Characteristic of genetic and t cell receptor repertoire of Chinese multiple primary lung cancer patients.
Authors: Liang Naixin , Liu Xinyu , Wang Yadong , Xue Jianchao , Jia Ziqi , Yang Xiaoying , Xu Huihui , Bing Zhongxing , Guo Chao , Tian Zhenyu , Gao Chao , Gu Dejian , Chen Rongrong , Xia Xuefeng , Yang Huaxia , Li Xiaoguang , Li Shanqing 
Published: June 2021

e20510

Background: As the incidence of lung cancer soars, the number of patients diagnosed with multiple primary lung cancers (MPLC) was also rising. It was already known that genetic and immune microenvironment were involved in oncogenesis and treatment of tumors. The aim of this study was to investigate genetic and T Cell Receptor (TCR) Repertoire characteristic in patients with multiple primary lung cancers. Methods: We queried 84 lesions analyzed by 1021 gene panel and TCRβ repertoire for 32 patients with MPLC profiled by NGS. Shannon index was calculated on the clonal abundance of all productive TCR sequences. T cell clonality was defined as 1 − (Shannon index)/ln(# of productive unique sequences). MOI was a measure of the similarity in the T cell repertoire between tissue and blood taking into account the specific rearrangements and their respective frequencies. Results: 98.7% (77/78) of lesions from 30 patients were detected somatic mutations and EGFR mutations were detected in 44.2% (34/77) lesions; BRAF were detected in 22.1% (17/77) lesions; and KRAS were detected in 14.3% (11/77) lesions. We found different combinations of three driving genes in 13 patients. Almost all lesions (97.4%) had mutations in the RAS-RTK pathway. Shared mutations were detected between different lesions from 8 patients, and two patients were intrapulmonary metastases; The others were more meet to convergent evolution. The overall immune characteristics of 76 lesions from 30 patients were further studied. The shannon index showed heterogeneity in difference lesions of each patients and the comparing the most and least shannon index lesions variations ranged between 0.066 to 3.344. The lesions with shared mutations showed higher Shannon index than the non-share lesions (7.31 vs 6.96; p = 0.011). The heterogeneity also identified in MOI and 55% MOI of lesions was less than 0.5. The lesions with MOI higher than 0.5 had some pathologically identical and some have shared mutations. Furthermore, the shared TCR between lesions in same patient were analyzed. The more than 78% of T cell clones were restricted to individual lesions, which indicated the presence of heterogeneity between lesions due to T cell clones distribution heterogeneity. Meanwhile, the shared TCR was significantly higher in identical pathology group than difference pathology group (17.18% vs 6.60%; p = 0.0006); Besides, we found that shared TCR was comparable in both shared mutations and non-shared mutations groups (13.1% vs 15.33%, p = 0.537). These results suggested that the pathology between lesions in patients was affected to 100% shared TCR. Conclusions: In conclusion, the multiple lesions of MPLC showed heterogeneity and this heterogeneity is due to the distribution of T cell clones between lesions. Besides, the MOI and shared TCR was higher in MPLC with same pathology, which may increase the understanding of MPLC and influence the treatment choice of MPLC patients.