Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma

Tanaka, Kosuke; Hida, Toyoaki; Oya, Yuko; Yoshida, Tatsuya; Shimizu, Junichi; Mizuno, Tetsuya; Kuroda, Hiroaki; Sakakura, Noriaki; Yoshimura, Kenichi; Horio, Yoshitsugu; Sakao, Yukinori; Yatabe, Yasushi

doi:10.1002/cncr.30539

Cited by 54 publications

(100 citation statements)

References 37 publications

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“…As reported previously, EGFR mutations, the most common target gene of lung adenocarcinoma, represented 75% of all the gene alterations and occurred more frequently in females, patients who had never smoked, the elderly, and acinar predominant adenocarcinoma (16)(17)(18)(19). Interestingly, Hong et al (20) found that EGFR mutations were significantly more frequent in tumors with GGO than in solid tumors, which was contrary to our findings.…”

Section: Discussioncontrasting

confidence: 97%

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Zhao¹,

Zhan²,

Li³

et al. 2018

J. Thorac. Dis.

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epidermal growth factor receptor (EGFR) (729, 58.5%), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) (83, 6.7%), human epidermal growth factor receptor 2 (HER2) (82, 6.6%), anaplastic lymphoma kinase (ALK) (23, 1.8%), phosphoinositide-3-kinase catalytic alpha polypeptide (PIK3CA) (20, 1.6%), Ret proto-oncogene RET (15, 1.2%), ROS proto-oncogene 1 receptor tyrosine kinase (ROS1) (12, 1.0%), B-raf proto-oncogene (BRAF) (9, 0.7%), neuroblastoma RAS viral (v-ras) oncogene homolog (NRAS) (3, 0.2%). Fourteen (1.9%) of 731 patients were PD-1 positive and 95 (13.0%) were PD-L1 positive in tumor cells. In men and smokers, there were more frequent KRAS mutations (both P<0.001) and PD-L1 positive tumors (P<0.001, P=0.005, respectively), and less frequent EGFR mutations (P=0.049, <0.001, respectively). In ground-glass opacity (GGO) or ground-glass nodules (GGN), there were more HER2 (P=0.033) but less EGFR (P=0.025) and PIK3CA mutations (P=0.012), and ALK translocations (P=0.014). EGFR (P<0.001), KRAS mutations (P=0.004) and PD-L1 positive tumors (P=0.046) were more frequent in older patients, while HER2 (P<0.001), ALK (P=0.005) and ROS1 aberrations (P=0.044) were less frequent.Invasive mucinous adenocarcinoma was significantly associated with KRAS and ALK aberrations (both P<0.001), while solid predominant adenocarcinoma was associated with ROS1 translocations (P=0.036) and PD-L1 expression (P<0.001). KRAS, HER2, and ALK aberrations were scarce in patients with EGFR mutations (all P<0.001), while PD-L1 positive tumors positively correlated with ALK translocations (P=0.031) and negatively correlated with HER2 mutations (P=0.019). Conclusions: Most patients with primary lung adenocarcinoma harbored target gene aberrations. The frequency of each alteration differed in patients depending on clinicopathologic characteristics.

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Section: Discussioncontrasting

confidence: 97%

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Zhao¹,

Zhan²,

Li³

et al. 2018

J. Thorac. Dis.

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“…In striking contrast to the driver landscape of Asian never‐smokers dominated by EGFR mutations, only 25.0% patients in our cohort were featured with activating EGFR . The discrepancy might be ascribed to younger age; however, previous studies concerning the difference of proportion of EGFR mutations between young and old patient groups were inconclusive . In addition, other fairly frequent events (e.g., TP53 , KRAS and KEAP1 ) in the TCGA cohort did not appear frequent in our cohort, which also demonstrated heterogeneity exist in the specific subgroup of NSCLC.…”

Section: Discussioncontrasting

confidence: 71%

“…However, only a few studies have investigated the genomic alterations of NSCLC occurring in young patients, and all of them focused on the mutational frequency of several certain driver events involved in lung cancer. Compared with older patients with NSCLC, higher incidence of ALK , ROS1 and RET fusions exist among the younger patients …”

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confidence: 98%

“…Among all lung cancer cases, 85% are non‐small‐cell lung cancer (NSCLC) with two main histological types of adenocarcinoma and squamous cell carcinoma . With the development of precision medicine, NSCLC has been increasingly recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup …”

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confidence: 99%

“…Although only 1.3–5.3% of patients with lung cancers are 45 years or younger at diagnosis, there is a trend of increasing incidence of lung cancer among young adults . Many recent studies have suggested that NSCLC occurring in young patients constitutes a disease entity with distinct clinicopathologic characteristics . Early‐onset NSCLC occurs more often in women and never‐smokers, presents a predominance of LUAD.…”

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Characteristics of genomic alterations of lung adenocarcinoma in young never‐smokers

Luo

Tian

Wang

et al. 2018

Intl Journal of Cancer

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Non‐small‐cell lung cancer (NSCLC) has been recognized as a highly heterogeneous disease with phenotypic and genotypic diversity in each subgroup. While never‐smoker patients with NSCLC have been well studied through next generation sequencing, we have yet to recognize the potentially unique molecular features of young never‐smoker patients with NSCLC. In this study, we conducted whole genome sequencing (WGS) to characterize the genomic alterations of 36 never‐smoker Chinese patients, who were diagnosed with lung adenocarcinoma (LUAD) at 45 years or younger. Besides the well‐known gene mutations (e.g., TP53 and EGFR), our study identified several potential lung cancer‐associated gene mutations that were rarely reported (e.g., HOXA4 and MST1). The lung cancer‐related copy number variations (e.g., EGFR and CDKN2A) were enriched in our cohort (41.7%, 15/36) and the lung cancer‐related structural variations (e.g., EML4‐ALK and KIF5B‐RET) were commonly observed (22.2%, 8/36). Notably, new fusion partners of ALK (SMG6‐ALK) and RET (JMJD1C‐RET) were found. Furthermore, we observed a high prevalence (63.9%, 23/36) of potentially targetable genomic alterations in our cohort. Finally, we identified germline mutations in BPIFB1 (rs6141383, p.V284M), CHD4 (rs74790047, p.D140E), PARP1 (rs3219145, p.K940R), NUDT1 (rs4866, p.V83M), RAD52 (rs4987207, p.S346*), and MFI2 (rs17129219, p.A559T) were significantly enriched in the young never‐smoker patients with LUAD when compared with the in‐house noncancer database (p < 0.05). Our study provides a detailed mutational portrait of LUAD occurring in young never‐smokers and gives insights into the molecular pathogenesis of this distinct subgroup of NSCLC.

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Comprehensive analysis of age‐related somatic mutation profiles in Chinese young lung adenocarcinoma patients

Yang

et al. 2019

Cancer Medicine

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Background Lung adenocarcinoma in young adults is a rare entity with the oncogenic genetic alterations associated being poorly understood. In the present study, the effect of genetic alterations in lung adenocarcinoma patients diagnosed in young patients is reported. Methods Twenty young lung adenocarcinoma patients (age years: median: 33.5, range: 24‐36) were enrolled in the current study and 24 patients who were at common age of the disease onset (age years: median: 61.5, range: 52‐79) were selected for comparison. Paraffin sections of lung adenocarcinoma were analyzed using the whole‐exome sequencing platform. Results Similar number of somatic mutations per tumor were found in the young patients and their older counterparts. Although no age‐related differences were detected in the numbers of lung adenocarcinoma patients harboring well‐known gene variants, mutations in FRG1 and KMT2C were associated with a younger age especially after correcting for tobacco smoking and sex (FRG1: P = 0.027, KMT2C: P = 0.046). Five genetic variants showed higher alteration frequencies in young patients compared to the unclassified East Asian population, suggesting these mutations as disease‐related hereditary germline variants. Conclusions These results suggest different characteristics of lung adenocarcinoma between the young and the patients at common age of onset. Young patients with lung adenocarcinoma have a distinctly unique prevalence of oncogenic genetic alterations.

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Unique prevalence of oncogenic genetic alterations in young patients with lung adenocarcinoma

Abstract: Younger patients with adenocarcinoma have a distinctly unique prevalence of oncogenic GAs. Comprehensive oncogenic GA screening is especially recommended for personalized medicine strategies in this population. Cancer 2017;123:1731-1740. © 2017 American Cancer Society.

Cited by 54 publications

References 37 publications

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Aberrant status and clinicopathologic characteristic associations of 11 target genes in 1,321 Chinese patients with lung adenocarcinoma

Characteristics of genomic alterations of lung adenocarcinoma in young never‐smokers

Comprehensive analysis of age‐related somatic mutation profiles in Chinese young lung adenocarcinoma patients

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