There are multiple ways in which genomic sequencing of patients’ cancer samples can be helpful, including cancer risk prediction, cancer prognosis and diagnosis, to identifying personalized and precision cancer treatments. There are many companies offering varied sequencing tests and the right test will need to be identified based on specific context and cancer type. Some tests are covered by insurance but most are based on self-pay.
Scanning through reviews, articles, blogs, recommendations etc post a cancer diagnosis can be overwhelming. There is a lot of information, new terminology and recommended tests which most of us are clueless about. Tumor sequencing, cancer/tumor profiling, next-generation sequencing, targeted panels, whole-exome sequencing, molecular characteristics of the cancer, are all the jargon that we encounter. What do these mean and how are these helpful?
What is Cancer Genome Sequencing?
Let us start with some cancer basics. Cancer is an uncontrolled growth of certain cells in our body that have become abnormal due to an accumulation of genetic changes in our cellular DNA, called mutations or genomic aberrations. DNA is made up of 4 alphabet nucleotides, the sequence of which makes up the genes that give instructions to make the proteins that drive the functions of our cells, tissues and organs. Sequencing is the decoding of the genomic content of the cells. DNA from the cancer cells and normal non-cancer cells can be isolated and thanks to the innovations and advances in next-generation sequencing technologies, can be deciphered at the level of the nucleotide sequence. Comparison of the cancer and control DNA sequences gives information on the new and acquired changes that when further analyzed give insights into the underlying abnormalities that are driving the disease.
Different Types of Sequencing
Identification of genomic mutations and abnormalities can be done through various techniques and tests including cytogenetic karyotyping, amplification of specific regions of DNA through polymerase chain reaction (PCR), identification of specific abnormalities and fusions using fluorescence in situ hybridization (FISH), genomic sequencing of a targeted panel of cancer specific genes, or the sequencing of the complete set of genes called whole-exome sequencing (WES) or the entire DNA of the cell can be sequenced as part of whole-genome sequencing (WGS). For clinical implementation of cancer profiling, the preferred option is targeted gene panel sequencing of cancer specific genes in the range of 30 – 600 genes, while WES and WGS are used more in the research domain. Advantages of targeted sequencing are lower costs, greater depth of sequencing and deeper analysis of specific regions of DNA that can be key drivers for the cancer.
Benefits of Cancer Genome Sequencing
For a cancer patient, one needs to pick the right test panel for their specific cancer type. Different cancers are associated with different sets of gene mutations and targeted panels from various companies cover different sets of genes. A higher depth of coverage of the genomic regions being sequenced has advantages over a breadth of coverage one can get with WES but it may miss some key findings. There is still a lack of standardization across sequencing tests and variability in results when sequencing DNA from the same sample across different tests, in many cases. There is also variability in sequence based on which part of the tumor sample is sequenced and differences seen between sequencing DNA from a solid tumor tissue sample and circulating tumor DNA from the same patient. However, despite the various challenges, the information obtained from sequencing of the cancer can be very useful in multiple ways as reviewed by scientists from the Wellcome Sanger Institute in the United Kingdom (Nanglia and Campbell, New Engl J Med., 2019). Some of the ways in which cancer genomic sequencing can help in diagnosing, treating and monitoring cancer are listed below:
- Cancer-risk prediction in a healthy individual who may have a family history of cancer. Sequencing of DNA from the blood sample of a healthy individual can provide information on existing germline mutations that may be present and may increase future cancer risk. Eg. presence of cancer-disposition gene mutations in BRCA, APC or VHL.
- Pharmacogenomics – germline genomics can identify single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes that could be used to identify patients at risk for toxic effects of chemotherapy.
- Epidemiology and Public Health – genomic sequencing of tumors from regions where there is a high incidence of a particular cancer type may help in identifying the environmental, diet or other exposures that could underlie the high incidence of cancer.
- Sequencing of early lesions can help with determining prognosis of the disease and need for intervention. Genomics with more numbers of mutations/aberrations and the type of mutations, may be identified as those that need early and more aggressive intervention.
- Cancer diagnosis by identification of driver mutations such as BCR_ABL, KRAS, TP53 and others can confirm the underlying cancer.
- Identification of tissue of origin for cancer of an unknown primary. Specific mutations are associated with specific cancer types.
- Tumor classification can be done on the basis of the composition of driver mutations and is linked to a disease biology that can be treated with specific targeted therapies.
- Predicting patient outcomes and provide better prognosis based on clinical and genomic data. Eg. Tumors with TP53 mutations have worse prognosis.
- Precision cancer treatment- Cancer patients have many mutations and the complement of mutations is unique for every cancer patient. Hence, a more personalized and customized combination treatment identification that can address the impact of all the abnormalities would be the holy grail for cancer treatment.
- Identifying resistance mechanisms by sequencing of the cancer that has not responded to prescribed treatments.
- Cancer monitoring through liquid biopsy of circulating tumor DNA or circulating tumor cells can help identify recurrence of disease or relapse without an invasive biopsy or surgery.
Hence as listed, there are multiple ways in which sequencing can be helpful although it is not mainstream in most oncology practice. There are a number of companies offering sequencing tests with different capabilities which as mentioned above will need to be identified based on specific context, cancer type and purpose. There are a few tests that are now getting reimbursed by government plans such as Medicare or the NHS but in many countries such as India and China, these tests are paid for by the patients.
Cancer patients often have to deal with different chemotherapy side effects which affect their quality of life and look out for alternative therapies for cancer.Taking the right nutrition and supplements based on scientific considerations (avoiding guesswork and random selection) is the best natural remedy for cancer and treatment related side-effects.