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For the patient


Haematological disorders
Haematological disorders affect primarily the bone marrow, the body’s main organ for the production of blood, as well as the blood and lymph nodes. Despite popular belief, not all haematological disorders are fatal, although a large proportion of them can be, especially if left untreated.  However, with modern chemotherapy regimes and the option of bone marrow transplantation, many leukaemias can be controlled, or even cured.

blastokittarablastokittara

Blast cells in Acute Myeloid Leukaemia 
 

Haematological disorders are divided into 4 broad, pathologically distinct groups.
Acute leukaemias generally have a more rapid course and if left untreated, will result in the death of the individual.

They are usually characterized by the proliferation of immature white blood cells, known as blasts, and lack of the mature, more differentiated forms of white blood cells, such as platelets and granulocytes. Acute forms of leukaemia are frequently seen in children, but they can occur in any age group.
Chronic leukaemias generally have a slower, more indolent course and physical symptoms may not develop for many years. They are characterized by the proliferation of more mature, sometimes abnormal, white blood cells. Examples of chronic leukaemias include chronic lymphocytic leukaemia (CLL), multiple myeloma, and others. Generally speaking, chronic leukaemias are most often seen in adults, although again they can occur in any age group.

 

Both acute and chronic leukaemias are further subdivided into myeloid or lymphoid, depending on the blood lineage that is affected.

 

Lymphomas are a group of haematological disorders of the lymphoid lineage that affect the lymph nodes. Typically, they present as an enlargement of a lymph node. In more advanced stages of lymphoma, infiltration of other tissues, such as the bone marrow, may be observed. Not all blood disorders are classed as leukaemia or lymphoma. Some types of haematological disorders, such as myelodysplastic syndromes, or idiopathic thrombocytopaenia purpura may never develop into leukaemia and can be managed with minimal drugs.

How do we study Haematological disorders?

Most haematological disorders are studied from the tissue that is infiltrated by the disease. This is usually the bone marrow, although in some cases like Chronic Lymphocytic Leukaemia (CLL), we can undertake our studies from peripheral blood. In cases of lymphoma, we study the affected lymph node following biopsy.

Why do we do genetic tests for Haematological disorders?

In cancer, genetic changes occur in the affected tissue, but are not present in the rest of the body. These are known as neoplastic changes. Some of those genetic changes cause abnormal cell division which results in the proliferation of one type of cell lineage or absence of another type of blood cell lineage. By identifying these genetic changes in our laboratory, we can give your doctor important information to help with the diagnosis of the disease. Some genetic changes are also associated with a specific prognosis according to trials conducted in the USA and UK.

While a number of these genetic changes are visible under the microscope, some are too small to be seen using microscopy and need specialized molecular techniques such as FISH (fluorescent in situ hybridization) or mutation analysis.

Following therapy, we will screen follow-up samples to assess the response to treatment and evaluate remission status. This can be done either using FISH, which has a sensitivity of 1 in a 1,000 (i.e. it can pick out 1 abnormal cell in 1,000) or real-time PCR, which has a sensitivity of 1 in 1,000,000.

Tests
Please click here for a complete list of tests and prices offered at Genomedica. Prices are approximate, please consult your doctor.

G-banded karyotype: this is often the starting point of our studies. A karyotype looks at all 46 chromosomes of the genome and can detect gross numerical and structural chromosome abnormalities.  By examining the karyotype, we can detect translocations, chromosome gains or losses and other genetic rearrangements. Some of these provide valuable prognostic and diagnostic information.

 

kari1

Karyotype of a male patient with AML and t(15;17), characteristic of Acute Promyelocytic Leukaemia

FISH: this is an acronym for a molecular technique known as fluorescent in situ hybridization. This technique labels specific parts of the DNA with fluorescently labelled probes (= known pieces of DNA) and provides information with regards to the number of copies of a gene or structural rearrangement of a specific piece of DNA. Some DNA rearrangements are diagnostic of a particular form of cancer. For example, identifying a fusion between part of the BCR and ABL genes is diagnostic of chronic myeloid leukaemia (CML). The resolution of FISH is approximately 20 to 30 times higher than that of G-banding and can often reveal abnormalities that are not visible by conventional microscopy.

bcd
BCR/ABL dual colour, dual fusion showing a pattern consistent with a BCR/ABL1 gene rearrangement and an extra fusion signal (an extra Philadelphia  chromosome was seen by G-banded cytogenetics). Red signal = ABL gene,
green signal = BCR gene.

 


Real-time PCR (RT-PCR): this is another molecular technique that can quantify the amount of a particular DNA product present in a sample. In oncogenesis, abnormal DNA sequences are present because of the fusion or rearrangement of pieces of DNA that would not normally be present in a normal sample. RT-PCR can quantify the amount of abnormal DNA present in a sample with a sensitivity of 1 cell in one million. This technique is therefore used to quantify the level of abnormal cells still present in the tissue following chemotherapy (minimal residual disease) and gives us an indication of the patient’s response to therapy.

Mutation analysis:
This is a molecular test that looks at changes in the DNA sequence, which occur only in the disease tissue. These changes are directly related to the cancer development process. Mutation analysis looks at DNA at the highest possible resolution level and can detect changes of even a single base pair.CGH expression arrays: this is a new technology in cancer that will help us to discover exactly what is happening at the genomic DNA level during the cancer process and ultimately provide more targeted cancer therapies. At present, we use this technology at a research level, but we anticipate that this technology will become part of our diagnostic toolkit in the next few years.

pdf Please click here for a complete list of tests and prices offered at Genomedica. Prices are approximate, please consult your doctor.

Oncology

Why do we perform genetic analysis?
Genetic changes occur in the tumour, which are not present in normal cells in the rest of the body. These genetic changes are often the primary cause of cancer cell proliferation and tumour formation. By studying genetic changes in the cancer cells we provide useful diagnostic and prognostic information to your doctor.

We conduct our studies from the primary tumour biopsy. A small piece or section of the biopsy will be sent to our laboratory for genetic testing. Other tests on the biopsy, such as histological analysis and immuno-histochemistry will be conducted simultaneously by other laboratories.

Tests offered:
FISH: this is an acronym for a molecular technique known as fluorescent in situ hybridization. This technique labels specific parts of the DNA with fluorescently labelled probes (= known pieces of DNA) and provides information with regards to the number of copies or structural rearrangement of a specific piece of DNA. Some DNA rearrangements are diagnostic of particular form of cancer. For example, identifying a rearrangement in the EWSR1 is diagnostic of Ewing sarcoma, a type of soft tissue sarcoma. We can perform FISH studies on a fresh piece of tumour biopsy, a touch prep, paraffin embedded tissue or cytospin.

Real-time PCR (RT-PCR): this is another molecular technique that can quantify the amount of a particular DNA product present in a sample. In oncogenesis, abnormal DNA sequences are present because of the fusion or rearrangement of pieces of DNA that would not normally be present in a normal sample. RT-PCR can quantify the amount of abnormal DNA present in a sample with a sensitivity of 1 cell in one million.

Mutation analysis
This is a molecular test that looks at changes in the DNA sequence, which occur only in the disease tissue. These changes are directly related to the cancer development process. Mutation analysis looks at the DNA at the highest possible resolution level and can detect changes of even a single base pair.

CGH expression arrays: this a new technology in cancer that will help us to discover exactly what is happening at the DNA level during the cancer process and ultimately provide more targeted cancer therapies. At present, we use this technology at a research level, but we anticipate that this technology will become part of our diagnostic toolkit in the next few years.

 

gene

Gene expression arrays (from Agilent) 
 


Specialized oncology tests

  • Breast cancer

HER2 amplification screen: In some forms of breast cancer, a gene called HER2/neu on chromosome 17, is amplified, i.e. it is present in several copies instead of the normal 2. Patients with HER2 amplification have been shown to respond to the drug Herceptin® (trastuzumab). Presence or absence of HER2 amplification does not give any prognostic information. The overall prognosis is dependent on many other factors.

CYP2D6: patient with reduced CYP2D6 enzymatic activity tend to have lower levels of endoxifen, a metabolite necessary for the metabolism of the drug tamoxifen. Patients with CYP2D6 mutations may have reduced efficacy in being able to metabolise tamoxifen and may therefore show grossly reduced response to the drug. We require 5-10 ml of peripheral blood in EDTA to carry out the CYP2D6 mutation screen.
RRM1: mutations of the RRM1 gene are associated with a better response to the drug gemcitabine.

Please contact Genomedica for more details.

bcdb

An amplified (right) compared to a normal (left) HER2 copy number.
Red signal = HER2 gene, green signal = centromere
17 control

 
  • Melanoma screen

Melanoma lesions are examined to look for changes in copy number of 3 different genetic regions on chromosomes 6 and 11. Melanomas, the most aggressive form of skin cancer harbour one or more genetic changes. A Spitz nevus on the other hand, shows no changes and is a benign tumour with a good prognosis.


CCND1, MYB, RREB1, ratio MYB/CEP6: copy number changes in one or more of these regions would confirm the diagnosis of malignant melanoma, especially in cases of equivocal macroscopic morphology.
BRAF: mutations of the BRAF gene (mutation V600E) are seen in approximately 60% of all lesions and are associated
with a higher probability for metastasis in the liver and other organs.
Please contact Genomedica for more details.

  • Soft tissue sarcoma

We use a number of FISH probes on soft tissue sarcoma biopsy for the diagnosis of Ewing sarcoma, synovial sarcoma, desmoplastic small round cell tumour and others.
Please contact Genomedica for more details.

  • Liposarcoma (fat tissue sarcoma)

In some types of fat tissue tumours we find an amplification of the gene MDM2. Amplification of MDM2 is seen in well-differentiated liposarcomas and dedifferentiated liposarcomas, which tend to be more aggressive forms of tumour, but are not seen in lipomas and spindle cell tumours. We perform the MDM2 screen at Genomedica.
Please contact the lab for further details.

 

mdm2

MDM2 gene amplification in a patient with aggressive de-differentiated liposarcoma.
Red signal = MDM2 gene, green
signal = centromere 12 control

 
  • Lung cancer

Approximately 70-75% of all lung cancers are known as non-small cell lung carcinomas. Mutations in a gene called EGFR (epidermal growth factor receptor) have been associated with a favourable prognosis in early stage lung carcinoma. Early studies suggest an improved survival in patients with EGFR mutations when treated with the drug gefitinib. We perform the mutation analysis of EGFR at Genomedica.

EGFR (Epidermal Growth Factor Receptor gene): patients that harbour an EGFR mutation respond better to therapy with tyrosine kinase inhibitors and are therefore suitable for treatment with the drug gefitinib (Iressa) and erlotinib (Tarceva).

ALK: the ALK-NPM fusion product is well documented in T-cell large anaplastic lymphomas and arises most frequently from the translocation t(2;5). A subset of patients with non-small cell lung carcinoma has been identified with an ALK-EML4 rearrangement. These patients respond favourably to kinase inhibitors. The ALK FISH probe is available in our laboratory to identify the presence of an ALK rearrangement from paraffin embedded sections of lung biopsy.

ERCC1 and RRM1: reduced expression of these 2 genes is associated with a better response to cisplatin-based adjuvant therapy, while cisplatin-based agents are not recommended for patients with upregulated expression of these genes.
Please contact the lab for further details.

  • Prostate cancer

Prostate cancer is the most common cancer in men in the Western world with an incidence rate of approx. 70 in 1,000. Formerly, men with symptoms of prostate cancer were screened for PSA (prostate specific antigen), a protein present in the blood stream. However, this test is not very accurate for the diagnosis of prostate cancer. Although still under trial, there are strong indications that a new genetic test for the gene PCA3 (prostate cancer antigen 3) provides a much more accurate marker for the presence of prostate cancer cells than PSA. The PCA3 gene is overexpressed in prostate cancer cells found in urine, thus providing a marker of malignancy in prostate cells.
Please contact the lab for further details.

  • Brain gliomas

Gliomas are a form of brain tumour. Depending on the type of cell affected, they are classified into oligodendrogliomas, astrocytomas or the mixed form oligoastrocytomas and the highly malignant form glioblastoma multiforme. Combined loss of the chromosome regions 1p and 19q has been shown to be associated more strongly with a diagnosis of oligodendroglioma and to confer a better prognosis than intact 1p/19q.

MGMT: methylation of the MGMT gene is strongly associated with 1p/19q co-deletion status and an independent prognostic marker that is associated with a better response to the drug temozolomide.
Please contact the lab for further details.


glioma

Oligodendroglioma showing loss of the 1p36 region.
Red signal = 1p36, green signal = 1q25 control

  • Colorectal cancer

KRAS και BRAF: mutations in these two genes are associated with poor response to anti-EGFR therapy, such as panitumumab and cetuximab.

TS (TYMS) and DPD (DYPD): mutations in the genes TYMS and DYPD are associated with TS and DPD enzyme deficiency, respectively, thus resulting in increased toxicity with 5-FU (5-fluorouracil) therapy.
ERCC1: reduced expression of this gene is associated with a better response to cisplatin-based adjuvant therapy, while cisplatin-based agents are not recommended for patients with upregulated expression of ERCC1.

MSI (microsatellite instability): increased microsatellite instability is known to be associated with an incomplete DNA repair mechanism. Patients with increased MSI respond better to drugs that inhibit thymidylate synthase, such as 5-FU, which inhibit DNA transcription.
Please contact the lab for further details.

  • Gastrointestinal stromal tumours

(GIST) C-KIT and PDGFRα: mutations of the genes C-KIT, in exons 9 and 11 and less frequently 13 and 17, as well as PDGFRα are associated with a more favourable response to the drug Imatinib mesylate (Glivec).

HER2/neu: as in the case with breast carcinoma, amplification of the gene HER2/neu identified in GIST biopsy, identifies a subgroup of patients with a favourable response to the drug trastuzumab (Herceptin®).

Please contact the lab for further details.

  • Bladder cancer

Copy number change of chromosomes 3, 7, 17 and 9p21: this test identifies genetic changes that are associated with disease progression to higher grade tumours. They can also be used in lower grade tumours as a predictive marker of disease progression. This test can be carried out on bladder biopsies as well as urine samples (Cytospin).
Please contact the lab for further details.

 
   
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