Abstract
Pulmonary invasive mucinous adenocarcinoma (IMA) is considered a variant of lung adenocarcinomas based on the current World Health Organization classification of lung tumors. However, the molecular mechanism driving IMA development and progression is not well understood. Thus, we surveyed the genomic characteristics of IMA in association with immune-checkpoint expression to investigate new potential therapeutic strategies. Tumor cells were collected from surgical specimens of primary IMA, and sequenced to survey 53 genes associated with lung cancer. The mutational profiles thus obtained were compared in silico to conventional adenocarcinomas and other histologic carcinomas, thereby establishing the genomic clustering of lung cancers. Immunostaining was also performed to compare expression of programmed death ligand 1 (PD-L1) and B7-H3 in IMA and conventional adenocarcinomas. Mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) were detected in 75% of IMAs, but in only 11.6% of conventional adenocarcinomas. On the other hand, the frequency of mutations in epidermal growth factor receptor (EGFR) and tumor protein p53 (TP53) genes was 5% and 10%, respectively, in the former, but 48.8% and 34.9%, respectively, in the latter. Clustering of all 78 lung cancers indicated that IMA is distinct from conventional adenocarcinoma or squamous cell carcinoma. Strikingly, expression of PD-L1 in ≥1% of cells was observed in only 6.1% of IMAs, but in 59.7% of conventional adenocarcinomas. Finally, 42.4% and 19.4% of IMAs and conventional adenocarcinomas, respectively, tested positive for B7-H3. Although currently classified as a variant of lung adenocarcinoma, it is also reasonable to consider IMA as fundamentally distinct, based on mutation profiles and genetic clustering as well as immune-checkpoint status. The immunohistochemistry data suggest that B7-H3 may be a new and promising therapeutic target for immune checkpoint therapy.
Highlights
Invasive mucinous adenocarcinoma (IMA), which represents 2–10% of all lung adenocarcinomas, is considered one of the most malignant subtypes and is associated with poor prognosis [1,2,3].IMA presents a unique histology among primary lung cancers, and is typified by columnar or goblet cells with basally located nuclei and pale cytoplasm containing varying amounts of mucin [4].the clinical presentation of IMA is distinct from that of conventional nonmucinous adenocarcinoma [5,6,7]
IMAs are strongly correlated with mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS), which are present in 28–87% of cases [4,5,6,7,8]
IMA and nonmucinous adenocarcinoma (NMA) patients were comparable in age, sex, lung function, smoking habit, tumor location, surgical procedure received, tumor size, pathological stage, and lymphatic or vessel invasion (Table 1, Supplementary Table S1)
Summary
Invasive mucinous adenocarcinoma (IMA), which represents 2–10% of all lung adenocarcinomas, is considered one of the most malignant subtypes and is associated with poor prognosis [1,2,3].IMA presents a unique histology among primary lung cancers, and is typified by columnar or goblet cells with basally located nuclei and pale cytoplasm containing varying amounts of mucin [4].the clinical presentation of IMA is distinct from that of conventional nonmucinous adenocarcinoma [5,6,7]. IMA presents a unique histology among primary lung cancers, and is typified by columnar or goblet cells with basally located nuclei and pale cytoplasm containing varying amounts of mucin [4]. Standard chemotherapy is the only treatment option at advanced stages, no targeted therapy has been demonstrated to be effective against IMA. The correlation between the genetic characteristics and immune-checkpoint expression is unclear and no specific immune checkpoint therapy is established for IMA, such therapy has recently attracted attention as treatment for non-small cell lung cancer. Molecular studies have been limited and therapeutic targets remain yet to be identified partly because IMA is relatively rare compared to other subtypes. We surveyed gene mutations in IMA by targeted next-generation sequencing, and propose a novel classification of lung cancers based on clustering of mutational profiles. We investigated by immunohistochemistry the potential of immune checkpoint blockade as therapy against IMA
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