Every person is unique, that is why every disease is different... We are unique because of the different information coded in our genes, which determines not only our basic traits, such as eye colour, height, etc., but also how susceptible we can be to different diseases or what our body's response to disease therapy may be. Identifying the link between certain genes or disorders in them and the risk of/or the development of a particular disease allows us to find the underlying mechanism that drives the disease, the critical structure or molecule to be used as a potential "target" for individualised therapy. This is at the core of the so-called "Personalised Medicine", which, in the narrow sense, includes the choice of specific "individual" treatment for a particular patient, and in broader terms includes an assessment of the personal risk of developing a disease and identifying personal measures to reduce it. Personalised Medicine provides opportunities for precise diagnosis, effective treatment and reduction of side effects and ineffective therapies.
The individual genetic features of each person – the presence of germline mutations in our genes, those that are inherited from our parents or the spontaneous occurrence of somatic mutations in some of our cells (usually tumour cells) that are not inherited – are also associated with the risk of developing a number of oncological diseases. Early identification of these "harmful mutations" allows to determine relatively precisely the course of the disease, as well as an individual optimal and effective therapy for the patient. The development of next-generation sequencing technologies (NGS) enables massive parallel sequencing – determining the order of nucleotides (structural units of DNA and RNA) – throughout our whole genome or in separate exomas and/or other target areas of DNA and RNA. Thus, through complete genomic and exomic or targeted sequencing, entire regions of disease-related genes as well as genes involved in major oncogenic signalling pathways in the cells of all types of solid tumours can be examined simultaneously and in a short time for "harmful mutations".
The use of large multigenic panels (simultaneous testing of a large number of genes) in NGS allows for synchronous analysis with high productivity and speed of a large number of genetic changes associated with an increased risk of developing cancer or indicating the effectiveness of a certain treatment, with less cost compared to single testing.
UMHAT "Saint Marina" EAD – Varna is equipped with Illumina MiSeq NGS System, best suited for smaller NGS panels.
There are two currently available gene panels at UMHAT "Saint Marina" EAD – Varna:
- Panel that offers coverage of:
Genes: BRCA1, BRCA2, CDH1 (E-Cadherin), PALB2, PTEN, TP53 (p53) – associated with an increased risk of developing cancer and predicting the response to PARP inhibitors.
- Panel that offers coverage of:
Exons in genes: BRAF, EGFR (ERBB1), KIT (CD117), KRAS, NRAS, PDGFRA.
"Hotspots" (nucleotide regions with extremely high mutation rates) in the genes: AKT1, ALK, CTNNB1, ERBB3, ESR1 (ERα), FOXL2, GNA11, GNAQ, IDH1, IDH2, MET, RAF1, RET.
Whole encoding areas: ERBB2 (HER-2, NEU), PIK3CA (p110-alpha), TP53 (p53) — changes associated with the response to different types of treatment.
It is estimated that 5-10 % of breast cancer cases in women are due to mutations in BRCA1 и BRCA2 genes (whereas the frequency in BRCA1 is slightly higher than in BRCA2). Women with proven mutations in these genes have a risk of breast cancer that is approximately five times higher than the normal risk, while the risk of ovarian cancer is up to thirty times higher. Hundreds of different types of mutations in these genes have been identified, and only some of them have been determined to be harmful (or pathological – related to the development of an oncological disease), while others have no proven impact. Significant "harmful" mutations in these genes may cause hereditary breast – ovarian cancer syndrome in the affected persons, and in some cases an entire cluster of genes can be affected, which acts in combination with environmental factors – BRCA1, BRCA2, CDH1 (E-Cadherin), PALB2, PTEN, TP53 (p53).
The risk of breast and ovarian cancer is higher in women with a high-risk BRCA1 mutation. Nonetheless, having a high-risk mutation does not guarantee that the woman will develop any type of cancer, or imply that any cancer that appears was actually caused by the mutation, rather than some other factor.
Leading international standards of conduct in oncological diseases recommend testing these genes in:
- Three or more cases of breast or ovarian cancer in the family;
- Two cases of breast cancer in the family affecting members under the age of 40;
- Male breast cancer;
- Ovarian cancer at a young age;
- Jewish women (of Ashkenazi descent) with diagnosed breast cancer under the age of 60;
- Early cancer affecting both breasts;
- Breast cancer and ovary cancer in one patient.
The demonstration of these mutations involves a number of actions to reduce the risk of developing an oncological disease or measures aimed at diagnosing it at an early stage:
- Surgical interventions that reduce the risk of developing cancer;
- Clinical and imaging tests to identify the disease at an early stage – clinical breast tests at 6 months, mammography and MRI each year.
On the other hand, BRCA1 and BRCA2 mutations are predictors for response to PARP inhibitors in various types of oncological diseases.
TP53 gene is associated with a predicted poor response to radiotherapy.
All international treatment standards recommend that patients with non-small cell lung cancer be tested for a set of mutations (including EGFR, ALK, ROS1, BRAF) in the first place, which allows for a choice of modern and optimal treatment.
The percentage of patients with EGFR mutation of the Caucasian race is about 10–15 %, according to various sources, and they are considered suitable for therapies with EGFR tyrosine kinase inhibitors as first-line treatment.
Mutations in ALK and ROS1 genes are predictors of a good response to another class of tyrosine kinase inhibitors that are already widely used in routine practice.
Mutations in BRAF gene nowadays not only provide a prognosis of the biological behaviour of the oncological disease, but also predict a good response to treatment with BRAF-inhibitors.
AKT1 gene is responsible for the regulation of protein kinase B (PKB). Although AKT1 mutations are rare, they are often associated with cancer (e.g. stomach cancer, lung cancer, breast cancer, ovarian cancer, prostate cancer and colon cancer). Clinical trials are currently under way that assess the effectiveness of direct AKT1 inhibitors.
PDGFRB encodes a receptor that is part of the larger family of protein tyrosine kinases associated with cell survival, growth and proliferation. The mutation of the gene causes a malignant disease called PDGFRB-associated chronic eosinophilic leukemia. It is also associated with other oncological diseases.
Phosphatidylinositol 3-kinase (PIK3), which is partly encoded by this gene, plays a role in the regulation of cell growth, survival, protein synthesis, and the regulation of certain hormones, including insulin. Mutation in this gene can lead to the development of various types of brain tumours, endometrial cancer and the less common colon, breast and ovary tumours. There are medications that are already being used effectively in the treatment of breast cancer.
All of the above examples indicate that NGS is a technology involving a large scale of analysis and potential to transform all aspects of cancer treatment from diagnosis, prognosis, therapy and application of various approaches to disease monitoring.
In addition to Illumina MiSeq Next-Generation Sequencing System, IMHAT "Saint Marina" – Varna, has also well-established and highly qualified experts that can direct the appropriate patients to genetic analysis, molecular biologists who can technically perform it, and geneticists that will provide consultations to the patients and their relatives. The presence of all these factors in the hospital guarantees the stability of the algorithm for conducting the analysis and application of modern targeted patient treatment.
Oncology revolution has been underway over the recent years thanks to innovative tests and analysis of key genes and increasingly frequent application of targeted state-of-the-art therapy.
Those wishing to get genetic testing may contact the specialists in one of the following ways:
From 08.00 to 13.00 on phone: 052 978 649 or e-mail: firstname.lastname@example.org