Table 1.

Biomarkers characteristics	Prognostic value	Predictive value
E-Cadherin   Transmembrane glycoprotein involved in calcium mediated adhesion, codified by gene CDH1 (chromosome 16q22.1). Its alterations lead to increased cell proliferation, invasion, and metastasis.	It is associated with worse prognosis and lower survival rate	It is associated with reduced response to conventional and targeted therapy
Microsatellite instability   Microsatellites are short repetitive sequences that can lose out base paring during replication. Defects in mismatch repair lead to MSI. Tumours with MSI usually have (i) later onset (ii) distal location (iii) intestinal histotype.	MSI-positive cancers are associated with (i) a better prognosis than MSI-negative (ii) higher survival rate (iii) lower local invasion capacity (iv) lower prevalence of lymph nodes involvement	—
PD-L1   It is the ligand of Programmed Death-1; it is responsible for inducing and keeping tolerance of peripheral T-cells. PD-1/PD-L1 pathway is used by neoplastic cell to escape immune surveillance.	—	PD-L1 overexpression is a predictive biomarker of response to Pembrolizumab
TP53   P53 is a nuclear protein that works as a transcriptional factor that activates apoptosis in case of DNA damage. It is codified by TP53 (chromosome 17p13). P53 alterations are often associated with CIN subtype.	There is a correlation between p53 overexpression and tumour size. The association with lymph nodes metastasis and shorter survival is still controversial	—
HER2   It is a tyrosine receptor kinase (RTK) belonging to EGFR family, codified by ERBB2 (chromosome 17q21). It is involved in cell survival and proliferation. HER2+ tumours are often located at the gastroesophageal junction and often associated with intestinal histotype.	Still controversial: some studies report a more aggressive disease with worse prognosis but other studies do not confirm it	It is a predictive biomarker of the response to trastuzumab and lapatinib
EGFR   It belongs to the family of tyrosine kinase receptors.	It is associated with slightly differentiated, to high stage tumours and to a low survival	The use of anti-EGFR (cetuximab and panitumumab) associated with chemotherapy did not show any improvement in the clinical outcomes
FGFR1-4   The fibroblast growth factor receptors belong to RTK family.	Under evaluation	Under evaluation
mTOR   The activation of many RTK induces the activation of PIK3/mTOR pathway. PIK3CA mutations frequently occur in EBV positive cancers.	PIK3CA mutation has been associated with (i) worse prognosis (ii) reduced survival rate (iii) increased lymph nodes metastasis	Constitutive activation of PIK3/mTOR pathway is predictive of the response to Everolimus
MET   It is a RKT belonging to the family of Hepatocyte Growth Factor Receptors (HGFR); it binds HGF/SF. Autophosphorylation of MET leads to the activation of downstream pathways responsible for cancer cells survival, proliferation, invasion, and metastasization.	It is associated with (i) more aggressive disease (ii) shorter survival	It is an important predictive biomarker of the response to rilotumumab