Investigation By Condition/Syndrome

Conditions and Syndromes

ALK (FISH) testing in NSCLC

Introduction

Chimeric gene fusions involving the ALK (anaplastic lymphoma kinase) gene are now recognised as oncogenic driver mutations in about 5% of all NSCLC. The most common genomic rearrangement involving the ALK gene is an inv(2)(p21p23), resulting in the creation of an EML4-ALK chimeric gene, although over 20 other partner genes have been described. Tumours with ALK genomic rearrangements are now considered as a new molecular subgroup of lung carcinomas. Tumours with ALK rearrangements show excellent response rates to inhibitors of ALK tyrosine kinase activity e.g. Crizotinib. Testing for ALK rearrangements can be by several methods e.g. ALK1 IHC, FISH analysis or reverse transcriptase PCR. ALK FISH analysis is regarded as the 'gold standard' method.

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BRAF Mutation Testing in Melanoma Samples

Introduction

BRAF is a proto-oncogene mutated in many types of cancers. The majority of BRAF mutations described occur at codon 600. Codon 600 mutations are present in between 40-60% of malignant melanomas. Melanomas with a mutation at codon 600 of BRAF show a higher likelihood of response to treatment with BRAF inhibitors e.g. Vemurafenib

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EGFR Mutation Testing in NSCLC (Adenocarcinoma) Samples

Introduction

EGFR is a protein found at high levels in many types of cancers, particularly non-small cell lung cancer (NSCLC). Activating mutations in the EGFR gene are present in a proportion of NSCLC tumours. Tumours with mutated EGFR show a higher likelihood of response to treatment with EGFR tyrosine kinase inhibitor drugs e.g. Iressa (Gefitinib).

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EGFR Mutation Testing in plasma (cfDNA)

Introduction

EGFR activating mutations are detected in ~11% of NSCLC (adenocarcinoma) UK patients and these patients show a higher likelihood of response to treatment with EGFR tyrosine kinase inhibitors. The EGFR resistance mutation p.T790M is also acquired in up to 60% of EGFR mutation positive patients who progress following EGFR-TKI therapy. Adequate biopsy material for EGFR mutation analysis is not always available on these patients. DNA circulating in plasma from blood can be used as an alternative as DNA is shed from tumour tissue at increased level in patients with active or advanced disease. Blood samples must reach the laboratory within 24hrs of sampling (ideally within 6hrs). Where this is not possible please contact the laboratory for advice.

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Gastro-Intestinal Stromal Tumours (GISTs)

Introduction

Gastro-intestinal stromal tumours (GISTs) are the most common mesenchymal tumour of the gastrointestinal tract. A majority of GISTs (80-85 %) have acquired activating mutations in c-KIT and 5-10 % have mutations in PDGFRA. Mutations in specific exons of c-KIT/PDGFRA are diagnostic of GIST and correlated with prognosis and response to Imatinib.

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KRAS, NRAS, BRAF and & PIK3CA Mutation Testing in Colorectal Tumour Samples

Introduction

KRAS, NRAS, BRAF & PIK3CA are oncogenes frequently somatically mutated in colorectal tumours. Activating somatic KRAS and NRAS mutations most frequently affect codons 12, 13, 59, 61, 117 & 146 of the KRAS/NRAS genes and codon 600 of BRAF. Presence of an activating KRAS/NRAS mutation in a colorectal tumour predicts a poor response to EGFR inhibiting therapy. The presence of a BRAF & PIK3CA mutations may be used as prognostic markers and for clinical trial selection.

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PIK3CA Mutation Testing

Introduction

The PIK3CA gene encodes a catalytic subunit of phosphatidylinositol 3-kinase (PI3K). Activation of the PI3K-AKT pathway is believed to play an oncogenic role in many cancer types. Somatic activating mutations in PIK3CA have been described in a wide range of tumour types including breast, ovarian and colorectal cancers. Mutations in PIK3CA are predominantly found at three functionally relevant hotspots located at codons 542, 545 & 1047.

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Somatic Cancer Next Generation Sequencing (NGS) Mutation Panel

Introduction

Oncogene driver mutations are identified across a wide range of tumours and therapies are increasingly being adopted into standard clinical practice whose clinical effectiveness is dependent on the presence or absence of oncogene mutations. Panel testing for a wide range of oncogene mutations uses limited pathology material effectively, reduces overall test turn-round and is more cost effective than serial testing. Panel testing can also be used to prescreen patients for clinical trial eligibility. This test identifies oncogene driver mutations (single nucleotide changes and insertion/deletions <40bp) across 24 clinically relevant oncogenes (AKT1, ALK, AR, BRAF, CTNNB1, DDR2, EGFR, ERBB2, FGFR3, GNA11, GNAQ, IDH1, IDH2, KIT; KRAS; MAP2K1; MET; NRAS; PDGFRA; PIK3CA; PTEN; RET; STK11; TP53)

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Tumour BRCA1/2 mutation testing in platinum sensitive relapsed ovarian cancer patients

Introduction

Patients with platinum sensitive relapsed ovarian cancer and germline or somatic mutations in BRCA1/2 may benefit from treatment with the poly ADP ribose polymerase (PARP) inhibitor Lynparza (Olaparib). BRCA1/2 mutation screening in FFPE tissue can identify patients with somatic BRCA1/2 mutations who may benefit from targeted therapy. The test has been designed to perform on DNA extracted from formalin fixed paraffin embedded (FFPE) tissue specimens and detect somatic mutations in samples with neoplastic cell content >20%.

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UGT1A1-28 Genotyping

Introduction

UDP-glucuronosyltransferase-1A1 or UGT1A1 is an enzyme encoded by the UGT1A1 gene. UGT1A1 is involved in metabolism of several drugs. The promoter of the UGT1A1 gene contains a common variant in the region of the TATA box promoter element. The most common variant A(TA-6)TAA accounts for ~50% of alleles whereas the UGT1A1*28 variant which has an extra TA dinucleotide A(TA-7)TAA can account for up to 40% of alleles. UGT1A1*28 is associated with lower expression levels of UGT1A1. Individuals who are homozygous for the UGT1A1*28 allele (~15% of the population) show reduced levels of glucoronidation by UGT1A1 and are at raised risk of a mild syndrome of hyperbilirubinaemia under conditions of stress (Gilbert syndrome). There is evidence that UGT1A1*28 homozygotes are at raised risk of adverse reactions to drugs that are metabolised by this pathway including irinotecan. UGT1A1*28 status can be used to guide dosage for irinotecan to minimise adverse reaction.

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