Laboratory of Molecular Oncology
The Laboratory of Molecular Oncology is the country’s leader in the field of genetic research into human tumors. It is one of the few research facilities in our country that has succeeded in introducing molecular diagnostics into routine practice in oncology.
The facilities and equipment of the Laboratory are in compliance with the high standards applicable to molecular and genetic research. The research projects of the Laboratory are financed by the Russian Science Foundation, the Russian Foundation for Basic research and other organizations.
Basic research aimed at studying the mechanisms of cancer and developing methods for cancer treatment
An important area of basic research pursued by the Laboratory has been studying the molecular pathogenesis of bilateral breast cancer as an example of a disease associated with strongly pronounced inherited predisposition to cancer.
In 2001 Professor Imyanitov defended his PhD dissertation titled “Molecular and Genetic Aspects of Pathogenesis of Bilateral Breast Cancer”. This paper and all the activities pursued by the modernized and revitalized Laboratory in this field have given a new direction to molecular oncology. In 2007 for the first time ever Suspitsin et al. conducted research into the correlation between individual characteristics of the human body and specificity of somatic mutations in tumors. A new efficient approach to the analysis of inherited cancer associated mutations and polymorphisms was proposed [Imyanitov et al., 2002; Kuligina et al., 2010]. It involved comparing people with extreme characteristics of cancer risk and tolerance.
This method allowed the researches to come to a number of vital conclusions regarding molecular epidemiology of breast, testicular, lung and stomach cancer. In 2010 Sokolenko et al. developed and introduced into clinical practice a breast cancer mutation panel used for hereditary breast cancer genetic testing of women living in the North-West region of Russia.
In 2012 the Laboratory of Molecular Oncology discovered that BLM gene mutations were a predisposing factor of hereditary breast cancer in Russian women [Sokolenko et al., 2012].
Molecular diagnostics and improved outcomes of cancer treatments
The vigorous groundbreaking work of Professor Imyanitov, his team and students helped to create game-changing molecular and genetic diagnostic techniques:
- analysis of sensitivity to cytostatic drugs based on the level of expression of specific molecules in the tumor, and
- analysis of predictive markers of response to target drugs.
These techniques, which are in compliance with the international standards, are now routinely used at all stages of cancer care provided by the Center and other cancer facilities in Russia. The Laboratory is focusing on two most promising areas – diagnosis of cancer hereditary syndromes and individualized cancer drug selection based on molecular characteristics of the tumor. The work in these areas has helped to significantly increase the clinical and economic efficacy of the use of expensive medications, decrease the rate and severity of side effects and, in many cases, prevent adverse outcomes of a disease. The Laboratory provides testing and diagnostic services to more than 3,000 people every year.
Some molecular and genetic tests are covered by compulsory insurance provided by local social insurance funds..
Hereditary tumor syndromes
Hereditary breast cancer is the most prevailing type of family tumors – its share of all breast cancer cases is 5-10%. The most common types of hereditary breast cancers are associated with high risks of ovarian cancers, that is why in medical literature the term ‘hereditary breast-ovarian cancer syndrome’ is usually used. Hereditary breast-ovarian cancer syndrome accounts for an even larger number of ovarian tumors – 10-20% of all ovarian cancer cases are due to a hereditary gene deficit.
The goals of testing for hereditary cancers are:
- to establish the hereditary nature of a cancer, which may require significant changes to the choice of treatment options, the extent of surgery and/or the type of therapy,
- to identify a genetic predisposition to cancer in yet healthy people, which, if there is such a predisposition, may help to devise a set of options to prevent the disease or diagnose it early.
It has been established that in Russian hereditary breast cancer patients so-called founder mutations, especially BRCA1 5382insC allele, account for up to 70-90% of all BRCA1 gene defects [Sokolenko et al., 2006; Sokolenko et al., 2007]. This study and other studies [Iyevleva et al., 2010] allowed creation of an affordable and efficient genetic test panel for family breast cancers which uses just a few PCR tests. Such studies has helped to promote and encourage the detection of hereditary breast cancer throughout the entire country.
The researchers of the Laboratory of Molecular Oncology showed that mutations in CHEK2 and NBS1 (NBN) genes were a major cause in the development of hereditary breast cancer among Russian cancer patients [Buslov et al., 2005; Chekmariova et al., 2006].
The Laboratory’s research into discovering new genetic determinants of hereditary breast cancer revealed another moderately penetrant risk factor – heterozygous mutations in the BLM gene [Sokolenko et al., 2012]. The BLM gene is a member of a protein family called RecQ helicases and is involved in maintaining genome stability. Homozygous inactivation in the BLM gene causes Bloom syndrome, which is characterized by severe growth retardation, impaired fertility and highly elevated cancer risk. As with BRCA1, mutations in the BLM gene in Russian patients is mostly limited to one allele – BLM с.1642 C>T (Q548X). These mutations can be found in 0.2-0.3% of the general population.
Selection of a therapy based on molecular characteristics of the tumor
Molecular tests help to knowingly determine which patients will benefit most from medical therapy. Such approach allows to increase the treatment response rate from 20-50% to 80-90%.
A number of research papers relating to EGFR mutations also has enormous clinical significance. Intragenic mutations of the epidermal growth factor receptor (EGFR) are present in about 20% of pulmonary adenocarcinomas; they affect the conformation of this receptor and make it highly susceptible to small molecule drugs – gefitinib and erlotinib. As a result, almost all patients with EGFR mutations who have received these drugs experience considerable decrease in the volume of tumors. Our Laboratory took part in a clinical trial of these drugs, which included only patients with EGFR mutations. All patients demonstrated considerable treatment success [Tjulandin et al., 2015].
In 2009, it was discovered that EGFR mutations could be found not only in lung cancers, but also in clear cell carcinomas of the kidneys; besides, they are associated with the pronounced tumor response to gefitinib treatment [Iyevleva et al., 2009]. Common EGFR mutations include interagenic deletions and point mutations. In their 2014 study Iyevleva et al. demonstrated that around 1% of mutations of this receptor were EGFR exon 19 insertions, which, along with the common mutations, were associated with gefitinib treatment sensitivity. This study is undoubtedly of great interest, since EGFR insertions cannot be detected by any available diagnostic test systems.
The Laboratory developed a universal PCR test for detecting ALK gene translocations, which, due to its superb technical and economic characteristics, has far greater advantages in comparison to common diagnostic techniques for detecting rearrangements of this gene, such as fluorescence in situ hybridization (FISH). In addition, new types of ALK gene translocation were identified [Iyevleva et al., 2015].
