Dataset Information

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

ABSTRACT:

Purpose

Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent KRAS mutations or specific gene fusions, most commonly involving NRG1. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.

Experimental design

A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n = 136) or hotspot 8-oncogene genotyping (n = 64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome sequencing and whole-transcriptome sequencing (WTS).

Results

Combined MSK-IMPACT and MSK-Fusion testing identified mutually exclusive driver alterations in 96% of IMAs, including KRAS mutations (76%), NRG1 fusions (7%), ERBB2 alterations (6%), and other less common events. In addition, WTS identified a novel NRG2 fusion (F11R-NRG2). Overall, targetable gene fusions were identified in 51% of KRAS wild-type IMAs, leading to durable responses to targeted therapy in some patients. Compared with KRAS-mutant IMAs, NRG1-rearranged tumors exhibited several more aggressive characteristics, including worse recurrence-free survival (P < 0.0001).

Conclusions

This is the largest molecular study of IMAs to date, where we demonstrate the presence of a major oncogenic driver in nearly all cases. This study is the first to document more aggressive characteristics of NRG1-rearranged IMAs, ERBB2 as the third most common alteration, and a novel NRG2 fusion in these tumors. Comprehensive molecular testing of KRAS wild-type IMAs that includes fusion testing is essential, given the high prevalence of alterations with established and investigational targeted therapies in this subset.

SUBMITTER: Chang JC

PROVIDER: S-EPMC8282731 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature

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Publications

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

Chang Jason C JC Offin Michael M Falcon Christina C Brown David D Houck-Loomis Brian R BR Meng Fanli F Rudneva Vasilisa A VA Won Helen H HH Amir Sharon S Montecalvo Joseph J Desmeules Patrice P Kadota Kyuichi K Adusumilli Prasad S PS Rusch Valerie W VW Teed Sarah S Sabari Joshua K JK Benayed Ryma R Nafa Khedoudja K Borsu Laetitia L Li Bob T BT Schram Alison M AM Arcila Maria E ME Travis William D WD Ladanyi Marc M Drilon Alexander A Rekhtman Natasha N

Clinical cancer research : an official journal of the American Association for Cancer Research 20210504 14

<h4>Purpose</h4>Invasive mucinous adenocarcinoma (IMA) is a unique subtype of lung adenocarcinoma, characterized genomically by frequent <i>KRAS</i> mutations or specific gene fusions, most commonly involving <i>NRG1</i>. Comprehensive analysis of a large series of IMAs using broad DNA- and RNA-sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically.<h4>Experimental design</h4>A total of 200 IMAs were analyzed by 410-gene DNA nex ...[more]

PMID: 33947695

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Project description:BackgroundThe mucinous histologic subtype accounts for 5% to 20% of colorectal cancer (CRC) cases but remains poorly characterized. The present study characterized the baseline characteristics, mutational profile, and clinical outcomes of patients diagnosed with mucinous CRC.Materials and methodsWe identified 1877 patients with metastatic CRC with available histologic findings and molecular profiling and summarized the baseline clinical and pathologic characteristics and overall survival (OS) stratified by the histologic type. The data from separate cohorts with consensus molecular subtype (CMS) and CpG island methylator information were also summarized.ResultsThe mucinous histologic type was found in 277 of the 1877 patients (14.8%) and was associated with an increased prevalence of microsatellite instability (P < .001) and a right-sided primary (P < .001). An increased frequency of CMS1 (microsatellite instability immune) and lower rates of CMS2 (canonical) were identified, with mucinous compared with nonmucinous adenocarcinoma (P < .0001). Mutations in SMAD4 (P < .001), GNAS (P < .001), ERBB2 (P = .02), BRAF (P < .001), and KRAS (P < .001) occurred at greater frequencies in the mucinous CRC cases, and TP53 (P < .001), APC (P < .001), and NRAS mutations (P = .03) were less common. Univariate (hazard ratio [HR], 1.38; 95% confidence interval [CI], 1.17-1.63; P < .001) and multivariate analysis (HR, 1.36; 95% CI, 1.12-1.64; P = .002) demonstrated that the mucinous histologic type is associated with worse OS. The features associated with the mucinous histologic subtype were independent predictors for shorter OS, including BRAF (HR, 1.74; 95% CI, 1.35-2.25; P < .001) and KRAS (HR, 1.42; 95% CI, 1.22-1.65; P < .001) mutations, right-sided location (HR, 1.20; 95% CI, 1.04-1.39; P = .01), and synchronous metastases (HR, 2.92; 95% CI, 2.49-3.42; P < .001).ConclusionCompared with nonmucinous adenocarcinoma, the mucinous histologic type is associated with a worse prognosis, even when controlling for known prognostic features. This unique biologic behavior should be considered in the treatment and prognostic assessment of patients with CRC.

Project description:BackgroundIntraoperative molecular imaging (IMI) with folate-targeted NIR tracers has been shown to improve lesion localization in more than 80% of lung adenocarcinomas. However, mucinous adenocarcinomas (MAs) and invasive mucinous adenocarcinomas (IMAs) of the lung, which are variants of adenocarcinoma, appear to have decreased fluorescence despite appropriate folate receptor expression on the tumor surface. We hypothesized that the etiology may be related to light excitation and emission through non-Newtonian fluid (mucin) produced by goblet and columnar cancer cells.MethodsIntraoperative data for 311 subjects were retrospectively reviewed from a prospectively collected 6-year database. For standardization, all patients underwent infusion of the same targeted molecular optical contrast agent (pafolacianine, folate receptor-targeted NIR fluorochrome) for lung cancer resections. Then, the ratio of the mean fluorescence intensity of the tumors and background tissues (TBR) was calculated. Tumors were examined for mucin, FRa, FRb, and immunofluorescent tracer uptake by a board-certified pathologist. The optical properties of mucin analyzed by imaging software were used to create in vitro gel models to explore the effects on NIR tracer fluorescence intensity.ResultsA large proportion (192, 62%) of the patients were female, with an average of 62.8 years and a 34-year mean pack smoking history. There were no severe (Clavien-Dindo > III) complications related to pafolacianine infusion. A total of 195 lesions in the study were adenocarcinomas, of which 19 (6.1%) were of the mucinous subtype. A total of 14/19 of the patients had a smoking history, and more than 74% of the IMA lesions were in the lower lobes. IMA lesions had a lower in situ TBR than nonmucinous adenocarcinomas (2.64 SD 0.23) vs (3.45 SD 0.11), respectively (p < 0.05). Only 9/19 (47%) were localized in situ. Tumor bisection and removal of mucin from IMAs significantly increased pafolacianine fluorescence, with resultant TBR not being significantly different from the control group (4.67 vs 4.89) (p = 0.19). Of the 16 lesions that underwent FR expression analysis, 15/16 had FR presence on cancer cells or tumor-associated macrophages in the tumor microenvironment. There was no statistically significant difference in fluorescence intensity during immunofluorescence analysis (4.99 vs 5.08) (p = 0.16). Physical removal of mucin from IMAs improved the TBR from 3.11 to 4.67 (p < 0.05). In vitro analysis of the impact of synthetic non-Newtonian fluid (agarose 0.5%) on NIR tracer fluorescence showed a decrease in MFI by a factor of 0.25 regardless of the concentration for each 5 mm thickness of mucin.ConclusionThe mucinous subtype of lung adenocarcinomas presents a unique challenge in pafolacianine-targeted IMI-guided resections. The presence of non-Newtonian fluids presents a physical barrier that dampens the excitation of the tracer and fluorescence emission detected by the camera. Knowledge of this phenomenon can allow the surgeon to critically analyze lesion fluorescence parameters during IMI-guided lung cancer resections.

Project description:BACKGROUND:With the exception of trastuzumab, therapies directed at receptor tyrosine kinases (RTKs) in gastroesophageal adenocarcinomas (GEA) have had limited success. Recurrent fibroblast growth factor receptor 2 (FGFR2) alterations exist in GEA; however, little is known about the genomic landscape of FGFR2-altered GEA. We examined FGFR2 alteration frequency and frequency of co-occurring alterations in GEA. SUBJECTS, MATERIALS, AND METHODS:A total of 6,667 tissue specimens from patients with advanced GEA were assayed using hybrid capture-based genomic profiling. Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA, and microsatellite instability was determined on 95 or 114 loci. Descriptive statistics were used to compare subgroups. RESULTS:We identified a total of 269 (4.0%) FGFR2-altered cases consisting of FGFR2-amplified (amp; 193, 72% of FGFR2-altered), FGFR2-mutated (36, 13%), FGFR2-rearranged (re; 23, 8.6%), and cases with multiple FGFR2 alterations (17, 6.3%). Co-occurring alterations in other GEA RTK targets including ERBB2 (10%), EGFR (8%), and MET (3%) were observed across all classes of FGFR2-altered GEA. Co-occurring alterations in MYC (17%), KRAS (10%), and PIK3CA (5.6%) were also observed frequently. Cases with FGFR2amp and FGFR2re were exclusively microsatellite stable. The median TMB for FGFR2-altered GEA was 3.6 mut/mb, not significantly different from a median of 4.3 mut/mb seen in FGFR2 wild-type samples. CONCLUSION:FGFR2-altered GEA is a heterogenous subgroup with approximately 20% of FGFR2-altered samples harboring concurrent RTK alterations. Putative co-occurring modifiers of FGFR2-directed therapy including oncogenic MYC, KRAS, and PIK3CA alterations were also frequent, suggesting that pretreatment molecular analyses may be needed to facilitate rational combination therapies and optimize patient selection for clinical trials. IMPLICATIONS FOR PRACTICE:Actionable receptor tyrosine kinase alterations assayed within a genomic context with therapeutic implications remain limited to HER2 amplification in gastroesophageal adenocarcinomas (GEA). Composite biomarkers and heterogeneity assessment are critical in optimizing patients selected for targeted therapies in GEA. Comprehensive genomic profiling in FGFR2-altered GEA parallels the heterogeneity findings in HER2-amplified GEA and adds support to the utility of genomic profiling in advanced gastroesophageal adenocarcinomas.

Dataset Information

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

Purpose

Experimental design

Results

Conclusions

Publications

Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes.

Similar Datasets

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