TY - JOUR
T1 - Genomic characteristics of invasive mucinous adenocarcinomas of the lung and potential therapeutic targets of B7-H3
AU - Nakagomi, Takahiro
AU - Goto, Taichiro
AU - Hirotsu, Yosuke
AU - Shikata, Daichi
AU - Yokoyama, Yujiro
AU - Higuchi, Rumi
AU - Otake, Sotaro
AU - Amemiya, Kenji
AU - Oyama, Toshio
AU - Mochizuki, Hitoshi
AU - Omata, Masao
N1 - Funding Information:
Funding: This study was supported by a Grant-in-Aid for Genome Research Project from Yamanashi Prefecture (to Y. Hirotsu and M. Omata) and by grants from Japanese Foundation for Multidisciplinary Treatment of Cancer (to T. Goto).
Publisher Copyright:
© 2018 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2018/12
Y1 - 2018/12
N2 - 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.
AB - 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.
KW - Clustering
KW - Immunocheckpoint
KW - Invasive mucinous adenocarcinoma
KW - Lung cancer
KW - Next-generation sequencing
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U2 - 10.3390/cancers10120478
DO - 10.3390/cancers10120478
M3 - Article
AN - SCOPUS:85058463190
SN - 2072-6694
VL - 10
JO - Cancers
JF - Cancers
IS - 12
M1 - 478
ER -
