The landscape of muti-PIK3CA variations of 10,000 Chinese solid-tumor patients.

Abstract

e15670 Background: PI3K/mTOR signaling pathway plays a central role in cancer biology. Our study aimed to explore the characteristics of multiple PIK3CA variations in the Chinese patient with solid tumors. Methods: Formalin fixed, paraffin embedded (FFPE) tumor samples and matched peripheral blood from 10,194 Chinese solid tumor patients were collected for next-generation sequencing based 450 genes panel assay. The testing was carried out by OrigiMed, a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China. Genomic alterations including SNV, short and long Indel, CNV, Fusion/Rearrangement were assessed. Microsatellite stable (MSS) status and TMB (tumor mutational burden) were also acquired by an NGS algorithm. Results: A total of 672 (6%) patients were identified harboring PIK3CA mutations, 93 (13.8%) of them had multiple PIK3CA mutations. Patients with multiple PIK3CA mutations included 51 females and 42 males with a mean age of 56 years old. Tumors with multiple PIK3CA mutations were composed of stage I (N = 14), II (N = 22), III (N = 18), IV (N = 25) and 14 without staging information. Cervical, breast, gastric and colorectal cancers were top ranked multiple-PIK3CA-mutant tumors (21%, 17%, 15%, 12% and 6%, respectively). TMB-H (≥10 mut/Mb) was significantly higher in multiple-PIK3CA-mutant tumors than that in single-PIK3CA-mutant tumors (60% vs 32%, P < 0.001). The MSS status was similar between multiple- and single-PIK3CA-mutant tumors (14% vs 11%). The most common PIK3CA alterations in both multiple- and single-PIK3CA-mutant tumors were E545 (36% vs 28%), H1047 (19% vs 24%) and E542 (16% vs 13%). Noticeably, the frequency of R88 (16% vs 3%, P < 0.0001), E726 (10% vs 0.8%, P < 0.0001), E453 (10% vs 1%, P < 0.0001), and M1043 (9% vs 0.8%, P < 0.0001) mutations were significantly higher in multiple-PIK3CA-mutant tumors than that in single-PIK3CA-mutant tumors. The top 3 most frequent PIK3CA dual mutation combinations were E545K+E726K, H1047R+E726K and E545K+R88Q. Among the co-mutated genes, copy numbers of ERBB2 were less altered in multiple-PIK3CA-mutant tumors than single-PIK3CA-mutant tumors (1% vs 6%, p < 0.05). Conclusions: This study, for the first time, revealed that approximately 13% PIK3CA positive Chinese solid tumor pts harboring multiple PIK3CA mutations. Several novel dual-PIK3CA-mutations were detected and multiple-PIK3CA-mutant pts more likely had high TMB, which may guide potential immunotherapy or PI3K-targeted therapy for multiple PIK3CA Chinese solid tumor patients.