Introduction:The information regarding therapeutically relevant genomic alterations in small cell lung cancer (SCLC) is not well developed. We analyzed the SCLC genome using an integrative approach to stratify the targetable alterations.Methods:We performed whole exon sequencing (n = 51) and copy number analysis (n =47) on surgically resected tumors and matched normal tissue samples from treatment-naive Japanese SCLC patients.Results:The demographics of the 51 patients included in this study were as follows: median age, 67 years (range, 42–86 years); female, 9 (18%); history of smoking, 50 (98%); and pathological stage I/II/III/IV, 28/13/9/1, respectively. The average number of nonsynonymous mutations was 209 (range, 41–639; standard deviation, 130). We repeatedly confirmed the high prevalence of inactivating mutations in TP53 and RB1, and the amplification of MYC family members. In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 36% of the tumors: PIK3CA, 6%; PTEN, 4%; AKT2, 9%; AKT3, 4%; RICTOR, 9%; and mTOR, 4%. Furthermore, the individual changes in this pathway were mutually exclusive. Importantly, the SCLC cells harboring active PIK3CA mutations were potentially targetable with currently available PI3K inhibitors.Conclusions:The PI3K/AKT/mTOR pathway is distinguishable in SCLC genomic alterations. Therefore, a sequencing-based comprehensive analysis could stratify SCLC patients by potential therapeutic targets.

DNA repair systems maintain the integrity of the genome; therefore, their activities are associated with mutation frequencies of cancer-related genes. Up to the present, a number of genes have been shown to be involved in DNA repair systems. 1 Some of the genes encode factors for base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), DNA doublestrand breaks repair (DSBR), or other repair pathways, while some others encode DNA polymerases that can bypass DNA damages. In addition, DNA damage response genes, which encode factors to transmit the signals of DNA damages to the cell cycle checkpoint machinery and to the monitoring systems controlling cellular apoptosis, can be regarded as a class of DNA repair genes. It has been considered that polymorphisms in DNA repair genes lead to interindividual differences in the capacities for repairing DNA damages; therefore, they could contribute to susceptibility to cancer. [2][3][4] Lung cancer is the leading cause of cancer-related deaths in the world, and genetic factors responsible for susceptibility to lung cancer have been searched for to establish novel and efficient ways of preventing the disease. Several epidemiologic studies have indicated that there are genetic factors to modify the risk of individuals to lung cancer. [5][6][7] Segregation analyses suggest that rare autosomal dominant genes may explain susceptibility to earlyonset lung cancer, but only a minority of lung cancer cases can be explained by the presence of such genes. 5-7 Therefore, more common genetic polymorphisms have been considered to affect the risk of lung cancer in the general population. Lung cancer patients were reported to have lower capacities to repair DNA damages than healthy individuals. 6,8 Therefore, it was indicated that polymorphisms of DNA repair genes are strong candidates for genetic factors responsible for lung cancer susceptibility. In fact, single nucleotide polymorphisms (SNPs) in several DNA repair genes were examined for associations with lung cancer risk, and a few SNPs, TP53-Arg72Pro, OGG1-Ser326Cys, XRCC1-Arg399Gln and XPD-Asp312Asn, showed associations. 3 Therefore, the significance of genetic polymorphisms in DNA repair genes in lung cancer risk is being revealed. However, to make their contribution on lung cancer risks clearer, polymorphisms in various classes of DNA repair genes should be more extensively examined for associations with the risk. For this reason, in this study, 36 DNA repair genes involved in diverse intracellular processes that maintain genome integrity (Table I) were searched for nonsynonymous (associated with amino acid changes) SNPs, and 50 SNPs detected were subjected to a case-control study to examine their associations with risks for lung cancer. Lung cancer subjects analyzed in this case-control study consisted of adenocarcinoma (ADC) and squamous cell carcinoma (SQC) cases. ADC and SQC are the first and second major histologic subtypes of lung cancer, respectively, and epidemiologic studies have indicated that ca...

EGFR-mutated lung cancers account for a significant subgroup of non-small cell lung cancers overall. Third-generation EGFR tyrosine kinase inhibitors (TKI) are mutation-selective inhibitors with minimal effects on wild-type EGFR. Acquired resistance develops to these agents, however, the mechanisms are as yet uncharacterized. In this study, we report that the Src-AKT pathway contributes to acquired resistance to these TKI. In addition, amplification of EGFR wild-type alleles but not mutant alleles was sufficient to confer acquired resistance. These findings underscore the importance of signals from wild-type EGFR alleles in acquiring resistance to mutant-selective EGFR-TKI. Our data provide evidence of wild-type allele-mediated resistance, a novel concept of acquired resistance in response to mutation-selective inhibitor therapy in cancer treatment. .

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Purpose: Although large-cell neuroendocrine carcinoma (LCNEC) of the lung shares many clinical characteristics with small-cell lung cancer (SCLC), little is known about its molecular features. We analyzed lung LCNECs to identify biologically relevant genomic alterations.Experimental Design: We performed targeted capture sequencing of all the coding exons of 244 cancer-related genes on 78 LCNEC samples [65 surgically resected cases, including 10 LCNECs combined with non-small cell lung cancer (NSCLC) types analyzed separately, and biopsies of 13 advanced cases]. Frequencies of genetic alterations were compared with those of 141 SCLCs (50 surgically resected cases and biopsies of 91 advanced cases).Results: We found a relatively high prevalence of inactivating mutations in TP53 (71%) and RB1 (26%), but the mutation frequency in RB1 was lower than that in SCLCs (40%, P ¼ 0.039). In addition, genetic alterations in the PI3K/AKT/mTOR pathway were detected in 12 (15%) of the tumors: PIK3CA 3%, PTEN 4%, AKT2 4%, RICTOR 5%, and mTOR 1%. Other activating alterations were detected in KRAS (6%), FGFR1 (5%), KIT (4%), ERBB2 (4%), HRAS (1%), and EGFR (1%). Five of 10 cases of LCNECs combined with NSCLCs harbored previously reported driver gene alterations, all of which were shared between the two components. The median concordance rate of candidate somatic mutations between the two components was 71% (range, 60%-100%).Conclusions: LCNECs have a similar genomic profile to SCLC, including promising therapeutic targets, such as the PI3K/AKT/ mTOR pathway and other gene alterations. Sequencing-based molecular profiling is warranted in LCNEC for targeted therapies.