The first comprehensive genomic characterization of rectal squamous cell carcinoma
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Updated: Aug 22, 2025
Development of Compendium for Esophageal Squamous Cell Carcinoma
Published on: April 12, 2024
Christoforos Astaras1, Claudio De Vito2, Prasad Chaskar2
1Medical Oncology Department, Geneva University Hospitals, 4 rue Gabrielle-Perret-Gentil, 1205, Geneva, Switzerland.
Background:
Rectal cancers represent 35% of colorectal cancers; 90% are adenocarcinomas, while squamous cell carcinoma accounts for 0.3% of them. Given its rarity, little is known concerning its pathogenesis, molecular profile and therapeutic management. The current treatment trend is to treat rectal squamous cell carcinoma by analogy to anal squamous cell carcinoma with definitive chemo-radiotherapy, setting aside surgery in case of local recurrence.
Methods:
We performed an in-depth genomic analysis (next-generation sequencing, copy number variation, and human papilloma virus characterization) on 10 rectal squamous cell carcinoma samples and compared them in silico to those of anal squamous cell carcinoma and rectal adenocarcinoma.
Results:
Rectal squamous cell carcinoma shows 100% HPV positivity. It has a mutational (PIK3CA, PTEN, TP53, ATM, BCL6, SOX2) and copy number variation profile (3p, 10p, 10q, 16q deletion and 1q, 3q, 5p, 8q, 20p gain) similar to anal squamous cell carcinoma. PI3K/Akt/mTOR is the most commonly affected signaling pathway similarly to anal squamous cell carcinoma. Most commonly gained or lost genes seen in rectal adenocarcinoma (FLT3, CDX2, GNAS, BCL2, SMAD4, MALT1) are not found in rectal squamous cell carcinoma.
Conclusion:
This study presents the first comprehensive genomic characterization of rectal squamous cell carcinoma. We confirm the existence of this rare histology and its molecular similarity with anal squamous cell carcinoma. This molecular proximity confirms the adequacy of therapeutic management based on histology and not localization, suggesting that rectal squamous cell carcinoma should be treated like anal squamous cell carcinoma and not as a rectal adenocarcinoma.
Insights
Rectal squamous cell carcinoma (RSCC) is a rare cancer with a molecular profile similar to anal squamous cell carcinoma (ASCC). This genomic similarity supports treating RSCC like ASCC, not rectal adenocarcinoma.
Area of Science:
- Oncology
- Genomics
- Molecular Pathology
Background:
- Rectal cancers are predominantly adenocarcinomas, with squamous cell carcinoma being rare (0.3%).
- Limited knowledge exists regarding the pathogenesis, molecular profile, and treatment of rectal squamous cell carcinoma.
- Current treatment often parallels anal squamous cell carcinoma, using chemoradiotherapy and reserving surgery for recurrence.
Purpose of the Study:
- To perform comprehensive genomic characterization of rectal squamous cell carcinoma.
- To compare the molecular profile of rectal squamous cell carcinoma with anal squamous cell carcinoma and rectal adenocarcinoma.
- To provide evidence for optimal therapeutic management strategies.
Main Methods:
- In-depth genomic analysis including next-generation sequencing, copy number variation, and human papilloma virus characterization.
- Analysis of 10 rectal squamous cell carcinoma samples.
- In silico comparison with publicly available data for anal squamous cell carcinoma and rectal adenocarcinoma.
Main Results:
- Rectal squamous cell carcinoma samples were 100% positive for human papilloma virus.
- Genomic profiles (mutations in PIK3CA, PTEN, TP53, ATM, BCL6, SOX2; copy number variations) were similar to anal squamous cell carcinoma.
- The PI3K/Akt/mTOR pathway was commonly affected, mirroring anal squamous cell carcinoma.
- Key genes altered in rectal adenocarcinoma were not typically found in rectal squamous cell carcinoma.
Conclusions:
- This study provides the first comprehensive genomic characterization of rectal squamous cell carcinoma.
- Rectal squamous cell carcinoma shares significant molecular similarities with anal squamous cell carcinoma.
- Therapeutic strategies for rectal squamous cell carcinoma should align with those for anal squamous cell carcinoma, not rectal adenocarcinoma.
