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CDKN2A Deletion Leading to Hematogenous Metastasis of Human Gastric Carcinoma
Juanli Qiao1, Yuan Tian1, Xiaojing Cheng2
1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Division of Etiology, Peking University Cancer Hospital and Institute, Beijing, China.
Introduction:
Somatic copy number deletion (SCND) of CDKN2A gene is the most frequent event in cancer genomes. Whether CDKN2A SCND drives human cancer metastasis is far from clear. Hematogenous metastasis is the main reason of human gastric carcinoma (GC) death. Thus, prediction GC metastasis is eagerly awaited.
Method:
GC patients (n=408) enrolled in both a cross-sectional and a prospective cohorts were analysed. CDKN2A SCND was detected with a quantitative PCR assay (P16-Light). Association of CDKN2A SCND and GC metastasis was evaluated. Effect of CDKN2A SCND by CRISPR/Cas9 on biological behaviors of cancer cells was also studied.
Results:
CDKN2A SCND was detected in 38.9% of GCs from patients (n=234) enrolled in the cross-sectional cohort. Association analysis showed that more CDKN2A SCND was recognized in GCs with hematogenous metastasis than those without (66.7% vs. 35.7%, p=0.014). CDKN2A SCND was detected in 36.8% of baseline pN0M0 GCs from patients (n=174) enrolled in the prospective study, the relationship between CDKN2A SCND and hematogenous metastasis throughout the follow-up period (62.7 months in median) was also significant (66.7% vs. 34.6%, p=0.016). Using CDKN2A SCND as a biomarker for predicting hematogenous metastasis of GCs, the prediction sensitivity and specificity were 66.7% and 65.4%. The results of functional experiments indicated that CDKN2A SCND could obviously downregulate P53 expression that consequently inhibited the apoptosis of MGC803 GC and HEK293T cells. This may account for hematogenous metastasis of GCs by CDKN2A SCND.
Conclusion:
CDKN2A SCND may drive GC metastasis and could be used as a predictor for hematogenous metastasis of GCs.
Insights
Somatic copy number deletion (SCND) of the CDKN2A gene is linked to gastric cancer metastasis. This finding suggests CDKN2A SCND may drive cancer spread and can serve as a predictive biomarker for hematogenous metastasis in gastric cancer patients.
Area of Science:
- Oncology
- Genetics
- Cancer Biology
Background:
- Somatic copy number deletion (SCND) of the CDKN2A gene is a frequent event in cancer genomes.
- The role of CDKN2A SCND in driving human cancer metastasis remains unclear.
- Hematogenous metastasis is a primary cause of mortality in gastric carcinoma (GC).
Purpose of the Study:
- To investigate the association between CDKN2A SCND and gastric cancer metastasis.
- To evaluate CDKN2A SCND as a potential biomarker for predicting hematogenous metastasis in GC.
- To explore the functional impact of CDKN2A SCND on cancer cell behavior.
Main Methods:
- Analysis of GC patients (n=408) across cross-sectional and prospective cohorts.
- Detection of CDKN2A SCND using a quantitative PCR assay (P16-Light).
- CRISPR/Cas9 gene editing to study the effect of CDKN2A SCND on cancer cell biological behaviors.
Main Results:
- CDKN2A SCND was detected in 38.9% of GCs in the cross-sectional cohort.
- GCs with hematogenous metastasis showed significantly higher CDKN2A SCND rates (66.7%) compared to those without (35.7%, p=0.014).
- CDKN2A SCND was associated with increased hematogenous metastasis risk in a prospective cohort (66.7% vs. 34.6%, p=0.016) and demonstrated predictive value (sensitivity 66.7%, specificity 65.4%).
- Functional experiments revealed CDKN2A SCND downregulates P53 expression, inhibiting apoptosis and potentially promoting GC hematogenous metastasis.
Conclusions:
- CDKN2A SCND may play a role in driving gastric cancer metastasis.
- CDKN2A SCND shows potential as a predictive biomarker for hematogenous metastasis in GC.
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