Background
According to the study in 2020, among all cancers, the mortality of lung cancer ranks first, with about 1.8 million death occurring, and the incidence of lung cancer ranks second, with more than 2.2 million new cases being diagnosed [
1]. Lung adenocarcinoma (LUAD) is the most frequent subtype [
2], accounting for more than 40% of all lung cancers [
3]. Despite considerable progress in both diagnosis and treatment, the five-year survival of patients with lung cancer remains very poor [
4].
TP53, coding the supermolecule p53, is located on human chromosome 17p 13.1 and plays a vital role in controlling cell cycle progression, aging, DNA repair and senescence, cell death, and cell metabolism [
5‐
7]. This function is achieved through its wild-type form. Once the
TP53 gene is mutated, it loses its position as a tumor suppressor gene and promotes tumorigenesis at the same time [
5,
8].
TP53 mutation is considered to be the most common kind of gene-specific changes in human cancers and occurs in almost every type of human tumours [
9‐
11]. Unlike other tumor suppressors that are usually inactivated by frameshift or nonsense mutation, most of the
TP53 mutation are missense mutation, and the same is true in lung cancer [
9,
12]. Previous studies have shown that
TP53 mutations can promote the metastasis of cancer cells [
13], some important somatic mutations can affect the effectiveness of LUAD immunotherapy [
14,
15]. In addition, abnormal
TP53 is considered to be an important prognostic factor for no-small-cell carcinoma (NSCLC) [
16]. However, to date, it is still unknown how
TP53 mutation affects LUAD patients.
To study the effect of TP53 mutation on LUAD patients, we consistently analyzed changes in somatic mutation data, clinical data, immune infiltration data, and gene expression obtained from the TCGA database. This research will enhance our understanding of TP53 mutation in LUAD and offer a reference for future studies.
Discussion
Despite a recent decline in incidence, lung cancer remains the leading cause of death by cancer [
26]. Previous studies had shown that compared with the corresponding wild-type tumors,
TP53 mutant NSCLC expressed higher levels of PD-L1 protein, promoted T cell infiltration, and enhanced tumor immunogenicity [
27,
28]. However, the characteristics of patients with
TP53 mutation in lung adenocarcinoma are still unclear. In this study, we have first clarified the effect of
TP53 mutation on the microenvironment and genetics of patients with LUAD, which will help us understand the underlying molecular mechanisms and be used clinically in the future.
The entire
TTN gene consists of 364 exons, located on chromosome 2q31, and its mutation is thought to be related to a variety of skeletal muscle and cardiomyopathy [
29]. In our study, we found that the mutation rate of
TTN was higher in the MU. The previous research has proved that
TTN and
TP53 mutations may have a combined effect in LUSC, and mutation in the TTN gene show good predictive value in LUSC, but this effect does not apply to LUAD [
30]. Another study indicated that the frequency of TTN mutation showed the highest correlation with the response rate to immune checkpoint blockades for individual tumor types, including LUAD [
31].
We also studied the associations of mutation with clinical features and outcomes. We found that the TP53 gene had a higher mutation rate in people younger than or equal to 65 years old, reaching 53.8%, and it was only 40% in people over 65 years.
old, which was consistent with the results of previous studies [
32,
33]. We also confirmed that
TP53 mutation did not affect the prognosis of patients with LUAD, it was consistent with the result of the study by Szymanowska, A., et al. [
34‐
39]. However, other studies suggested that patients with mutation of the TP53 gene had a poor prognosis [
15,
32,
33,
40,
41]. This phenomenon was worth studying. In fact, only the OS of patients who received specific treatment was considered to be related to the mutation of
TP53. In contrast, for patients who had not received treatment, the mutation of
TP53 did not affect the prognosis. In addition, we found that there was no difference in
TP53 mutation between genders; both were 47%, the same was true for Marrogi, A. J., et al. [
42]
At the same time, we found that the mutation had a significant impact on gene expression, such as
DEFA5 and NPY, which had higher expression in the MU.
DEFA5 is an alpha-defensins [
43], produced and secreted by Paneth cells [
44]. It was reported that
DEFA5 peptide was highly presented in cancers, including lung cancer [
45]. In gastric cancer, the overexpression of
DEFA5 can inhibit cell proliferation and tumor growth [
46]. Similarly, in esophageal squamous cell carcinoma,
DEFA5 can inhibit the growth of cancer cells by down-regulating the expression of E-cadherin [
47]. All these indicated that
DEFA5 may have a specific tumor inhibitory effect. But further researches are needed to clarify the specific mechanisms of
DEFA5 affecting LUAD.
NPY gene was not only highly expressed in the MU, but also in a relatively central position in the PPI map. NPY encoded by the
NPY gene is a 36 amino acid neuropeptide, which is involved in the regulation of a large number of physiological and pathophysiological processes in the cardiopulmonary system, immune system, nervous system and endocrine system [
48]. Some studies have shown that high expression of NPY can affect the cell cycle and promote tumor invasion and metastasis [
49,
50], also in LUAD [
33].
We also studied the changes in the function of differentially expressed genes. The results showed that the effect of mutation on gene function was closely related to cell division. For instance, after GSVA analysis, we found that the cell cycle and homologous recombination were significantly up-regulated in the MU. Regulation of cell cycle is a complicated biological process, and numerous regulatory proteins, including
TP53, participate in it [
51]. Homologous recombination repairs DNA double-strand breaks in S-phase post -replication or G2 in a generally error-free manner [
52]. A previous study showed that wild-type
TP53 could inhibit replication-associated homologous recombination [
53].
Significantly upregulated and downregulated miRNAs were also identified, such as miR-371a-5p (logFC = 7.62,
p < < 0.001) and miR-122-5p (logFC = − 3.87,
p < < 0.001). Previous studies have revealed that miR-371a-5p can affects the MAPK signaling pathway, which is closely related to cell apoptosis and lipid metabolism [
54,
55]. In contrast, the overexpression of miR-371a-5p can promote the proliferation and metastasis of cancer cells [
56]. Research by Yue, L. and J. Guo et al. showed that miR-371a-5p promoted the development of pancreatic cancer [
57]. However, the role of miR-371a-5p in LUAD needs to be further investigated. The low expression of miR-122-5p is more common in the MU in our research. As a tumor suppressor gene [
58], it plays a crucial role in inhibiting the metastasis and epithelial-mesenchymal transition of NSCLC [
59].
DLX6-AS1 regulated the most differentially expressed genes. The high expression of DLX6-AS1 is related to the disease stage, positive lymph node metastasis, and poor tumor differentiation in advanced NSCLC [
60]. The low expression of
DLX6-AS1 can significantly inhibit the proliferation, migration, and invasion of NSCLC cells and induce apoptosis [
61‐
63]. But in our study,
DLX6-AS1 is highly expressed in the MU.
We have also focused on the relationship between
TP53 mutation and immunity. In terms of immune genes, we found that VGF and PGC are the most apparent up-regulated and down-regulated immune genes. A study indicated that
VGF significantly promotes the resistance of human lung cancer cells to
EGFR kinase inhibitors and is also related to the poor survival of patients with LUAD [
64]. Matsumoto, T., et al. believed that
VGF is only expressed in neuroendocrine carcinoma-derived cells and can be used as a new serological diagnostic marker for pulmonary neuroendocrine tumors [
65].
PGC-1α is a crucial transcription regulator of genes that control energy metabolism and mitochondrial biogenesis through its partner transcription factors: nuclear respiratory factors and PPARs [
66]. Overexpression of PGC-1α enhanced the efficacy of PD-1 blockers in lung cancer [
67]. Both costimulating and co-inhibitory molecules have higher expression in the MU, including PD1 and PDL1. PD1 is located on lymphocytes, and PDL1 is located on antigen presenting cells. Their interaction leads to tolerance of the immune system to tumor cells. Sun, H., et al. believed that mutant TP53 may enhance PD-L1 expression by activating the newly acquired function of BCL2L1 /JAK3/STAT1 signaling [
68]. However, in several reports of anti-PD-1/PD-L1 therapy for NSCLC, the expression of PD-L1 in tumors has been considered to be a standard and predictive biomarker for poor prognosis [
14,
69]. Previous studies had shown that the survival outcome of patients with various types of cancer treated by immunotherapy was significantly related to the immune cells infiltrated in the tumor [
70]. In our study, we found that macrophages M1 and T cells CD4 memory activated were comparatively upregulated in the MU, while mast cells resting and dendritic cells resting were downregulated. A report indicated that mast cells could promote growth and metastasis by producing IL-1β during LUAD progression [
71].
Our study also has some limitations. First, the information from the TCGA database lacks some essential clinicopathological information, such as the patient’s treatment; secondly, to verify our results, another independent cohort study and more in vitro or in vivo studies should be conducted.
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