BGI Genomics, BGI-Shenzhen, Shenzhen, China
Weiwei Li , Yuan Qiu , Hanzhang Chen , Haihong Yang , Qiuhua Deng , Liping Liu , Dakai Xiao , Changbin Zhu , Wenxi Jiang , Di Shao , Yongping Lin , Jianxing He
Background: Inhibition of PI3K/AKT/mTOR pathway has emerged as a promising anticancer strategy. Measuring genetic alterations in PI3K/AKT/mTOR pathway are critical for clinical decision making for patients with lung cancer. This study aims to analyze PI3K/AKT/mTOR pathway-related gene mutations in non-small cell lung cancer (NSCLC) in a consecutive cohort. Methods: 536 surgically resected tumor tissues were collected. Target region capture sequencing for 508 cancer-related genes was conducted on MGI-seq 2000 platform. Results: PI3K/AKT/mTOR pathway genes were mutated in 120 samples (22.4%). Female or older patients displayed higher mutation incidence of PI3K/AKT/mTOR pathway (P = 0.06 for female, P = 0.05 for patients ≥60 y). In NSCLC samples, mutations mainly occurred in NF1/2(18/499), PTEN (7/499), MTOR (4/499), TSC1/2(18/499), PIK3CA (26/499), PDK1 (2/499), AKT1/2/3 (5/499) and KRAS (49/499) genes. Genetic alterations of AKT2 (p = 0.003), mTOR (P = 0.03), PTEN (P = 0.005) and PIK3CA (P < 0.001) are preferred to occur in squamous NSCLC. PIK3CA variants (p.E542K, p.E545K, p.Q546K) were more enriched in non-squamous NSCLC, while amplification of PIK3CA was more prevalent in squamous NSCLC (P = 0.038). Histologically, TSC1/2 mutations were more correlate with micro-invasion subtype in non-squamous NSCLC (P = 0.002). Meanwhile, PIK3CA alterations, especially, amplification occurred more often in keratinizing squamous NSCLC (P < 0.001). In addition, four patients with biallelic NF1 loss of function mutations were exclusively found in non-squamous NSCLC without co-occurrence of mutation in known driver genes like EGFR or TP53, which indicated biallelic loss of function of NF1 might be sufficient to drive oncogenesis of non-squamous NSCLC. Conclusions: PI3K/AKT/mTOR pathway alterations present a heterogenous distribution across various types of lung malignancies especially in NSCLC. As more small molecule inhibitors developed to target PI3K/AKT/mTOR pathway, this study might shed light on further clinical investigation of these lately developed therapeutic approaches.
Mutation | Wild type | P-value | Mutation | Wild type | P-value | ||
---|---|---|---|---|---|---|---|
TSC1/2 | 0.002 | NF1/2 | 0.143 | ||||
Invasive | 7 | 343 | Invasive | 15 | 335 | ||
Micro-invasive | 6 | 87 | Micro-invasive | 1 | 92 | ||
In situ | 4 | 16 | In situ | 1 | 19 | ||
Keratinizing | 0 | 14 | Keratinizing | 2 | 12 | ||
Non keratinizing | 1 | 10 | Non keratinizing | 0 | 11 | ||
KRAS | 0.055 | PIK3CA | < 0.001 | ||||
Invasive | 38 | 312 | Invasive | 14 | 336 | ||
Micro-invasive | 4 | 89 | Micro-invasive | 0 | 93 | ||
In situ | 5 | 15 | In situ | 1 | 19 | ||
Keratinizing | 1 | 13 | Keratinizing | 7 | 7 | ||
Non keratinizing | 1 | 10 | Non keratinizing | 2 | 9 |
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