P16 gene promoter methylation is associated with oncogenesis and progression of gastric carcinomas: A systematic review and meta-analysis

Gastric carcinoma is the fourth leading cause of malignancy-related mortality and the fifth most common cancer worldwide, with more than one million new cases annually (Sung et al., 2021, Machlowska et al., 2020). In terms of treatment, it is managed through surgery, possibly in conjunction with chemoradiotherapy modalities. However, due to the vagueness of clinical manifestations, most cases are diagnosed at advanced stages, resulting in a poor prognosis (Digklia and Wagner, 2016, Patel and Cecchini, 2020).

In epidemiological terms, gastric adenocarcinomas are more common in males, and the median age at diagnosis is 70 years, although 10% of cases are detected before 45. Around 50% of cancer incidents might be provoked by environmental agents, mostly dietary habits and social behavior (Machlowska et al., 2020). We also highlight the asymmetries between gastric cancers that develop in the West and in the East, since in some Asian countries the screening methods, the average survival, the main risk factors, the chemotherapeutic agents used, and even some surgical techniques differ from the counterparts verified in North America or Western Europe (Chan et al., 2019, Griniatsos and Trafalis, 2018).

Gastric oncogenesis is a multifactorial process, involving infection by Helicobacter pylori and Epstein Barr, exogenous carcinogens, activation of oncogenes, inhibition of suppressor genes, gastric epithelial apoptosis, and disruption of cell cycle regulation (Wu et al., 2014, Shi et al., 2014 Oct 14). In addition to gene alterations, several studies have already pointed out the relevance of epigenetics in triggering the aforementioned mechanisms (Figueiredo et al., 2013, Tahara and Arisawa, 2015).

In turn, the p16 gene is characterized as the second most significant tumor suppressor gene, behind only TP53. It belongs to the INK4 gene family, which is composed of four members: p16INK4A, p15INK4B, p18INK4C, and p19INK4D, all of which share biological properties related to cyclin inhibition, with consequent antiproliferative and tumor suppressor activities (Serra and Chetty, 2018, Chen et al., 2021, Yuan et al., 1999a).

Possible derangements that induce p16 inactivation, producing hyperproliferative and potentially oncogenic cellular conditions, include point mutations, homozygous deletions, hypermethylation, and loss of heterozygosity. Although each specific neoplasm has a predilection for a certain type of gene alteration, hypermethylation represents the majority of p16 dysfunctions in gastric adenocarcinomas (34%), while mutations or deletions are rare in this malignancy (0% −2%) (Li et al., 2011, Jiao et al., 2018, McKenzie et al., 2010).

In this context, by studying the associations of the p16 gene promoter methylation with outcomes related to gastric carcinogenesis, it is possible to strengthen the biomolecular knowledge about this neoplasm and, ultimately, foster the development of new diagnostic or therapeutic modalities that reduce lethality (Sherr et al., 2016, Demaria, 2018a, Kohli et al., 2017, Zeng et al., 2019, Cai et al., 2020).

Furthermore, the development of a systematic review on this topic is of singular importance, given the controversial findings regarding the biomolecular stratification of gastric adenocarcinomas (Machlowska et al., 2020). Thus, the aggregation of multiple observational studies in a meta-analysis, bringing more definitive conclusions, is essential for evidence-based clinical judgment.

The present research aims to investigate the potential association of the p16 gene promoter methylation with gastric carcinogenesis, appreciate the frequency of this epigenetic alteration in gastric neoplastic specimens, compared to the homologous one in non-tumor tissues, and ponder the phenotypic characteristics of the malignancies with which it is associated.

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