Symptoms relate to a genetic cause
Oncogenes and tumor suppressor genes code for proteins that control strategic checkpoints of cell proliferation and differentiation. Mutations in these genes can deregulate these control points, giving rise to immortal cells able to avoid apoptosis, to proliferate, to invade the surrounding tissue and to metastasize in distant organs and tissue.
Two types of genetic variants have to be distinguished. Germline (hereditary) mutations which are present in every cell in the body and can be passed on to the next generation. Here, genetic testing can provide early detection of an inherited tumor predisposition and allow individualized cancer screening to reduce cancer risk.
Somatic (acquired) mutations occur in the developing cancerous cells/tissue only and are thus not heritable. The variants affect all genes including those which upon mutation will induce tumor specific behavior. The detection of gene variants or mutation within a particular sample increases the understanding of the tumor behavior and is therefore the basis for an individualized cancer therapy with a better assessment of diagnosis, prognosis and therapy.
- Affected individuals
- Unaffected individuals with a positive family history of oncogenetic disease
For inherited cancer syndromes the identification of a pathogenic variant can confirm a genetic diagnosis with great impact on the patients’ health. Testing should be done for sequence variants as well as for copy number variants. For a most comprehensive interpretation of the analysis results and phenotype, thorough clinical information is critical. A comprehensive medical report includes a tailored diagnostic strategy, recommendations and differential diagnosis, if applicable. For somatic analysis, clinical information with information on disease symptoms and the results of tumor biopsies, staging and initiated therapies are important. A full medical report including analysis results and their proper interpretation on the basis of the clinical information provides the basis for further tailored diagnostic and therapeutic strategy.
What do we know about oncogenetics?
Medicine is benefitting from a huge amount of research into the genetics of many different cancers. We now understand cancer oncogenetics much better, however there is still much to learn; the information below is just a sample of gene-specific information which can be assessed to improve clinical care and patient outcome.
Hereditary cancer genetics
Certain mutations result in increased risk for hereditary cancer, and lead to development of many cancers, including breast, ovarian, colorectal, bowel, uterine, prostate, pancreatic, renal, liver and melanoma.
Breast cancer – An estimated 5–10% of all breast cancers are directly attributable to inherited gene mutations1,2,3. Hereditary breast cancers tend to develop earlier in life than sporadic cases, and new primary tumors are more likely to develop in both breasts.
BRCA1 and BRCA2 mutations are the most common causes of hereditary breast and ovarian cancers, but other genes are also associated with hereditary malignancies. For example, mutations in genes involved in the repair of double-stranded DNA breaks, such as ATM, BRIP1, CHEK2, PALB2 and RAD51D, represent further mechanisms of hereditary carcinogenesis. All of these genes are tumor-suppressor genes that in one way or another inhibit cell proliferation.
Colorectal cancer – Approximately 30% of colorectal cancers are familial4, a subset of which have a strong genetic cause. Lynch syndrome is the most common form of hereditary CRC, but additional cancer syndromes are also associated with increased CRC risk, such as familial adenomatous polyposis (FAP), MYH associated polyposis (MAP), and juvenile polyposis syndrome (JPS). Lynch syndrome, also known as hereditary non-polyposis colon cancer (HNPCC) is caused by variants in the MLH1, MSH2, MSH6 and PMS2 genes. Patients are at increased risk of developing bowel cancer (accounting for 2–5% of bowel cancers4) and also stomach, small bowel, gallbladder, and womb and ovarian cancer in women.
FAP and MAP are caused by variants in the APC and MYH genes respectively. They are rare diseases that cause 1% of bowel cancers4 due to the growth of hundreds of non-cancerous polyps that develop in the bowel at a young age and become cancerous over time.
Renal cancer – Renal cancer is most common in older patients with a positive family history. There are a number of inherited conditions that increase the risk of developing renal cancer, including Birt-Hogg-Dubé (BHD) syndrome, caused by mutations in the FLCN gene, von Hippel-Lindau disease caused by mutations in the VHL gene, and others.
Somatic cancer genetics
Lung cancer is the most common cancer causing more deaths than colorectal, breast and prostate cancers combined5. The incidence and mortality of lung cancer are high throughout the world, accounting for 1.8 million patients and 1.6 million deaths in 20126. Risk for lung cancer is largely dependent on environmental and other factors (smoking, exposure to toxic chemicals, family history), however targeted gene sequencing has identified recurrent lung-cancer-associated somatic mutations in EGFR, KRAS, TP53 and other genes, that have an influence on therapy and prognosis.
Acute myeloid leukemia (AML) is an aggressive malignancy of the bone marrow of myeloid precursor cells which blocks normal differentiation and maturation and increases proliferation. Malignant cells replace normal bone marrow, causing a decrease in red blood cells and platelets, and symptomatic easy bruising and bleeding, fatigue and increased risk of infection due to a lack of normal white blood cells. AML is one of the most common leukemias in adults (~25% of all leukemia of adults in the Western world)7 with an overall five-year survival of 40–45% in young patients and less than 10% in the elderly8. Targeted sequencing has identified recurrent AML-associated mutations in FLT3, NPM1, KIT, CEBPA, TET2 and other genes.8
Breast/ovarian cancer is one of the most common cancers, affecting about 12% of women in the general population9. Identification of somatic mutations in BRCA1/2 genes in patients affected with breast/ovarian cancer indicates whether the patient is a candidate for specific targeted therapy.
Colorectal cancer (CRC) is the third most commonly diagnosed cancer in the world with a cumulative lifetime risk of approximately 5–6%10. CRC is a progressive and multistep disease, resulting either from inherited or non-inherited mutations. Defects in the genes involved with DNA mismatch repair, tumor suppressors and genes from the RAS/MAPK pathway lead to an accumulation of somatic pathogenic variants in a cell, which may result in malignant proliferation and appearance of CRC clinical symptoms. Approximately 30–50% of colorectal tumors are known to have a mutated KRAS, indicating that up to 50% of patients with CRC might respond to anti-EGFR antibody therapy11.
The correct profiling of mutations in cancer genes represents a fundamental step in the diagnosis and treatment of these malignancies. Certain mutations result in increased risk of hereditary cancer, and lead to development of breast, ovarian, colon, gastric, renal or other cancers.
Testing for oncology
Scientific Articles on Oncogenetics
Robustness of comprehensive DNA- and RNA-based assays at diagnosis of acute myeloid leukemia using blood and bone marrow stored on filter cards
"Molecular analyses in hematologic malignancies gained considerable importance in the last decade at diagnosis and for minimal residual disease (MRD). In our study, we performed a comparison of state-of-the-art cytogenetics, FISH and molecular diagnostic assays based on standard liquid peripheral…
Protein kinase inhibitors are widely used in chemotherapeutic cancer regimens. Maleimide derivatives such as SB-216763 act as GSK-3 inhibitor targeting cell proliferation, cell death and cell cycle progression.
Next-Generation Sequencing of the BRCA1 and BRCA2 genes for the diagnostics of breast and/or ovarian cancer
We explored a more efficient genetic screening strategy based on next-generation sequencing of the BRCA1 and BRCA2 genes in 210 hereditary breast and/or ovarian cancer patients.
- Easton DF, et al. Breast and ovarian cancer incidence in BRCA1- mutation carriers. Breast Cancer Linkage Consortium. Am J Hum Genet. 1995 56:265-71.
- Edlich et al. Breast cancer and ovarian cancer genetics. J Long Term Eff Med Implants. 2005;15(5):533-45. Review.
- Tai YC, et al. Breast cancer risk among male BRCA1 and BRCA2 mutation carriers. J Natl Cancer Inst. 2007 99:1811-4.
- Colon cancer risk review. American cancer society website, 2015
- Centers for Disease Control and Prevention. National Center for Health Statistics. CDC WONDER Online Database, compiled from Compressed Mortality File 1999-2014 Series 20 No. 2T, 2016.
- World Health Organization. GLOBOCAN 2012: Estimated cancer incidence, mortality and prevalence worldwide in 2012. Lyon, France: International Agency for Research on Cancer. 2014 Jan.
- Cancer Genome Atlas Research Network. Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia. N Engl J Med. 2013 May 30;2013(368):2059-74.;
- Petrucelli N, Daly MB, Feldman GL. BRCA1 and BRCA2 Hereditary Breast and Ovarian Cancer. 1998 Sep 4 [Updated 2013 Sep 26]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2016. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1247/
- Grady WM. Genetic testing for high-risk colon cancer patients. Gastroenterology. 2003 May 31;124(6):1574-94.
- Wilson PM, Labonte MJ, Lenz HJ. Molecular markers in the treatment of metastatic colorectal cancer. Cancer J. 2010 May-Jun. 16(3):262-72.
What can CENTOGENE do for you and your patients?
CENTOGENE has identified genetic variants associated with oncological diseases in more than 250 different genes.
CENTOGENE has a comprehensive range of testing and expertise available to enhance cancer diagnosis, prognosis, treatment selection and monitoring. We have targeted services for hereditary and somatic cancer, and numerous cancer-specific gene panels available, such as CentoCancer®, a specially designed cancer risk-related panel. We offer genetic testing for the most common disease types such as breast and colon cancer, and hundreds of single gene tests through to whole exome (WES) and whole genome sequencing (WGS).
CENTOGENE is a global leader in the diagnosis of rare genetic diseases and has received multiple international accreditations (ISO, CAP and CLIA) that confirm the highest standards for diagnostic testing and reporting. Our experience combined with our scientific expertise and medical competence has allowed the application of state-of-the-art technologies and the development of a unique, multiethnic mutation database.
In CentoMD®, the world’s largest mutation database for rare diseases, 57% of which is made up of unpublished variants, we have carefully created and documented all variants that have clinical relevance for related symptoms supporting the precise diagnosis of an oncological disease.