Theranostics 2021; 11(3):1364-1376. doi:10.7150/thno.51725

Research Paper

Molecular stratification by BCL2A1 and AIM2 provides additional prognostic value in penile squamous cell carcinoma

Xingliang Tan1,2,3*, Dong Chen1,2,3*, Shengjie Guo1,2,3*, Yanjun Wang1,2,3*, Yuantao Zou1,2,3, Zhiming Wu1,2,3, Fangjian Zhou1,2,3, Zike Qin1,2,3, Zhuowei Liu1,2,3, Yun Cao2,3,4✉, Chunhua Lin5✉, Gangjun Yuan6✉, Kai Yao1,2,3✉

1. Department of Urology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China.
2. State Key Laboratory of Oncology in Southern China, Guangzhou 510060, China.
3. Collaborative Innovation Center of Cancer Medicine, Guangzhou 510060, China.
4. Department of Pathology, Sun Yat-Sen University Cancer Center, Guangzhou 510060, China.
5. Department of Urology, The Affiliated Yantai Yuhuangding Hospital of Qingdao University, Yantai, Shandong 264000, China.
6. Department of Urology Oncological Surgery, Chongqing University Cancer Hospital, Chongqing, 400030, China.
*These authors contributed equally in this study.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Tan X, Chen D, Guo S, Wang Y, Zou Y, Wu Z, Zhou F, Qin Z, Liu Z, Cao Y, Lin C, Yuan G, Yao K. Molecular stratification by BCL2A1 and AIM2 provides additional prognostic value in penile squamous cell carcinoma. Theranostics 2021; 11(3):1364-1376. doi:10.7150/thno.51725. Available from

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Background: Lymph node metastasis is the most unfavorable prognostic factor of penile squamous cell carcinoma (PSCC). However, patients with the same lymph node status have different outcomes, and molecular classifiers for precise prognostic assessments are lacking.

Methods: Comprehensive genomic profiling and high-content proliferation screening were performed in eight PSCC and normal tissue pairs and in cell lines. BCL2A1 and AIM2 were selected and further evaluated by qPCR and Western blot. The clinical relevance and prognostic value of the target genes were validated via immunohistochemistry in a cohort of 220 PSCC patients with a defined pN stage. Finally, the biological functions and molecular mechanisms of BCL2A1 and AIM2 were investigated in vitro and in vivo.

Results: BCL2A1 and AIM2 were both upregulated in PSCC tissues and associated mostly with cell proliferation. Staining for either BCL2A1 or AIM2 revealed that both are correlated with pN status, extranodal extension, clinical stage and cancer-specific survival (CSS). Compared to patients who are single-positive or double-negative for BCL2A1 and AIM2, those overexpressing both genes had a higher risk of tumor progression and the poorest survival in the pN0 (5-year CSS: 63.3% vs. 94.9% and 100.0%, respectively, p = 0.000) and pN+ subsets (5-year CSS: 24.1% vs. 45.7% and 55.1%, respectively, p = 0.035). Molecular biofunction and mechanistic studies demonstrated that BCL2A1 and AIM2 knockdown inhibited tumorigenesis via the AIM2/NF-κB/BCL2A1/MAPK/c-Myc signaling pathway.

Conclusions: BCL2A1 and AIM2 promote PSCC progression. Integrating BCL2A1 and AIM2 as novel molecular classifiers with pN stage provides additional information for the prognosis and treatment of PSCC patients.

Keywords: penile squamous cell carcinoma, comprehensive genomic profiling, BCL2A1, AIM2, molecular classifier