Amoy Diagnostics Co., Ltd. All other authors have declared no conflicts of interest.