Key points

Introduction

Lung cancer continues to remain a serious global problem and one of the leading causes of cancer-related death worldwide. The past decade has witnessed significant advances in next-generation sequencing technologies, which have made it possible to study cancer genomes in unprecedented detail and gain a better understanding of the alterations that underlie cancer development and progression. Comprehensive genomic analyses of lung cancer have been reported by several groups and consortia, such as The Cancer Genome Atlas (TCGA). The aim of this review is to highlight some of the important findings reported in these studies and discuss their clinical significance.

Introduction

Lung cancer continues to remain a serious global problem and one of the leading causes of cancer-related death worldwide. The past decade has witnessed significant advances in next-generation sequencing technologies, which have made it possible to study cancer genomes in unprecedented detail and gain a better understanding of the alterations that underlie cancer development and progression. Comprehensive genomic analyses of lung cancer have been reported by several groups and consortia, such as The Cancer Genome Atlas (TCGA). The aim of this review is to highlight some of the important findings reported in these studies and discuss their clinical significance.

Somatic mutations in lung cancer

Acquisition of somatic point mutations is one of the common mechanisms by which normal cells undergo malignant transformation. Cancer cells continually accrue a variety of mutations and are exposed to stresses, such as hypoxia, treatment, and attacks by the host immune system. As a result, cancer cells with mutations that confer upon them a survival advantage (often referred to as driver mutations) are selected over time. Because driver mutations increase the survival fitness of cancer cells, these mutations are likely to be over-represented and recurrent in cancer samples that are obtained from different patients, compared with other bystander or passenger mutations that do not offer a growth advantage to the cancer cell. Studies often use sophisticated statistical algorithms to identify significantly mutated genes. These algorithms take into account several factors that influence mutation rate, such as gene size, background mutation rate, DNA repair mechanisms (genes that are more actively transcribed into RNA have lower mutation burdens due to transcription-coupled repair), and replication timing (genes that are replicated later during cell division are more prone to mutations). Although these statistical predictions by themselves do not imply a biological role for genes in cancer, they can be extremely useful in identifying gene alterations for further functional studies.

Lung cancer genomes have a high burden of mutations, with approximately 8 mutations/megabase (Mb) or million base-pairs compared with other cancer types, such as pediatric tumors or acute leukemias. This high mutation burden in lung cancers is attributed to cigarette smoke exposure and abnormal activity of cell intrinsic mutagenic processes, such as APOBEC cytidine deaminase enzymes, and poses a challenge for identifying low-frequency driver alterations from passenger alterations. Exposure to cigarette smoke also results in a characteristic mutation pattern in tumors. Genomes of tumors from smokers are enriched for transversions, where a pyrimidine (cytosine or thymine) is replaced by a purine (adenine or guanine) or vice versa. In contrast, genomes of lung adenocarcinomas (LUADs) from never-smokers have an approximately 10-fold lower mutation burden (0.6 mutations/Mb) and are enriched for transitions, where a purine is replaced by a purine or a pyrimidine by a pyrimidine.

Using statistical algorithms, studies have reported recurrent mutations in tumor suppressors, such as TP53, STK11, NF1, RB1, PTEN , and CDKN2A , and oncogenes, such as KRAS, EGFR, MET , and PIK3CA in lung cancer. While some of these alterations are shared by different subtypes of lung cancer, others are histology specific. For instance, LUADs are characterized by mutations in genes, such as EGFR, KRAS, BRAF, ERBB2 , and MET , that activate the receptor tyrosine kinase (RTK)/RAS/RAF signaling pathway. Unlike LUADs, small cell lung cancers (SCLCs) rarely show mutations in the RTK/RAS/RAF signaling pathway. These tumors are typically characterized by comutation of the tumor suppressors, TP53 and RB1 , and alterations in genes that regulate neuroendocrine differentiation. Similarly, although LUAD and squamous cell lung cancer (SQLC) share mutations in genes, such as PIK3CA, CDKN2A, and TP53 , SQLCs additionally demonstrate mutations that deregulate squamous differentiation. In a recent analysis, only a 12% overlap was seen when genes mutated at a statistically significant level in 660 LUADs and 484 SQLCs were compared with each other. More similarity was observed between significantly mutated genes in LUAD and other tumor types, such as glioblastoma and colorectal cancer, and between SQLC and head and neck squamous cell and bladder cancers, than between LUAD and SQLC in this study. These findings suggest that genomic alterations tend to differ between different subtypes of lung cancer, possibly reflecting the differences in the cells from which these tumors arise and the distinct mutational processes that underlie the malignant transformation of these cells.

Activating mutations in previously known RTK/RAS/RAF pathway genes, such as KRAS, EGFR, ERBB2, BRAF, and MET , were seen in approximately 62% of the 230 LUAD samples sequenced by TCGA. Samples in which such known RTK/RAS/RAF pathway alterations were not detected were labeled “oncogene negative.” When oncogene-positive and oncogene-negative samples were analyzed independently, other RTK/RAS/RAF pathway alterations, such as mutations in RIT1 and NF1 , were found significantly enriched in the oncogene-negative sample subset, emphasizing the importance of such analyses in identifying new driver alterations. Similarly, analysis of combined genomic data from different tumor types (irrespective of the site of origin) can identify novel driver alterations by improving the statistical power to detect low-frequency alterations, because some cell survival pathways are commonly altered in all cancer types. Such analyses could be particularly helpful in identifying low-frequency alterations in tumors with a high mutation burden, such as lung cancer.

Campbell and colleagues analyzed SQLC and LUAD samples together and found 14 genes to be mutated at a statistically significant level, which were not identified when samples from either subtype were individually analyzed. Furthermore, on combining sequencing data from an additional 274 LUAD samples with samples from the TCGA data set, low-frequency alterations in RTK/RAS/RAF pathway genes, SOS1 and RASA1 , and Rho kinase signaling genes, VAV1 and ARHGAP35, were identified in this study. Because only a fraction of LUAD patients with RTK/RAS/RAF pathway alterations are targetable with currently approved therapies, such large-scale sequencing studies and analyses are likely to lead to the discovery of novel clinically useful targets.

Copy number alterations

The human genome is diploid in nongerm cells, and, therefore, every cell has 2 copies of a gene (excluding genes on the sex chromosomes in men). Copy number alterations (CNAs) refer to deviations in this number. CNAs can vary in size and, depending on the genomic region they involve, result in several-fold gain (amplification) of oncogenes and/or loss (deletion) of multiple tumor suppressors simultaneously, playing an important role in malignant transformation. CNAs are frequently observed in lung cancer genomes.

Similar to somatic mutations, some CNAs are seen in all subtypes of lung cancers whereas others tend to be enriched in specific histologic subtypes. For instance, losses involving the short arm of chromosome 3 (3p) and tumor suppressors that are frequently mutated in lung cancer, such as CDKN2A and PTEN , are commonly observed in both SCLC and non-SCLCs (LUAD and SQLC). The 3p region harbors multiple tumor suppressors, such as VHL, RASSF1A, FHIT, and FUS1 . On the other hand, amplification of a segment of the long arm of chromosome 3 is frequently observed in SQLCs. This region contains genes, such as SOX2, PIK3CA, HES1 , and TP63, which play a critical role in oncogenesis, development, and squamous differentiation. SOX2 amplifications are also seen in SCLC. SOX2 is a transcription factor that plays a role in the development of lung epithelium and pluripotency and is considered to be a lineage-survival oncogene in SQLC. Similarly, focal amplification of the region on chromosomal arm 14q that contains NKX2-1 ( TTF1 ) is seen in approximately 14% of LUAD samples. Similar to SOX2 in SQLC, NKX2-1 is considered a lineage-survival oncogene in LUAD. Lung cancers also show amplifications in TERT (a ribonucleoprotein that is crucial for the synthesis of telomeric DNA); oncogenic transcription factors MYC, MYCN , and MYCL1 ; and RTKs, such as PDGFRA, KIT, FGFR1 , and MET .

Similar to mutations, combined analysis of LUADs and SQLCs can also allow the detection of recurrent low-frequency CNAs common to both subtypes. Recurrent amplifications around MAPK1 , which participates in RAS/RTK/RAF signaling, and deletion of β2-microglobulin of ( B2M ), which is an integral part of the major histocompatibility complex, were observed in both LUADs and SQLCs when these samples were analyzed together. Amplification peaks near RTK/RAS/RAF signaling genes, FGFR1-WHSC1L1 , PDGFRA-KIT-KDR , and MAPK1 , in oncogene-negative LUADs were observed at a statistically significant level in this analysis. Although some CNAs, such as MET amplification, can be targeted with tyrosine kinase inhibitors, the therapeutic significance of the vast majority of CNAs remains to be explored.

Chromosomal rearrangements

Translocations are structural rearrangements that bring 2 otherwise nonadjacent regions in the genome together. When 2 otherwise separated genes are brought together, the translocation can result in the production of an aberrant fusion protein. Fusion proteins contribute to oncogenesis by resulting in the inactivation of tumor suppressors (such as TP73 ) or abnormal activation of oncogenes. For instance, translocations in oncogenes, such as ALK, RET , and ROS1 , result in the activation of several signaling pathways that are crucial for cancer cell survival. The discovery of RTK translocations in a subset of patients with lung cancer has allowed the targeting of these tumors with tyrosine kinase inhibitors, such as crizotinib, ceritinib, and alectinib, which has improved patient survival significantly. These drugs are currently approved for use in patients with LUAD whose tumors contain ALK or ROS1 fusions. Although there are no approved targeted therapies for tumors with RET fusions in lung cancer, there are reports to suggest responses with RET inhibitors, such as cabozantinib and vandetanib, that are approved for use in thyroid cancer ( Table 1 ).

Table 1

Summary of currently Food and Drug Administration–approved therapies with proven or possible clinical activity (based on limited data/isolated case reports) in selected patients with lung cancer

Gene	Alteration	Food and Drug Administration–Approved Drugs with Proven Clinical Efficacy	Comments
EGFR	Mutation	Erlotinib, gefitinib, afatinib, and osimertinib	Osimertinib is currently approved for use in patients progressing on EGFR inhibitors who test positive for the T790M mutation.
BRAF	Mutation (V600E), gusion	Vemurafenib, , a dabrafenib , a +/− trametinib , a	These drugs are currently approved for use in BRAF -mutated metastatic melanoma. The targetability of BRAF fusions in lung cancer is unknown. Responses to trametinib and combination therapy with sorafenib, bevacizumab, and temsirolimus have been reported in patients with other BRAF fusion–positive malignancies.
ERBB2	Mutation (exon 20 insertion)	Trastuzumab, , a afatinib , a	Trastuzumab and lapatinib are approved for breast cancer and afatinib for EGFR -mutated lung cancer. Trastuzumab is also approved for use in gastric cancer.
MET	Amplification, mutation (exon 14 skipping)	Crizotinib, , a cabozantinib , a	Cabozantinib is approved for use in renal cell and medullary thyroid cancer. Crizotinib is approved for ALK and ROS1 rearranged lung cancer.
ALK	Fusion	Crizotinib, ceritinib, alectinib	Ceritinib and alectinib are approved in patients who are intolerant to or have progressed on crizotinib.
ROS1	Fusion	Crizotinib, ceritinib , a	Crizotinib is currently the only drug approved for use in ROS1 rearranged lung cancer.
RET	Fusion	Vandetanib, , a cabozantinib , a	These drugs are currently approved for use in patients with medullary thyroid cancer.
NTRK1	Fusion	Crizotinib , a	Stable disease was reported in one patient in this case report with crizotinib.
DDR2	Mutation	Dasatinib , a +/− erlotinib , a	This mutation was reported in SQLC. Dasatinib is approved for use in chronic myeloid leukemia.

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