Cancer Diagnosis in a Drop of Blood

A new technique could allow clinical laboratories to detect cancer from even the smallest of samples

Cancer remains a leading cause of death worldwide, due, in large part, to our inability to detect cancer at an early stage of the disease when treatment by surgery, radiotherapy and chemotherapy is most effective. In contrast, treatment of late-stage cancers, which have spread beyond their original site, is much more problematic. Five-year colorectal cancer survival rates, for example, are about 90% for stage I disease, but less than 10% for stage IV disease.

Unfortunately, current cancer diagnostics are poor, and it is all too common for a cancer to grow undetected and remain undiagnosed until it has invaded surrounding tissues or even metastasized to distant organs. Current cancer detection methods vary for different cancers, but none are ideal and almost all are expensive, invasive, unpleasant, inaccurate and often have low patient uptake. This can be illustrated by looking at detection of the top five cancers by mortality:

  • lung cancer is detected by X-ray or low dose computed tomography
  • colorectal cancer by colonoscopy or fecal tests
  • breast cancer by mammography
  • prostate cancer by digital rectal examination or by a blood test for prostate specific antigen (PSA)
  • there is no effective current method for detection of pancreatic cancer.

The only blood test here is the PSA test, which, although not highly accurate for prostate cancer, is commonly used simply because it is the best test available and is low cost and easy to use both for the patient and for the clinician.

There is a huge unmet medical need-and potentially a huge market-for accurate, low cost, patient-friendly blood tests for cancer detection. For these reasons, many academics and companies are trying to develop solutions to this problem. Blood tests for traditional protein cancer biomarkers such as PSA, CEA, CA125 and AFP have been in common use for more than 30 years-more for the monitoring of cancer treatment than for detection-and no genuinely useful new markers have been identified in decades, even using mass spectrophotometry proteomics methods. Despite this, some workers continue in the quest for simple circulating protein cancer biomarkers.

Another area of development is the detection of circulating tumor cells (CTCs) in patients’ blood samples. This involves the isolation of tumor cells shed from a cancer into blood circulation to show the presence of a cancer. However, these methods are technically difficult and are more likely to detect metastasizing cancers than early stage cancers.

At a fundamental level, cancer is a disease of genetic and epigenetic misregulation. For this reason, I personally believe that the best hope for successful blood-based cancer detection methods also lies in genetic or epigenetic blood tests, and it is on these that I shall devote the rest of this article.

Many researchers are involved in the development of genetic cancer blood tests involving the sequencing of circulating tumor DNA (ctDNA), including a large corporate endeavor called GRAIL.1

To understand ctDNA, one must understand basic chromosome structure. Chromosomes are made up of a long chain of nucleosomes – a bit like starch is made of long chains of glucose molecules. Each nucleosome is a ball of histone proteins and the DNA in a chromosome is wound around successive nucleosomes like beads on a string. When a cell dies the chromosomes are cut up into individual nucleosomes, each containing about 160 base pairs of DNA, and some of these are shed into the blood. ctDNA is contained in nucleosomes, shed into the blood from dead cancer cells. The nucleosome-associated DNA fragments can be sequenced to search for cancer-associated mutations that indicate the presence of cancer.

One of the most commonly mutated genes in cancer is the p53 gene, which is mutated in about 43% of colorectal cancers, 39% of lung cancers, 33% of pancreatic cancers, 25% of breast cancers and 18% of prostate cancers.2 Thus, detection of any single genetic mutation will fail to detect the majority of cancers.

All cancers do contain mutations, however, so detection of multiple mutations rather than any single mutation will lead to increasing sensitivity for cancer detection. A ctDNA test developed at Stanford University for lung cancer involving ctDNA analysis for 534 cancer mutations in 139 different genes was able to detect 85% of lung cancers with 96% specificity.3

Another area of research is the detection of DNA sequences that are chemically altered-or methylated-in cancer. A good example is the Epi proColon test for colorectal cancer by detection of methylated SEPTIN-9, which detects 68% of cancers with 78% specificity. The main challenges with ctDNA sequencing and methylated sequencing methods for cancer detection lie in the large amount of blood required (5-10ml) and the degree of technical complexity and cost involved, but this may lessen with future advances in DNA sequencing technology. The large amount of blood required makes the test unable to be added to an annual blood draw so there must be a separate draw, which can be inconvenient for patients. Regarding cost, GRAIL hopes to be able to reduce the cost of such tests to $1,000.1

The structure of nucleosomes in cancer cells as part of a chromosome chain is quite different than that of nucleosomes in healthy cells. The chromosomes of cancer cells contain altered combinations of histone proteins, chemically modified histone proteins, chemically modified DNA and different proteins attached to the chromosomes (i.e. the estrogen or androgen receptors). All of these can be detected in nucleosomes circulating in the blood.

A new test captures, identifies and measures these altered nucleosomes as indicators of the presence of cancer, stage of cancer and the type of cancer. The advantages are many: first, nucleosome changes occur very early in cancer disease progression andthis method can detect early stage I cancers and even pre-cancers to facilitate removal of a nodule, lump or polyp before cancer develops at all. Second, the technology requires only a drop of blood so the tests can be done as part of a routine health check. Third, this is done by utilizing ELISA (Enzyme Linked Immunosorbent Assay), which is low cost, robust and can perform thousands of tests per day. The goal of this technique is that it will revolutionize cancer outcomes for patients by making early cancer detection as simple as a cholesterol test.


  1. Illumina’s bid to beat cancer with DNA tests. Antonio Regalado. MIT Technology Review. Jan 10 2016.
  2. TP53 Mutations in Human Cancers: Origins, Consequences, and Clinical Use. Magali Olivier, Monica Hollstein, and Pierre Hainaut. Cold Spring Harb Perspect Biol 2010;2:a001008.
  3. Sensitive dectection of colorectal cancer in peripheral blood by septin 9 DNA methylation assay. R. Grützmann and e. al., PLoS One, vol. 3, no. 11, p. e3759, 2008.

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