Comprehensive Genomic Profiling (CGP) assesses the genes that code for proteins in our body for normal function. CGP assay looks broadly for gene alterations (all the classes of genetic alterations), or harmful changes, anywhere in the genetic code (exonic regions) in our DNA.
All cancers contain genetic changes, or mutations, in the genetic code of their cells. More mutations per coding area of the genome result in more newly formed abnormally expressed proteins (neo-antigens). Studies have found that more the neo antigens more good candidate is for immunotherapy due to immunogenicity.
CGP assesses all the genes in the tumor tissue and provides information on how much tumor genome is mutated (assessing all the genetic alterations SNV/Indels, CNAs, Gene Fusions, etc.). More genes it interrogates, the better is the resolution. The mutation burden in the tumor tissue is termed as TMB or Tumor mutational burden as a predictor of Immunotherapy treatment.
Another genomic signature and predictor of Immunotherapy is MSI or microsatellite instability which is the result of a deficient mutation in the genes that correct the mismatches in our DNA during replications. MS is the highly repetitive region in our genome and there are more than 6,00,000 MS loci in our genome. CGP assesses all the MS sites to inform about MSI. MSI is also a tissue agnostic biomarker for Immunotherapy treatment.
Cancer is the disease of the DNA. It occurs when the normal DNA sequence gets changed due to factors like poor lifestyle, cigarette smoking, etc.
Immunotherapy is a type of cancer treatment that focuses on enhancing the immune system's ability to fight cancer.
Comprehensive Genomic Profiling (CGP) is a method used to detect all cancer-causing DNA/RNA variants (changes in the DNA/RNA sequences) in a single assay to provide insights on Mutational burden (total number of harmful changes in the DNA that is driving cancer) and Microsatellite instability (excessive mutation in the DNA) that can are associated with cancer, from the tumor tissue to guide immunotherapy treatments.
The sequencing method is done to evaluate the order of the DNA sequence in our genome, A more sophisticated method of sequencing is called Next-Generation Sequencing (NGS). NGS allows us to evaluate many genes of cancer simultaneously.
Next-generation sequencing can be performed on material from a patient's tumor that has been biopsied or surgically removed or even from liquid biopsy to identify the genetic cause that is driving cancer.
Next-Generation Sequencing (NGS) is a sequencing method that evaluates the genes present in the DNA. There are several sequencing methods but NGS is the most advanced in its functions. It evaluates many genes of cancer simultaneously.
During an NGS test, a biopsy sample is taken from the patient, and NGS is applied to these samples to detect the presence of the mutated genes. Thus, the information obtained provides a clear-cut idea for the cause of cancer.
There are a few key circumstances in which Comprehensive Genomic Profiling is most useful.
Getting a Comprehensive Genomic Profiling testing done is more important when:
Recent studies show that combination therapy (Chemotherapy + Immunotherapy) provides better outcomes when compared to monotherapy (only Chemotherapy) as the union of anti-cancer drugs enhances efficacy compared to the single-drug approach because it targets key pathways in an additive manner. CGP provides the right information as to which monotherapy or combination therapy will work.
Though cancer is the disease of the genome (Changes in our DNA), not all cancers are hereditary. Some cancers are caused due to mutation (Changes in our DNA) in our germ cells (egg/sperm) and are considered hereditary as the mutated genes are passed from generation to generation. For example, cancers such as Breast, Ovarian, Prostate, Pancreatic, Colorectal are mostly hereditary in nature. If multiple family members have the same type of cancer, then the mutated gene is present in the family. Genetic testing is advised to estimate the risk in this matter.
Not all cancers are hereditary. For a family member to be at risk of having cancer depends upon the family history of cancer. This means that if the family has a history of certain cancers then it is likely that cancer can be passed from one generation to another. In such cases, it is advised to take up Genetic testing to estimate the risk of inheriting cancer-causing genes. Some of the examples of hereditary cancers are Breast, Ovarian, Prostate, Pancreatic cancer, etc.
This does not mean that a person gets cancer through hereditary. Cancer can be hereditary and non-hereditary too. Similarly, a person can encounter cancer through habits like smoking or a poor lifestyle. Therefore, it is necessary to have a Genetic test done to obtain clarity on whether you are susceptible to cancer in the future or not.
FFPE stands for “Formalin-Fixed Paraffin-Embedded”. It is a form of preservation and preparation for biopsy specimens that are used in pathological examination, experimental research, and diagnostic assays/tests.
FFPE blocks are found with the concerned pathologist in the hospital where the patient has undergone surgery or the biopsy procedure.
When a biopsy sample is extracted from a patient for analysis, they are preserved in FFPE blocks so that the tissue or sample is not degraded by bacteria or other environmental factors. These are known as Formalin-Fixed Paraffin-Embedded blocks or FFPE blocks.
The preserved sample in FFPE blocks is taken to the hospital laboratory and if in case you need to issue the sample then you can contact the hospital laboratory for the issuance of the FFPE blocks.
Technical
A Histopathology report is prepared by a Pathologist which entails the comprehensive description of the tissue taken at the time of the surgery. There are two main types of histopathology reports:
Each cancer is genomically different with different subtypes and each subtype has different characteristics. A histopathology report or a histopathologist identifies the nature of the abnormality (cancer subtype characterization, and stratification), its grade, and for some cancers, its responsiveness to certain treatments. To customize the precision treatment, information on the subtypes, stage of cancer, and grades are important. This is the reason why we require a Histopathology report for cancer biomarker testing.
Histopathology implies a laboratory examination of any kind of tissue.
The biopsy or surgically removed sample from the patient is preserved and given to the pathologist. The pathologist examines the tissue and prepares a report out of it called the Histology Report.
The report contains information like what kind of tissue, what tumor is observed, the appearance of the cells, etc.
The purpose of understanding this information is that, when two patients have Lung cancer, it doesn't mean that the same mutated genes are causing lung cancer in both of them. Therefore, it is evident that cancer has different subtypes. To understand these subtypes, grades, and the reaction of cancer cells towards different treatments, it is necessary to create a summarized report. This will help the doctor to suggest the specific treatment required for cancer.
Technical
A Histopathology report is prepared by a Pathologist which entails the comprehensive description of the tissue taken at the time of the surgery. There are two main types of histopathology reports:
Each cancer is genomically different with different subtypes and each subtype has different characteristics. A histopathology report or a histopathologist identifies the nature of the abnormality (cancer subtype characterization, and stratification), its grade, and for some cancers, its responsiveness to certain treatments. To customize the precision treatment, information on the subtypes, stage of cancer, and grades are important. This is the reason why we require a Histopathology report for cancer biomarker testing.
Histopathology implies a laboratory examination of any kind of tissue.
The biopsy or surgically removed sample from the patient is preserved and given to the pathologist. The pathologist examines the tissue and prepares a report out of it called the Histology Report.
The report contains information like what kind of tissue, what tumor is observed, the appearance of the cells, etc.
The purpose of understanding this information is that, when two patients have Lung cancer, it doesn't mean that the same mutated genes are causing lung cancer in both of them. Therefore, it is evident that cancer has different subtypes. To understand these subtypes, grades, and the reaction of cancer cells towards different treatments, it is necessary to create a summarized report. This will help the doctor to suggest the specific treatment required for cancer.
Every step in the DNA Next-Generation Sequencing process undergoes Quality Control checks. The tumor tissue sample and content of the tissue (DNA/RNA) integrity is measured vigorously and it is the main source for accurate results.
DNA/RNA QC failed means that the integrity of the nucleic acid (DNA/RNA) is not up to the mark for the Next-Generation Sequencing run. It may require fresh tissue or another FFPE tissue block from where the tissue will be extracted again for the sequencing and evaluation.
A Tissue Biopsy-based Genetic Test is considered the standard in the diagnosis of cancer. However, for diagnosing primary tumors or determining the stage of metastatic lesions in tissues where it is difficult to extract a sample, a liquid biopsy might provide a reliable alternative. Liquid Biopsy sometimes provides false-negative/positive results. Reflex testing is recommended on the tissue sample.
DNA/RNA QC failed means that the integrity of the nucleic acid (DNA/RNA) is not up to the mark for the Next-Generation Sequencing run. It may require fresh tissue or another FFPE tissue block from where the tissue will be extracted again for the sequencing and evaluation.
Tissue biopsies are utilized when a tumor's location is known and thus the doctors will be able to extract the affected tissue for analysis. Liquid biopsies are used for screening and identifying mutations in cancer cells that are not localized in any organ.
Since 90% of cancers are solid tumors, doctors prefer to conduct Tissue biopsies which are then preserved in FFPE blocks.
Yes, as per treatment guidelines it is advised to test for BRCA gene testing if the patient is having Breast cancer. However, if the patient is having a strong hereditary Breast and Ovarian cancer history running in the family she is recommended for 1st line Germline Gene Testing for Homologous Recombination Repair pathway genes (HRR) that also includes BRCA genes. If the patient is having no family history of hereditary cancer then a somatic mutation gene testing panel is recommended. For comprehensive treatment outcomes, both germline and somatic gene testing is recommended.
Though BRCA genes are the high-risk genes that contribute approx. 20% of hereditary breast cancers and also other types of cancers (ovarian, pancreatic, etc), it is advisable by different medical guidelines that any cancer that is driven by a mutation in the BRCA or any other HRR genes get tested for the BRCA and HRR family genes.
BRCA genes are tumor suppressor genes that are of two types BRCA-1 and BRCA-2, a mutation in these genes results in breast and other types of hereditary cancers. BRCA genes are also major genes involved in the repair of the double-strand DNA breakage.
A genetic test of BRCA analyses all the possible variants that can be Pathogenic (disease-causing), Likely pathogenic (90% chance it can cause disease), and a negative test which means that no BRCA gene mutation was found.
However, analyzing your cancer risk is still difficult. The test result is considered a “true negative” only if it finds that you don’t carry a specific BRCA mutation that’s already been identified in a relative.
A negative test result doesn’t mean that you won’t get Breast Cancer.
A VUS, also known as a Variant of Uncertain/Unknown Significance, occurs when the genetic test analysis finds a genetic variant that may or may not be associated with an increased risk of cancer. It is advised to talk with your genetic counselor/doctor to understand how to interpret this finding and decide on an appropriate follow-up.
There are a few important terminologies to be remembered when analyzing a report and they are:
It is always advised to talk with your doctor to understand how to interpret the report and decide on an appropriate follow-up.
HRR or Homologous Recombination Repair genes are a set of genes that are responsible for the double-strand (dsDNA) break repair in the genome, maintaining the genomic integrity, and conserving the exact DNA sequence for normal functioning of the cell.
Homologous Recombination Deficiency test (HRD) is done to test the normal functioning of the HRR genes.
The evidence suggests that deficiency in HRR (HRD) genes are associated with many types of hereditary cancers. HRD cancers are a good candidate for PARP inhibitor targeted therapy and chemotherapy.
HRR or HRD is the same test rather it’s a different way of saying the condition. HRR pathway is a cascade of dsDNA repairing events where all the HRR genes are important and contribute equally where one gene can’t operate with the help of the other. For example, the PALB2 gene provides instructions to make a protein that works with the BRCA2 protein in the HRR pathway. BRCA gene testing alone gives inconclusive information whereas evaluation of all the HRR genes gives a comprehensive disease outlook for its better management.
Our body has the mechanism to repair the mutations (harmful genetic changes) in several ways. One such pathway is HRR (homologous recombination repair pathways). In this pathway, the DNA is repaired, integrity is maintained and the sequence is conserved.
Cancer identified through HRR gene testing can be treated with PARP inhibitors, targeted therapy, and chemotherapy.
The interesting factor about this pathway is that the genes involved are dependent on each other and equally contribute to their functions for repairing the DNA. So, when only the BRCA test is done the information provided is inconclusive, unlike analyzing all the HRR genes which give a comprehensive disease outlook for its better management.
Mutations in breast cancer genes (BRCA-1/2), significantly increase the risk of Breast cancer (Male/Female), Ovarian cancer, Prostate cancer, Pancreatic cancer, Melanoma, and other BRCA related hereditary cancers and cancer syndromes.
If a BRCA gene mutation is detected, there are NCCN guidelines that state to use the PARP inhibitors as a treatment option. But, if it is hereditary, then it is advised to consult a doctor to reduce the risk of having those cancers through lifestyle management, surgeries, or by any other means.
BRCA test detects two important genes and that is BRCA-1/2, these two are high risk genes meaning harmful changes in them can cause cancer or increase the risk of having certain types of cancers. The detection of these genes indicates whether the patient is at higher risk of encountering breast cancer or other related hereditary cancers like ovarian, pancreatic, etc.
Testing becomes useful only when the causative agent of cancer is known (that is how did cancer occur?). This is where the BRCA test becomes an important part as it detects the harmful changes (mutations) associated that can cause cancer. So, when the specific pathway is known, the doctors can prescribe treatments that are specific to the pathway and therefore the treatment becomes effective.
Lung cancer is common cancer that takes multiple genomic altered pathways to coexist.
Limited or hotspots-based biomarker testing identifies alterations that are restricted to a single gene or set of genes that increase the risk of potentially missing clinically actionable mutations in additional genes.
Comprehensive Genomic Profiling (CGP) edges out by detecting multiple Biomarkers in a Single Assay from less tissue and in less time, identifying Actionable Alterations with more confidence providing finer resolution of tumor composition, providing information on Immunotherapy by comprehensively assessing genomic signatures like TMB and MSI.
Lung cancer panel test identifies alterations restricted to a single gene or set of genes. Lung cancer is formed due to multiple mutated genes, therefore identifying single/multiple genes will result in missing out on a significant portion of the genomic information. Therefore, the treatment recommended will be insufficient for treating cancer.
In the case of CGP, it detects multiple genes that are mutated, provides information for immunotherapy treatments and or targeted treatments, uses less tissue for analysis, and obtains results in less time thereby, countering the issues faced in the previous panel.
MSI or Microsatellite Instability is the result of deficient mutations in the genes (dMMR genes) that correct the mismatches in our DNA during replications. It is also a predictor of Lynch Syndrome and informs about the risk of having Colorectal cancers.
MS is the highly repetitive region in our genome and there are more than 6,00,000 MS loci in our genome. Comprehensive NGS panel assesses all the MS sites to inform about MSI.
MSI is also a tissue agnostic biomarker for Immunotherapy treatment as per FDA.
Our cells have certain specialized genes called MMR that are involved in mechanisms to repair mutations. But when the repair mechanism genes are mutated, the chances of repair are drastically reduced and accumulation of mutation will result in various diseases like cancer. This is known as MSI which can be identified as repetitive sequences in the DNA. This also acts as an indicator for Lynch syndrome (hereditary colorectal cancer) and also highlights the risk of having colorectal cancer.
MSI is detected by a comprehensive NGS panel. According to FDA, MSI acts as a tissue agnostic biomarker (a clear indication of cancer) for immunotherapy treatment.
Some cancers are caused due to germline gene mutation which is passed from generation to generation and runs in the family. 5-10% of such cancers are hereditary in nature. Hereditary cancers are a rare event in the population.
Hereditary Cancer Genetic Testing evaluates the risk of one’s chance of developing cancer in their lifetime by genetic testing from the blood by NGS. It estimates by searching specific changes in the genes of our DNA.
Cancer can be hereditary or non-hereditary. Hereditary cancers are cancers that pass from one generation to another. Almost 5-10% of cancers are hereditary like Breast cancer, Ovarian cancer, etc.
When one takes up Hereditary Cancer Genetic Testing, the patient gets to know whether they are at risk of developing cancer in their lifetime. To test this, the doctors need blood / saliva samples from the patient and the analysis is conducted using NGS.
All the information of the test is enlisted in the Solution section > Genomics > Somatic test/Hereditary cancer test section. https://4basecare.com/solutions/genomics/
The best person for this question is a treating doctor or genetic counselor. Some indications are generalized for the public interest. Some cancers have ample recommended clinical markers and immunotherapy that works well. In this case, tests that provide information on DNA/RNA variants and also on Immunotherapy markers are preferred. However, for a rare type of malignancies like Sarcoma, the most comprehensive genomic insights are required for the development of a precise treatment regime.
It is advised to consult your Oncologist or Onco Genetic Counsellor because they are experts who have wide knowledge about various cancers and the required treatment that is suitable for the individual.
There are several types and subtypes of cancers where different DNA/genomic biomarkers drive the disease. Different medical guidelines have devised different targeted and immunotherapy and or combination of treatments based on the genomic biomarkers. The doctors profile the tumor genome of the patient to personalize the cancer treatment. So, the doctors and Onco genetic counselors are the key persons who can guide you to choose the relevant test.
Cancer is a collective abnormal condition of our genome. It is the result of the harmful changes in our DNA. The central dogma of molecular biology entails how the flow of information is stored in DNA as genes, transcribed into RNA, and finally translated into proteins.
In DNA, exome is the protein-coding part and most of the DNA alterations associated with genetic disorders are concentrated in the exonic regions and cancer is no exception.
Whole-Exome Sequencing provides information by assessing associated DNA alterations that are driving diseases like cancer. On the contrary, RNA profiling is essential in providing functional elements of the genome and understanding the development of the disease and its molecular form, it also provides the dynamic nature of the transcriptome.
Limited gene test only analyses the known genes and the alteration associated with them and the test result is inconclusive as the chances of missing out on some novel or therapeutically emerging mutations are high.
Whole exome and RNA profiling eliminates the risk of missing mutations as it gives comprehensive coverage of exonic regions by assessing DNA variants and dynamic data by profiling RNAs (gene fusion and splice variants). Consolidated Immunotherapy and Targeted therapy decisions can be obtained from whole-exome and RNA sequencing.
In DNA, the exome is the part of the DNA where all the instructions of the proper functioning of the cell are stored. Most of the genetic changes that drive cancer reside in this region. Assessing the whole of the exons gives a better resolution that drives the disease. Other technologies assess bits of exons one at a time, hence missing out on comprehensive insights for cancer treatment. Whole-exome (DNA) and transcriptome (expressed RNA) profiling by Next-Gen Sequencing method assess all the necessary changes that are driving the disease in a single experiment in less time compared to other tests.
PD-L1 or Programmed Death Ligand-Protein-1 is a protein that marks and blocks normal cells from getting attacked by immune cells. Cancer cells being abnormal for the body uses PD-L1 as a defensive shield against immune cell attack and escape by expressing PD-L1 marking them as normal cells of the body. PD-L1 testing evaluates the expression of PD-L1 protein in the cancer cells by the Immunohistochemistry method. Based on the specified testing cut-off value, one can prove to be a good candidate for Immunotherapy.
Our immune system is highly complex and advanced. PD-L1 acts as a marker for normal cells, which prevents the immune cells from destroying normal cells.
Some cancer cells have a mechanism to possess PD-L1 and therefore escape the screening of immune cells. This is how cancer gets unnoticed for a long time.
This test detects the expression of PD-L1 in cancer cells by the Immunohistochemistry method (laboratory method that uses an antibody to detect specific antigens in the tissue).
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