Genomic Characteristics of Invasive Mucinous Adenocarcinomas of the Lung and Potential Therapeutic Targets of B7-H3

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.

Primary Driver Mutations in GTF2I Specific to the Development of Thymomas

“…Thus, we designed our primers for the polymerase chain reaction of the region inclusive of this single nucleotide variation. The primers were designed for use in targeted sequencing using Ion AmpliSeq Designer (Thermo Fisher Scientific) as described previously [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 , 38 ].…”

Association of Mutation Profiles with Postoperative Survival in Patients with Non–Small Cell Lung Cancer

“…We searched the literature and selected these genes based on the following criteria: (a) Genes often involved in lung cancer reported in The Cancer Genome Atlas [ 40 ] and other projects; or (b) genes frequently mutated in lung cancer in the Catalogue of Somatic Mutations in Cancer (COSMIC) database [ 41 ]. The primers for targeted sequencing were designed to cover the hot-spot mutations present in the lung cancer-associated genes, using the Ion AmpliSeq designer software (Thermo Fisher Scientific), as reported previously [ 42 , 43 , 44 , 45 , 46 , 47 , 48 ]. Sequencing libraries were prepared using Ion AmpliSeq Library Kit Plus (Thermo Fisher Scientific), according to the manufacturer’s instruction.…”

Identification of Clonality through Genomic Profile Analysis in Multiple Lung Cancers

“…These genes were selected after a literature search based on the following criteria: (a) genes involved in lung cancer according to The Cancer Genome Atlas [4,5] and other, similar projects [6][7][8][9][10] or (b) genes frequently mutated in lung cancer according to the Catalogue Of Somatic Mutations In Cancer (COSMIC) database [11]. Ion AmpliSeq designer software (Thermo Fisher Scientific) was utilized for the primer composition, as previously reported [1,12,13]. An Ion AmpliSeq Library kit (Thermo Fisher Scientific) was utilized for the preparation of sequencing libraries.…”