Sequencing Genome of Cancer Patient

Sequencing Genome of Cancer Patient

Cancer genome sequencing is the whole genome sequencing of a single, homogeneous or heterogeneous group of cancer cells. It is a biochemical laboratory method for the characterization and identification of the DNA or RNA sequences of cancer cell(s). The first report of cancer genome sequencing appeared in 2006. In this study 13,023 genes were sequenced in 11 breast and 11 colorectal tumors. A subsequent follow up was published in 2007 where the same group added just over 5,000 more genes and almost 8,000 transcript species to complete the exomes of 11 breast and colorectal tumors. The first whole cancer genome to be sequenced was from cytogenetically normal acute myeloid leukaemia by Ley et al. in November 2008. The first breast cancer tumor was sequenced by Shah et al. in October 2009, the first lung and skin tumors by Pleasance et al. in January 2010, and the first prostate tumors by Berger et al. in February 2011.

History

Historically, cancer genome sequencing efforts has been divided between transcriptome-based sequencing projects and DNA-centered efforts.

The Cancer Genome Anatomy Project (CGAP) was first funded in 1997 with the goal of documenting the sequences of RNA transcripts in tumor cells. As technology improved, the CGAP expanded its goals to include the determination of gene expression profiles of cancerous, precancerous and normal tissues.

The CGAP published the largest publicly available collection of cancer expressed sequence tags in 2003.

The Sanger Institute's Cancer Genome Project, first funded in 2005, focuses on DNA sequencing. It has published a census of genes causally implicated in cancer, and a number of whole-genome resequencing screens for genes implicated in cancer.

The International Cancer Genome Consortium (ICGC) was founded in 2007 with the goal of integrating available genomic, transcriptomic and epigenetic data from many different research groups. As of December 2011, the ICGC includes 45 committed projects and has data from 2,961 cancer genomes available.

How do I know if tumor DNA sequencing is right for me?

Consult your health care provider to discuss the possibility of tumor DNA sequencing as part of your care. Tumor DNA sequencing is most common (and most beneficial) for patients with cancer types that may be susceptible to treatment with a targeted therapy. These patients are commonly tested for the genetic mutation the therapy targets. For example, genetic testing is a routine part of care for colorectal and lung cancer.

In addition, some oncologists may recommend tumor DNA sequencing for patients with advanced cancer that is not responding to standard treatment or for which no standard treatment is available. This may help identify other treatments that might be effective given the cancer’s genetic makeup.

In other cases, tumor DNA sequencing may be available to you if you are participating in a clinical trial that includes a sequencing test. Several ongoing precision medicine trials, such as NCI-MATCH and NCI-COG Pediatric MATCH, are using tumor DNA sequencing to assign patients to investigational treatments based on the genetic alterations in their tumors.

How is tumor DNA sequencing done?

If you and your health care providers decide to make tumor DNA sequencing part of your care, they will remove a sample of your tumor and, in some cases, a sample of your healthy cells. They may obtain these samples during surgery, if it is part of your treatment plan. In other cases, you may need to have a biopsy.

Your samples will be sent to a specialized lab, where researchers will isolate your DNA and then use a machine called a DNA sequencer to “read” it. They will then analyze the sequence of your DNA to determine if there are any genetic alterations that make your tumor susceptible to certain treatments. They may also examine the DNA sequence of your healthy cells to determine if you have any inherited, or germline, mutations that increase your risk of cancer and can also influence treatment decisions.

Based on your tumor’s unique genetic alterations, the specialized lab may generate a report that lists treatments your tumor is likely to respond to. Your health care team will discuss the results with you to make a personalized treatment decision.

What kinds of sequencing tests are available?

DNA sequencing tests can have a broad or a targeted focus. Targeted DNA sequencing tests, also called multigene panels, are the most frequently used sequencing test for patient care. These tests analyze specific “driver” mutations. Some targeted sequencing tests analyze alterations that are common in a single cancer type, whereas others analyze alterations that may be found in many cancer types.

Broad DNA sequencing tests analyze the sequence of large regions of DNA rather than specific mutations. For example, whole-genome sequencing reads the sequence of the entire DNA in your cells—what’s known as the genome. Another broad test, called whole-exome sequencing, reads the sequence of all of your genes, known as the exome. Most cancer-causing DNA changes occur in genes, but DNA changes outside of genes can also drive cancer growth. Because whole genome and whole exome tests have not been directly compared, it is not clear if one type of test is more beneficial to patients.

In addition, a quantitative mRNA expression test can also gather information about what treatments may work best for you. For example, one quantitative mRNA test commonly used for cancer care analyzes 21 different genes that can cause breast cancer and predicts whether a patient with breast cancer is likely to benefit from chemotherapy treatment.

What do the results of a tumor DNA sequencing test mean?

Multigene panel tests clearly indicate whether you have a genetic alteration in your tumor that can be targeted by an existing therapy. Because broad tumor DNA sequencing tests analyze more regions of DNA, they may be more difficult to interpret. For example, they may identify genetic alterations that do not cause cancer (benign) or whose effects are not known (of unknown significance). Alterations that are benign or of unknown significance do not aid patient care.

Tumor DNA sequencing tests may also uncover the presence of inherited alterations that increase cancer risk (hereditary cancer syndromes) or that are associated with diseases or conditions other than cancer. These are known as incidental, or secondary, findings. Finding that you carry an inherited genetic alteration may have implications not only for you, but also for your close blood relatives. For this reason, it is important to consult a genetic counselor to help interpret the results of DNA sequencing tests.

What are the limitations of tumor DNA sequencing tests?

Genetic tests do not benefit every patient. For example, they might not identify the DNA alteration that is driving the growth of your tumor. Or they might find such an alteration but it cannot be targeted by existing therapies. And even if you have an alteration that can be targeted by an existing therapy, other unique aspects of your biology (such as how your body breaks down a drug) can influence how you actually respond to the therapy.

Another limitation is that tumors are composed of cancer cells with varied, or heterogeneous, genetic alterations. Therefore, a small sample of cancer cells obtained from a biopsy may not accurately represent a heterogeneous tumor. This could mean that DNA sequencing tests may identify a potential treatment that can act against some, but not all, of your cancer cells. Cancer cells that are not targeted by the treatment have the potential to continue growing, causing the tumor to come back.

In addition, the genetic alterations in a tumor can change over time, but a sequencing test only captures a “snapshot” of the alterations present at one point in time. This means that the results of a sequencing test obtained one year ago may not accurately reflect the genetic alterations present in your cancer cells at this moment.