Combination of conventional immunohistochemistry and qRT-PCR to detect ALK rearrangement

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Abstract

Background

Compared with FISH and qRT-PCR analyses, immunohistochemistry (IHC) is the preferred screening test in most pathology practices for ALK-rearrangement detection. With 100% sensitivity and 98% specificity, the VENTANA ALK (D5F3) IHC assay has been approved in the EU and some Asian countries for ALK-rearrangement detection. However, an automated Ventana IHC platform is not available in most pathology labs. In this study, we evaluated the applicability of conventional IHC with D5F3 antibody in routine pathological practice and proposed detection methods and procedures that ensure that patients with ALK+ are not missed.

Methods

FISH and IHC analyses were performed on 297 lung adenocarcinoma cases. VENTANA IHC and qRT-PCR assay were applied to evaluate ALK-fusion status in the discordant cases of FISH and IHC. The association of ALK+ with clinicopathological characteristics was statistically analyzed.

Results

IHC had 100% sensitivity and 81.8% specificity for detecting ALK+. Eight ALK-expressed cases were ALK-, five of which had ALK fusion detected by qRT-PCR analysis. Three of these five cases showed ALK expression using VENTANA IHC assay. ALK+ was associated with younger age and lymph node metastasis in this Chinese lung adenocarcinoma patient cohort.

Conclusions

The advantages of low cost and 100% sensitivity allow conventional IHC to serve as a robust diagnostic tool for screening patients with ALK+, especially in pathology labs without a VENTANA IHC platform. For cases in which ALK is weakly expressed, qRT-PCR is necessary as a diagnostic test for ALK-fusion detection.

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The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2269448351088278.

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Most cited references 18

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Cancer Statistics, 2008

A. Jemal, R. Siegel, E. Ward … (2008)

Each year, the American Cancer Society estimates the number of new cancer cases and deaths expected in the United States in the current year and compiles the most recent data on cancer incidence, mortality, and survival based on incidence data from the National Cancer Institute, Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries and mortality data from the National Center for Health Statistics. Incidence and death rates are age-standardized to the 2000 US standard million population. A total of 1,437,180 new cancer cases and 565,650 deaths from cancer are projected to occur in the United States in 2008. Notable trends in cancer incidence and mortality include stabilization of incidence rates for all cancer sites combined in men from 1995 through 2004 and in women from 1999 through 2004 and a continued decrease in the cancer death rate since 1990 in men and since 1991 in women. Overall cancer death rates in 2004 compared with 1990 in men and 1991 in women decreased by 18.4% and 10.5%, respectively, resulting in the avoidance of over a half million deaths from cancer during this time interval. This report also examines cancer incidence, mortality, and survival by site, sex, race/ethnicity, education, geographic area, and calendar year, as well as the proportionate contribution of selected sites to the overall trends. Although much progress has been made in reducing mortality rates, stabilizing incidence rates, and improving survival, cancer still accounts for more deaths than heart disease in persons under age 85 years. Further progress can be accelerated by supporting new discoveries and by applying existing cancer control knowledge across all segments of the population.

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Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

Klarisa Rikova, Ailan Guo, Qingfu Zeng … (2008)

Despite the success of tyrosine kinase-based cancer therapeutics, for most solid tumors the tyrosine kinases that drive disease remain unknown, limiting our ability to identify drug targets and predict response. Here we present the first large-scale survey of tyrosine kinase activity in lung cancer. Using a phosphoproteomic approach, we characterize tyrosine kinase signaling across 41 non-small cell lung cancer (NSCLC) cell lines and over 150 NSCLC tumors. Profiles of phosphotyrosine signaling are generated and analyzed to identify known oncogenic kinases such as EGFR and c-Met as well as novel ALK and ROS fusion proteins. Other activated tyrosine kinases such as PDGFRalpha and DDR1 not previously implicated in the genesis of NSCLC are also identified. By focusing on activated cell circuitry, the approach outlined here provides insight into cancer biology not available at the chromosomal and transcriptional levels and can be applied broadly across all human cancers.

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Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

Alice Shaw, Beow Yeap, Mari Mino-Kenudson … (2009)

The EML4-ALK fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLC). To aid in identification and treatment of these patients, we examined the clinical characteristics and treatment outcomes of patients who had NSCLC with and without EML4-ALK. Patients with NSCLC were selected for genetic screening on the basis of two or more of the following characteristics: female sex, Asian ethnicity, never/light smoking history, and adenocarcinoma histology. EML4-ALK was identified by using fluorescent in situ hybridization for ALK rearrangements and was confirmed by immunohistochemistry for ALK expression. EGFR and KRAS mutations were determined by DNA sequencing. Of 141 tumors screened, 19 (13%) were EML4-ALK mutant, 31 (22%) were EGFR mutant, and 91 (65%) were wild type (WT/WT) for both ALK and EGFR. Compared with the EGFR mutant and WT/WT cohorts, patients with EML4-ALK mutant tumors were significantly younger (P < .001 and P = .005) and were more likely to be men (P = .036 and P = .039). Patients with EML4-ALK-positive tumors, like patients who harbored EGFR mutations, also were more likely to be never/light smokers compared with patients in the WT/WT cohort (P < .001). Eighteen of the 19 EML4-ALK tumors were adenocarcinomas, predominantly the signet ring cell subtype. Among patients with metastatic disease, EML4-ALK positivity was associated with resistance to EGFR tyrosine kinase inhibitors (TKIs). Patients in the EML4-ALK cohort and the WT/WT cohort showed similar response rates to platinum-based combination chemotherapy and no difference in overall survival. EML4-ALK defines a molecular subset of NSCLC with distinct clinical characteristics. Patients who harbor this mutation do not benefit from EGFR TKIs and should be directed to trials of ALK-targeted agents.

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Author and article information

Journal

Journal ID (nlm-ta): Diagn Pathol

Journal ID (iso-abbrev): Diagn Pathol

Title: Diagnostic Pathology

Publisher: BioMed Central

ISSN (Electronic): 1746-1596

Publication date Collection: 2014

Publication date (Electronic): 14 January 2014

Volume: 9

Page: 3

Affiliations

[1 ]Department of Pathology, Cancer Institute & Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, 100021, China

Article

Publisher ID: 1746-1596-9-3

DOI: 10.1186/1746-1596-9-3

PMC ID: 3924409

PubMed ID: 24422905

SO-VID: ce06d3cb-671e-49f4-80a3-ac83e4f01d72

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

Combination of conventional immunohistochemistry and qRT-PCR to detect ALK rearrangement

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Abstract

Background

Methods

Results

Conclusions

Virtual slides

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Karger: Oncology

Most cited references 18

Cancer Statistics, 2008

Global survey of phosphotyrosine signaling identifies oncogenic kinases in lung cancer.

Clinical features and outcome of patients with non-small-cell lung cancer who harbor EML4-ALK.

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