Integrated molecular characterization of esophageal basaloid squamous cell carcinoma: a subtype with distinct RNA expression pattern and immune characteristics, but no specific genetic mutations

Abstract

Esophageal basaloid squamous cell carcinoma (bSCC) is a subtype of squamous cell carcinoma (SCC) with a different behavior and poor prognosis. Exploring bSCC's molecular characteristics and treatment strategies are of great clinical significance. We performed multi-omics analysis of paired bSCC and common SCC (cSCC) using whole exome sequencing and a NanoString nCounter gene expression panel. Immunohistochemistry was used for verification of candidate biomarkers. Different treatment response was analyzed on both patients receiving neoadjuvant treatment and late-stage patients. The common genetically-clonal origin of bSCC and cSCC was confirmed. No significant differences between their genetic alterations or mutation spectra were observed. Mutation signature 15 (associated with defective DNA damage repair) was less prominent, and tumor mutational burden (TMB) was lower in bSCC. bSCC with an RNA expression pattern resembling cSCC had a better survival than other bSCCs. Moreover, bSCC showed significant upregulation of expression of genes associated with angiogenesis response, basement membranes, and epithelial-mesenchymal transition, and downregulation of KRT14 (squamous differentiation) and CCL21 (associated with immune response). Immunohistochemistry for SFRP1 was shown to be highly sensitive and specific for bSCC diagnosis (p < 0.001). In addition, bSCC receiving neoadjuvant immuno-chemotherapy had a worse pathological response than bSCC receiving neoadjuvant chemotherapy (but without statistical significance), even in bSCC positive for PD-L1. Our results demonstrated the molecular characteristics of esophageal bSCC as a subtype with a distinct RNA expression pattern and immune characteristics, but no specific genetic mutations. We provided a useful biomarker, SFRP1, for diagnosis. After outcome analysis for six bSCCs with neoadjuvant immunotherapy treatment and four late-stage bSCCs with immunotherapy, we found that immunotherapy may not be an effective treatment option for most bSCCs. This may also provide a clue for the same subtypes of lung and head and neck cancer. Our study highlighted the heterogeneity among bSCC patients, and might explain the conflicting results of bSCC outcomes in existing studies.

A very rare case of spontaneous regression of basaloid squamous cell carcinoma of the lung

“…7 They also reported a worse response of immune-chemotherapy in basaloid squamous cell carcinoma. 7 This poor immune response tendency might be similar in the same subtype of lung cancer, and might be the reason for the rarity of SR in basaloid squamous cell carcinoma.…”

“…It has previously been reported that basaloid squamous cell carcinoma accounts for 3.9%–5.2% of all lung squamous carcinomas, and typically show rapid clinical progression, rapid growth rate, and a poorer prognosis compared to conventional squamous cell carcinoma of the lung 5,6 . Li et al performed the molecular characteristic comparison of basaloid squamous cell carcinoma and common squamous cell carcinoma of the esophageal, and reported that basaloid squamous cell carcinoma showed downregulation of CCL21 which associated with immune response 7 . They also reported a worse response of immune‐chemotherapy in basaloid squamous cell carcinoma 7 .…”

“…Li et al performed the molecular characteristic comparison of basaloid squamous cell carcinoma and common squamous cell carcinoma of the esophageal, and reported that basaloid squamous cell carcinoma showed downregulation of CCL21 which associated with immune response 7 . They also reported a worse response of immune‐chemotherapy in basaloid squamous cell carcinoma 7 . This poor immune response tendency might be similar in the same subtype of lung cancer, and might be the reason for the rarity of SR in basaloid squamous cell carcinoma.…”