Oncology

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Cancer is a genetic disease characterized by the rapid and uncontrolled growth of abnormal cells. It is one of the leading causes of death worldwide. Cancer is a multi- stage process which starts from genetic alterations in the DNA of normal cells, known as mutations. Accumulation of genetic alterations causes the now cancerous cells to multiply and form a mass, known as a tumor, which can grow and spread to other parts of the body.

90-95% of cancer types occur sporadically without an inherited genetic cause and 5-10% of cancer cases can run in families (inherited).

Inherited mutations (genetic variants) can exist from birth and can be passed down from parents to their children, increasing the risk of developing cancer in the future.

Identifying inherited variants and estimating the risk for cancer development provides the opportunity to identify the most appropriate preventive measures, offer better clinical management and/or undergo timely routine monitoring.

Everyone inherits one copy of the gene pair from the mother and another one from the father. When a genetic mutation is present in the germ cells (which means eggs or sperm from parents) and inherited to the individuals from birth, it is referred to as germline mutation. 

Not all germline mutation carriers will develop cancer. However, carrying a germline mutation in a oncogene, tumor suppressor or DNA repair genes may increase the likelihood of developing cancer in a lifetime.

A somatic mutation, or acquired mutation, happens in somatic (body) cells instead of germ cells and will not pass to offspring. A somatic mutation is frequently caused by  environmental factors, such as smoking or exposure to carcinogens.

Classes of Cancer Genes: genes related to Cancer Development are of different functional classes: 

• Oncogenes are mutated genes that lead to uncontrollable cell growth and cancers. Mutated HER2 is one of the examples, which play a role in developing cancer such as breast cancers.
• Tumor suppressor genes are responsible for taming abnormal cell growth. They act as a braking system to stop the cell from out-of-control growth. Mutations in tumor suppressor genes can disrupt its regulation or function and eventually lead to cancer. P53 is a well-known tumor suppressor gene whose mutations were commonly found in cancers.
• DNA repair genes: Somatic mutations may happen randomly during the complex cell division process. DNA repair genes, such as ATM, BRCA1, BRCA2, MSH2, and MSH6, are responsible for repairing mismatches in DNA. When a DNA repair gene is mutated, somatic mutation may accumulate at a higher rate over time.

In most cases, cancer is not caused by a single gene mutation, it usually takes several mutations impacting multiple genes to develop cancer. 

Understanding the genetics of cancer may help understand the diagnosis, treatment, and prevention of the disease.

Families or individuals with the following cancers or syndromes shall be tested for risk of hereditary cancer: 

• Hereditary Breast & Ovarian Cancer Syndrome
• Nervous System Cancer
• Endocrine Cancer
• Pancreatic Cancer
• Renal Cancer
• Prostate Cancer
• Thyroid Cancer
• Gynecological Cancer
• Retinoblastoma
• Hereditary Nonpolyposis Colorectal Cancer
• Paragangliomas
• MEN Syndrome
• Lynch Syndrome
• Von-Hippel Lindau syndrome
• Li-Fraumeni Syndrome
• Peutz-Jeghers

• Treatment and relapse monitoring in cancer patients
• Understanding secondary acquired resistance mutations during the course of treatment
• Monitor patients during the initiation of baseline therapy and at regular intervals for assessment of clinical response to the treatment

Cancer patients who fall in one of the following categories can get tested with liquid

biopsy: 

• The biopsy material is degraded or damaged or poorly fixed
• The tumor content is insufficient in the existing biopsy material
• No available tumor tissue biopsy
• For those patients whose clinical condition is not suitable for an invasive procedure

Genatechs provides NGS based Liquid biopsy testing panels.  The advantages of this test using NGS technology are as follows:

• High sensitivity and ability to detect low-frequency mutation
• Unlike RT-PCR, NGS has the advantage of multi-gene profiling in a single assay providing on the exon covering HOTSPOT mutation, with a minimal amount of DNA without compromising on the sensitivity and specificity
• Reduced turnaround time

• Patients who are diagnosed with a solid tumor and molecular profiling is needed for personalized therapy
• Patients who have resistance to other therapies (e.g. chemotherapy) and
  molecular profiling is needed for personalized therapy
• Patients who want to expand their treatment opportunities and want genetic testing for novel immunotherapy biomarkers (MSI and TMB)

Tumor profiling is a laboratory-based method which identifies mutations, genomic biomarkers (such as Tumor Mutational Burden, TMB; and Microsatellite Instability, MSI) as well as other molecules including proteins which can be responsible for cancer development and resistance to treatment. 

Different molecular profiling techniques, such as immunohistochemistry and genetic testing, can help in deep molecular characterization of the tumors either at the protein or the gene level.

Tumor profiling allows the investigation of genomic mechanisms involved in tumor formation, including microsatellite instability and fusion genes, as well as enabling investigation of tumor mutation burden analysis.

Microsatellites are repeated sections of DNA, 1-6bp long, that are found throughout the entire genome and account for approximately 3% of it. Due to their repeated sequences, microsatellites are prone to a high mutation rate. Microsatellite instability (MSI) is a cause of unique molecular alterations and hypermutated phenotypes. It is triggered by an impaired DNA mismatch repair (MMR) system, which frequently results from germline or somatic mutations or promoter hypermethylation of genes in the DNA MMR system, such as MLH1, MLH2, MSH6, and PMS2.

Determined as a predictive biomarker and can support the selection of patients who may benefit from immune checkpoint inhibitor (ICI) therapy. TMB is defined as the number of somatic coding, non-synonymous variants in the tumor genome per megabase and is associated with the development of neoantigens that trigger antitumor immunity.

Occur across a wide spectrum of tumor types. Gene fusions arise as a result of genomic rearrangements, including chromosomal inversions, interstitial deletions, duplications, or translocations, and can drive both the development and progression of cancer. Sequencing efforts have identified rare oncogenic fusions across several forms of cancer. Many of these fusions have proven to be viable targets or are the subject of promising ongoing research.

Histopathological examination and genetic testing can determine the tumor profile and guide management and treatment plans.

Solid tumors represent approximately 90% of adult cancers. In up to 40% of patients, complex genomic alterations are identified, which can serve as biomarkers to predict response to specific therapies and/or prognosis.

Your physician can choose from individual targeted therapy tests, gene panels or a single comprehensive gene panel.

Tests cover markers that are of diagnostic, prognostic, and therapeutic importance. Based on individual leukemia subtype there are various markers to be evaluated according to a work-up by bodies like World Health Organization (WHO) and American Society for Hematology (ASH). The diagnostic markers can be tested during the presentation of the disease, whereas prognostic and therapeutic markers can be tested while making therapeutic decisions.

• Leukemias are 7th most occurring cancers in terms of incidence as well as mortality rate
• Acute Myeloid Leukemia (AML)- The most common type of leukemia in adults
• Acute Lymphoblastic Leukemia (ALL)
  • The most common malignancy in children
  • Accounts for 75% of all childhood leukemia and 25% of all childhood cancers
• Chronic Myeloid Leukemia (CML)- Accounts for 15-20% of diagnosed leukemia cases in adults
• Myelodysplastic Syndrome (MDS)
  •  A disease of the elderly with a median age of 70 years
• Myeloproliferative Neoplasms (MPN)- More commonly diagnosed in people over the age of 50 years and rarely occurs in young people