Somatic mutation spectrum of non-small cell lung cancers (NSCLCs) from African Americans (AAs).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6038-6038
Author(s):  
Philip Edward Lammers ◽  
Velmalia Matthews-Smith ◽  
Ya-Lin Yun ◽  
Yumei Pan ◽  
Snjezana Zaja-Milatovic ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
North American Population ◽  
Molecular Testing ◽  
Chi Square ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Anaplastic Lymphoma ◽  
Ffpe Tumor

6038 Background: In the AA population, previous studies have presented conflicting data on the frequency of EGFR mutations (Reinersman JTO 2011;Leidner JCO 2009), while frequencies of other gene mutations and translocations, including anaplastic lymphoma kinase (ALK), have not been described. Methods: 161 archival FFPE tumor specimens from self reported AA patients with any stage NSCLC from 1997-2010 were collected from 3 sites in Tennessee (132 samples) and one site in Michigan (29 samples). Samples were evaluated for known recurrent driver mutations in EGFR, KRAS, BRAF, NRAS, AKT1, PI3KCA, PTEN, HER-2, MEK1 by standard SNaPshot/sizing assays, and translocations in ALK by FISH. Clinical data was collected on 119 patients. Chi-square was used to compare the frequency of mutations in subgroups and Kaplan-Meier and log rank were used to calculate and compare PFS between groups. Results: 5.0% of tumors had EGFR mutations, 14.9% had KRAS mutations, 0.6% had a BRAF, AKT1, PI3KCA, or HER2 mutation, and 0% had NRAS, PTEN, or MEK1 mutations. Of 35 ‘pan-negative’ non-squamous specimens, 0 had ALK translocations. PFS was the same in those with and without KRAS mutation (p=0.74) and showed a trend towards improvement in those with EGFR mutation (p=0.08). The frequency of EGFR mutations was higher in samples from Detroit versus those from Tennessee (17% vs 2.3%, p<0.01), as was the frequency of adenocarcinoma (62% vs 44%, p<0.05). The frequency of EGFR mutations in never smokers was higher in the samples from Detroit versus Tennessee (83% vs 7.1%, p<0.01). Conclusions: In the largest tumor mutational profiling study of NSCLC from AAs to date, EGFR mutations occurred less frequently than would be expected from a North American population. We noted a regional difference, with fewer EGFR mutations in Tennessee than in Michigan, a finding that may have been the result of more adenocarcinoma samples from Michigan. The rates of other mutations and translocations including ALK were low. While lung cancer tumors should continue to undergo routine molecular testing to prioritize therapy, future comprehensive genotyping efforts should focus on identifying novel driver mutations in this population. Funding: 5RC1CA162260 R01CA060691 R01CA87895.

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

2019 ◽  
Vol 19 (23) ◽  
pp. 2128-2142 ◽  
Author(s):  
Hao He ◽  
Chang Xu ◽  
Zhao Cheng ◽  
Xiaoying Qian ◽  
Lei Zheng
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Egfr Tki ◽  
Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

Genetic Alterations in Chinese Resected Lung Cancer with Invasive Mucinous Adenocarcinoma: Genomic Profiling and Prognostic Value Analysis

2021 ◽  
Author(s):  
James D. Klingensmith
Keyword(s):  
Mucinous Adenocarcinoma ◽  
Pi3k Pathway ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Genetic Profile ◽  
Kras Mutations ◽  
Genetic Characteristics ◽  
Value Analysis ◽  
Invasive Mucinous Adenocarcinoma

Lung invasive mucinous adenocarcinoma (IMA) is a unique histological subtype with different clinical and pathological characteristics. Despite prior genomic investigations on lung IMA, little is known about the genetic features and prognosis-related biomarkers in Chinese surgically resected lung IMA. IMA showed a distinct genetic profile, with more diversified driver mutations and co-occurrence of tumor drivers/suppressors than non-IMA. From non-IMA to mixed-IMA to pure-IMA, the frequency of EGFR (72.0 percent vs. 40.0 percent vs. 23.1 percent, p=0.002) and ALK (undetected vs. 20.0 percent vs. 26.9%, p=0.015) changes exhibited a trend of steady decline and rise, respectively. KRAS mutations were more common in pure-IMA than in mixed-IMA, however the difference was statistically insignificant (23.1 percent vs. 4.0 percent, p=0.10). Pure-IMA had a lower rate of TP53 mutation than mixed-IMA and non-IMA (23.1 percent vs. 52.0 percent vs. 56.0 percent, p=0.03). Furthermore, IMA had fewer arm-level amplifications (p=0.04) and more arm-level deletions (p=0.004) than non-IMA, with a steady drop in amplification and rise in deletion frequency from non-IMA to mixed-IMA to pure-IMA, respectively. Patients with EGFR mutations (mDFS=30.3 vs. 16.0 months, HR=0.19, P=0.027) and PI3K pathway mutations (mDFS=36.0 vs. 16.0 months, HR=0.12, P=0.023) had longer DFS than patients with poorly differentiated tumors (mDFS=14.1 vs. 28.0 months, HR=3.75, p=0.037) or KRAS mutations (mDFS=13 KRAS mutations, PI3K pathway changes, and tumor differentiation status were all shown to be independent predictors with statistically significant effects on IMA patients' clinical outcomes in multivariate analysis. Our research shed light on the genomics of Chinese lung IMA that had been surgically removed. In IMA patients with stage III illness, we also discovered many genetic characteristics that might be used as indicators for postoperative recurrence.

scholarly journals MUC5AC enhances tumor heterogeneity in lung adenocarcinoma with mucin production and is associated with poor prognosis

2020 ◽  
Vol 50 (6) ◽  
pp. 701-711
Author(s):  
Yujie Dong ◽  
Lijuan Zhou ◽  
Dan Zhao ◽  
Kun Li ◽  
Zichen Liu ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Lung Adenocarcinoma ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Kras Mutations ◽  
Mucin Production ◽  
Thyroid Transcription Factor 1 ◽  
Thyroid Transcription Factor ◽  
Transcription Factor 1

Abstract Objective The clinicopathological significance of Mucin5AC (MUC5AC) in lung adenocarcinoma with mucin production is still unclear. This study aimed to explore MUC5AC expression in lung adenocarcinoma with mucin production and its correlation with histological subtypes, common driver mutations and its impact on prognosis. Methods MUC5AC and thyroid transcription factor 1 immunohistochemistry was performed on surgical samples from 90 patients with lung adenocarcinoma with mucin production. Common driver mutations including EGFR and KRAS mutations and ALK rearrangement were detected by established methods. Results MUC5AC was significantly associated with lymphovascular invasion (P = 0.023) and tumors with intra-cytoplasmic mucin (P &lt; 0.001). Moreover, MUC5AC was more significant in invasive mucinous adenocarcinoma (P &lt; 0.001), as well as in tumors with KRAS mutations (P = 0.005) and a lack of thyroid transcription factor 1 expression (P &lt; 0.001). Conversely, MUC5AC was less significantly detected in acinar predominant adenocarcinoma (P = 0.036) and tumors with EGFR mutations (P = 0.001). Notably, MUC5AC in non-pure mucinous subtype of lung adenocarcinoma with mucin production showed more aggressive behavior, distinct expression pattern and a lack of significant correlation with thyroid transcription factor 1 (P = 0.113) when compared with pure mucinous subtype. MUC5AC-positive tumors were significantly associated with a worse prognosis compared to MUC5AC-negative tumors (P &lt; 0.001). A multivariate survival analysis showed that MUC5AC was an independent prognosis factor for poor prognosis (P = 0.006). Conclusions The clinicopathological features of non-pure mucinous subtype of lung adenocarcinoma with mucin production were distinct and should be distinguished from pure mucinous subtype. MUC5AC was associated with poor prognosis and could be a potential therapeutic target for this distinct type of lung adenocarcinoma that has few effective treatments.

Concomitant Presence of EGFR and ALK Fusion Gene Mutation in Adenocarcinoma of Lung: A Case Report and Review of the Literature

2017 ◽  
Vol 31 (2) ◽  
pp. 244-248
Author(s):  
Nishitha Thumallapally ◽  
Hana Yu ◽  
Mohammad Farhan ◽  
Uroosa Ibrahim ◽  
Maricel Odiami
Keyword(s):  
Molecular Mechanisms ◽  
Fusion Gene ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Alk Rearrangement ◽  
Anaplastic Lymphoma ◽  
Adenocarcinoma Of Lung ◽  
Practical Guidelines ◽  
Oncogenic Driver

Empirical evidence has long suggested that oncogenic driver mutations in non-small-cell lung cancer are mutually independent. However, recent studies reported in pertinent literature reveal that concomitant epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangement can occur in a subset of patients with NSCLC. In order to shed further light on this issue, we report a case of adenocarcinoma of lung harboring both EGFR mutation in exon 21 (L861Q) and ALK rearrangement. This allows us to speculate on likely molecular mechanisms underlying this uncommon phenomenon, while also offering some practical guidelines on the therapeutic options that could benefit patients diagnosed with this dual-positive tumor.

Smoking history and frequency of somatic KRAS mutations in adenocarcinoma of the lung

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7573-7573
Author(s):  
V. A. Miller ◽  
G. J. Riely ◽  
M. G. Kris ◽  
D. Rosenbaum ◽  
J. Marks ◽  
...  
Keyword(s):  
Cigarette Smoking ◽  
Mutational Analysis ◽  
Smoking History ◽  
Egfr Mutations ◽  
Molecular Testing ◽  
Kras Mutations ◽  
Exon 2 ◽  
Significant Difference ◽  
Never Smokers ◽  
Lung Adenocarcinomas

7573 Background: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are more common in patients with adenocarcinoma, especially those who smoked < 15 pack years (py). KRAS mutations are found in ∼25% of lung adenocarcinomas, most commonly in codons 12 and 13 of exon 2 (∼85%) and have been associated with poor prognosis in resected disease [Winton NEJM 2005] and resistance to EGFR tyrosine kinase inhibitors [Pao PLoS Med 2005]. KRAS mutations are uncommon in non-small cell lung cancer histologies other than adenocarcinoma. We sought to determine the association between quantitative measures of cigarette smoking and presence of KRAS mutations in lung adenocarcinomas. Methods: Standard direct sequencing techniques were used to identify KRAS codon 12 and 13 mutations in lung adenocarcinoma specimens from surgical resections between 2001 and 2006 and tumor specimens sent for KRAS molecular analysis in 2006. Surgical specimens were obtained from an institutional tumor bank. Detailed smoking history (age at first cigarette, packs per day, years smoked, years since quitting smoking) was obtained from the medical record and a patient-completed smoking questionnaire. Results: KRAS mutational analysis was performed on 408 lung adenocarcinomas from 242 women and 166 men. Median age was 68 (range 33–89). KRAS mutations were present in 19% (78/408, 95% CI 15 to 23%). The frequency of KRAS mutation was not associated with age or gender. The presence of KRAS mutations was not related to smoking history with 15% (9/61) of never smokers having KRAS mutations compared with 19% (51/275) of former smokers. When compared with never smokers, there was no significant difference in frequency of KRAS mutations for tumors from patients with 1–5 py (5%, p=0.44), 6- 10 py (12%, p=0.99), 11–15 py (25%, p=0.45), 16–25 py (16%, p=0.99), 26–50 py (25%, p=0.129), 51–75 py (20%, p=0.48), >75 py (20%, p=0.47) history of cigarette smoking. Conclusions: While the incidence of EGFR mutations has a strong inverse relationship with the amount of cigarettes smoked, allowing the selective molecular testing for EGFR mutations, the frequency of KRAS mutations cannot be predicted by age, gender, or smoking history. KRAS mutational analysis of all adenocarcinomas is required to reliably identify patients with KRAS mutations. No significant financial relationships to disclose.

A retrospective analysis of the prevalence of EGFR or KRAS mutations in patients (pts) with crizotinib-naïve and crizotinib-resistant, ALK-positive non-small cell lung cancer (NSCLC).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 8083-8083
Author(s):  
Justin F. Gainor ◽  
Anna M. Varghese ◽  
Sai-Hong Ignatius Ou ◽  
Sheheryar Kabraji ◽  
Mark M Awad ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Acquired Resistance ◽  
Kinase Domain ◽  
Repeat Biopsy ◽  
Egfr Mutations ◽  
Tyrosine Kinase Domain ◽  
Kras Mutations ◽  
Anaplastic Lymphoma ◽  
Biopsy Specimens ◽  
Alk Positive

8083 Background: Anaplastic lymphoma kinase (ALK) gene rearrangements define a distinct molecular subset of NSCLC. Recently, several studies have reported that ALK+ pts occasionally harbor concomitant mutations in other oncogenic drivers. Methods: We retrospectively analyzed tumor genotyping data from 1,683 pts with NSCLC seen at 3 U.S. centers from 2009 – 2012 to determine rates of overlapping alterations in EGFR, KRAS and ALK. Mutations in EGFR and KRAS were mainly identified using the SNaPshot multiplexed assay (>95% of cases). ALK FISH was performed in all cases. To determine if this prevalence is impacted by crizotinib, we also updated our earlier analysis (Katayama et al., Sci Transl Med, 2012) of a series of repeat biopsy specimens from 34 crizotinib-resistant, ALK+ pts. Resistant specimens were examined using ALK FISH, SNaPshot, and direct sequencing of the ALK tyrosine kinase domain (TKD). Results: Screening identified 301 (17.8%) EGFR mutations, 465 (27.6%) KRAS mutations, and 75 (4.4%) ALK rearrangements. EGFR mutations and ALK rearrangements were mutually exclusive. 4 pts with KRAS mutations also had abnormal ALK FISH patterns, involving isolated 5’ green probes (3/4 cases) and an isolated 3’ red probe that was unusually small (1/4 cases). Sufficient tissue was available for confirmatory ALK immunohistochemistry (clone 5A4, Novacastra, UK) in 3 of these cases, all of which were negative for ALK expression. Among pts with ALK+ NSCLC and acquired crizotinib resistance, repeat biopsy specimens remained ALK fusion positive in 28/28 (100%) cases. Secondary mutations in the ALK TKD (1151Tins, L1196M, G1202R, S1206Y, and G1269A) were identified in 7/34 (20.6%) cases. L1196M was the most common secondary mutation (3/34, 8.8% cases). ALK gene amplification was present in 3/28 (10.71%) pts. No EGFR or KRAS mutations were identified in 23 crizotinib-resistant, ALK+ pts with sufficient tissue for testing. Conclusions: Functional ALK rearrangements were mutually exclusive with EGFR and KRAS mutations in a large Western patient population. This lack of overlap was also observed in ALK+ pts with acquired resistance to crizotinib.

scholarly journals The development of potential targets in the treatment of non-small cell lung cancer

2016 ◽  
Vol 11 (1) ◽  
pp. 225-231
Author(s):  
Jimin Zhang ◽  
Zhihui Lin
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Driver Mutations ◽  
Small Cell Lung ◽  
Braf Mutations ◽  
Kras Mutations ◽  
Anaplastic Lymphoma

AbstractThe oncogenic driver mutations have been found that not only have potential sensitivity to epidermal growth factor receptor but also can inhibit anaplastic lymphoma kinase tyrosine kinase; more and more interest has been evoked in discovering additional targets to non-small cell lung cancer (NSCLC). Recently, many novel underlying oncogenic gene alterations have been identified, such as HER2 insertions, BRAF mutations, PIK3 mutations, FGFR1 amplifications, DDR2 mutations, KRAS mutations, MET amplification, ROS1 rearrangements, ALK rearrangements, and RET rearrangements. In this review, we will discuss the discovery of these potential targets and the application of each in NSCLC and of small molecular inhibitors on these potential targets.

Somatic mutations of EGFR and KRAS in pure bronchioloalveolar carcinomas and adenocarcinomas of the lung with bronchioloalveolar features

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 21111-21111
Author(s):  
I. J. Dahabreh ◽  
S. Murray ◽  
H. T. Spiliadi ◽  
E. A. Karagiani ◽  
A. Stamatelopoulos ◽  
...  
Keyword(s):  
Egfr Inhibitors ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Cell Content ◽  
Clinicopathologic Factor ◽  
Exon 2 ◽  
Asian Ethnicity ◽  
Lung Cancers ◽  
Egfr Expression ◽  
Clinicopathologic Parameters

21111 Background: EGFR mutations are more common in lung cancers from female, non-smoking patients of Asian ethnicity with adenocarcinoma histology. We investigated the relationship between clinicopathologic parameters and mutations of EGFR and KRAS in patients with pure bronchioloalveolar carcinomas (BACs) and adenocarcinomas (ADCs) with BAC features, not previously treated with EGFR inhibitors. Methods: We retrospectively reviewed the files of patients who were diagnosed with pure BACs or ADCs with BAC features between February 2001 and May 2005. Demographics, stage and smoking histories were recorded. Paraffin embedded tissue blocks were retrieved and re-examined using the WHO 1999/2004 histological criteria for lung cancers. EGFR expression, detected by immunohistochemistry, was scored from 0 to +3. Expression was considered positive when the score was +1, or higher. DNA was isolated from paraffin blocks (containing at least 75% tumor cell content) and exons 18–21 of the EGFR gene and exon 2 of the KRAS gene were amplified by PCR and bi-directionally sequenced. The chi-squared test and regression analysis were used to identify parameters correlating with EGFR or KRAS mutations. Results: A total of 46 patients were eligible for this study. Tissue was available from 43 patients, 19 with pure BAC and 24 with ADC with BAC features. There were 27 (62.8%) males and 16 (37.2%) females, all of Greek descent. Mean age was 62.7 years (range, 41–79). There were 34 smokers and former smokers (79%) and 9 never-smokers (21%). Tumors were classified as mucinous (20), non- mucinous (19) or mixed (4). We detected somatic EGFR mutations in 7 patients (including common mutations, delEx19, L858R, G719C), and KRAS codon 12 mutations in 13 patients. EGFR and KRAS mutations were mutually exclusive. No clinicopathologic parameters correlated with the presence of EGFR or KRAS mutations. Conclusions: Among Greek lung cancer patients with pure BACs or ADCs with BAC features, unselected for response to EGFR inhibitors, the incidence of KRAS or EGFR mutations was 30.2% and 16.3% respectively. EGFR and KRAS mutations were mutually exclusive but no clinicopathologic factor predicted the presence of mutations in either gene. Further molecular analysis is ongoing. No significant financial relationships to disclose.

Ethnic difference of driver mutation frequencies and correlations between driver mutations and histologic subtypes in lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 1552-1552
Author(s):  
Yuki Yamane ◽  
Koichi Goto ◽  
Akikazu Kawase ◽  
Katsuya Tsuchihara ◽  
Sachiyo Mimaki ◽  
...  
Keyword(s):  
Lung Adenocarcinoma ◽  
Ethnic Difference ◽  
The United States ◽  
Driver Mutation ◽  
Egfr Mutations ◽  
Driver Mutations ◽  
Cancer Center ◽  
Histological Subtypes ◽  
Kras Mutations ◽  
Met Amplification

1552 Background: The frequencies of known driver mutation in lung adenocarcinoma from patients in the United States have been reported by the NCI’s Lung Cancer Mutation Consortium (LCMC), indicating driver mutations were detected in 54% (280/516) of tumors. In this report, mutations found: EGFR 17%, KRAS 22%, HER2 0.6%, PIK3CA 1.2%, BRAF 2%, MET amplification 0.6%, MAP2K1 0.4%, NRAS 0.4%, AKT 0%, ALK rearrangements 7%. However little is known about ethnic difference of driver mutation frequencies and correlations between driver mutations and histological subtypes in lung adenocarcinoma. Methods: Known driver mutations in tumors from 97 Japanese patients with lung adenocarcinoma who underwent surgical resection between 1999 and 2003 in National Cancer Center Hospital East were analyzed by next-generation sequencing and confirmed by Sanger sequencing. Correlations between driver mutations and histological subtypes were also assessed. Results: Driver mutations were detected in 72% of tumors. Mutations found: EGFR 57%, KRAS9%, HER2 2%, PIK3CA 2%, BRAF 1%, MET amplification 1%, MAP2K1 0%, NRAS 0%, AKT 0%. Due to the limitation of rearrangement detection by exon-sequencing, ALK rearrangements were not analyzed. Compared with the report by LCMC, the frequency of EGFR mutations was high and that of KRAS mutations was low in the present study. All mutations were mutually exclusive. The number of predominant histological subtypes of tumors harbored EGFR mutations were papillary 28, acinar 3, solid 5, lepidic 19. That with KRAS mutations showed papillary 2, acinar 2, solid 2, lepidic 3, and HER2 mutations showed papillary 1 and acinar 1. Two tumors harbored PIK3CA mutations showed both histological acinar pattern. Each of BRAF mutation and MET amplification showed lepidic and papillary pattern, respectively. Conclusions: It was suggested that there should be ethnic difference of driver mutation frequencies in lung adenocarcinoma between Asian and non-Asian patients, although the details of ethnic distribution included in LCMC study has not been opened. In addition, each driver mutations did not correspond to specific histological subtypes of lung adenocarcinoma.

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