SHMT2 is Associated with Tumor Purity, CD8+ T Immune Cells
Infiltration, and a Novel Therapeutic Target in Four Different
Human Cancers
Authors: Usman Muhammad , Hameed Yasir , Ahmad Mukhtiar , Iqbal Muhammad Junaid , Maryam Aghna , Mazhar Afshan , Naz Saima , Tanveer Rida , Saeed Hina , Bint-e-Fatima  , Ashraf Aneela , Hadi Alishba , Hameed Zahid , Tariq Eman , Aslam Alia Sumyya 
Published: January 2022

Aims:
This study was launched to identify the SHMT2 associated Human Cancer
subtypes.

Background:
Cancer is the 2nd leading cause of death worldwide. Previous reports revealed the
limited involvement of SHMT2 in human cancer. In the current study, we comprehensively analyzed
the role of SHMT2 in 24 major subtypes of human cancers using in silico approach and identified a
few subtypes that are mainly associated with SHMT2.

Objective::
We aim to comprehensively analyze the role of SHMT2 in 24 major subtypes of human
cancers using in silico approach and identified a few subtypes that are mainly associated with
SHMT2. Earlier, limited knowledge exists in the medical literature regarding the involvement of
Serine Hydroxymethyltransferase 2 (SHMT2) in human cancer.

Methods:
In the current study, we comprehensively analyzed the role of SHMT2 in 24 major
subtypes of human cancers using in silico approach and identified a few subtypes that are mainly
associated with SHMT2. Pan-cancer transcriptional expression profiling of SHMT2 was done using
UALCAN while further validation was performed using GENT2. For translational profiling of SHMT2,
we utilized Human Protein Atlas (HPA) platform. Promoter methylation, genetic alteration, and copy
number variations (CNVs) profiles were analyzed through MEXPRESS and cBioPortal. Survival
analysis was carried out through Kaplan–Meier (KM) plotter platform. Pathway enrichment analysis
of SHMT2 was performed using DAVID, while the gene-drug network was drawn through CTD and
Cytoscape. Furthermore, in the tumor microenvironment, a correlation between tumor purity, CD8+
T immune cells infiltration, and SHMT2 expression was accessed using TIMER.

Results:
SHMT2 was found overexpressed in 24 different subtypes of human cancers and its
overexpression was significantly associated with the reduced Overall survival (OS) and Relapse-free
survival durations of Breast cancer (BRCA), Kidney renal papillary cell carcinoma (KIRP), Liver
hepatocellular carcinoma (LIHC), and Lung adenocarcinoma (LUAD) patients. This implies that
SHMT2 plays a significant role in the development and progression of these cancers. We further
noticed that SHMT2 was also up-regulated in BRCA, KIRP, LIHC, and LUAD patients of different
clinicopathological features. Pathways enrichment analysis revealed the involvement of SHMT2
enriched genes in five diverse pathways. Furthermore, we also explored some interesting
correlations between SHMT2 expression and promoter methylation, genetic alterations, CNVs,
tumor purity, and CD8+ T immune cell infiltrates.

Conclusion:
Our results suggested that overexpressed SHMT2 is correlated with the reduced OS
and RFS of the BRCA, KIRP, LIHC, and LUAD patients and can be a potential diagnostic and
prognostic biomarker for these cancers.