Myotonic dystrophy type 1 (DM1), an inherited disease affecting muscles, was one of the first described “expanding repeat” disorders. In these 50…
New Urine DNA Test Can Predict Bladder Cancer a Dozen Years Before Symptoms
A urine test for DNA pieces bearing 10 key mutations can indicate early inklings of bladder cancer, according to a report at the European Association of Urology meeting in Milan last month. Urothelial carcinoma is the most common type of bladder cancer, according to the National Cancer Institute.
The technique is called urinary comprehensive genomic profiling (uCGP). It copies telltale DNA sequences in urine, using a tool called “UroAmp,” developed at Convergent Genomics. Like other cancers tests, it is being pioneered on people who already have the cancer to detect recurrence or response to treatment. If validated on many patients, the test might then be used for screening – that is, as part of the initial diagnostic process.
Lead researcher Dr. Florence Le Calvez-Kelm, from the International Agency for Research on Cancer in Lyon, said at the meeting, “Diagnosis of bladder cancer relies on expensive and invasive procedures such as cystoscopy, which involves inserting a camera into the bladder. Having a simpler urine test that could accurately diagnose and even predict the likelihood of cancer years in advance could help to spot more cancers at an early stage and avoid unnecessary cystoscopies in healthy patients.”
I thought it might be helpful to explain the role of mutations in cancer.
What’s DNA Got To Do With It?
All cancers are genetic. That is, mutations hamper such functions as cell division rate, control of cell death, and DNA repair.
The two types of cancer genes are oncogenes – which cause cancer when revved up – and tumor suppressors – which cause cancer when deleted. For example, an oncogene might normally control the rate of cell division, but a mutation lifts control of the rate. In contrast, a tumor suppressor gene might normally turn off cell division, and its removal lifts that control. In either case, cells divide and pile up into a solid tumor, expand a lining, or overwhelm the bloodstream.
Exposure to carcinogens, like nicotine or asbestos, can trigger these mutations. That’s why some cancers are considered “environmental,” but it is the change in DNA sequence that lifts control of cell division.
But people who avoid carcinogens still get cancer, from natural errors in DNA replication that insert the “wrong” base as a gene is copied. Like typos, these errors alter the protein that an oncogene or tumor suppressor gene encodes. More mutations happen, unfolding in certain sequences like an increasingly complex choreography of cancer.
All cancers are genetic, but only 5 to 10 percent are also inherited. In inherited cases, a person gets one mutation from the sperm or egg, copied in every cell. Then, when a second mutation occurs in the same gene, cancer starts – the site set by the cell type and place – such as lung, colon, skin, anywhere. Cancer, therefore, is a consequence of both mutation and location, which I wrote about in The Lancet.
In the other 90 to 95 percent of cancers, the two mutations arise in the same body cell – not in a sperm or egg. If that’s in a breast, it’s breast cancer; in the liver, then liver cancer. These much more common cancers are termed somatic, because the mutations happen in somatic, or body, cells. The inherited cancers are called germinal, because they start in a germ cell (sperm or egg). The necessity of two mutations was described in 1971 as the two-hit hypothesis of cancer by Alfred Knudson as part of the description of the first tumor suppressor gene mutation, behind the eye cancer retinoblastoma.
The distinction between somatic and germinal cancer has important implications for relatives of patients. The BRCA cancers, caused by mutations in tumor suppressor genes, provide a good example. Relatives of people with BRCA cancers face a highly elevated risk of developing the associated cancers themselves, because inheriting the first mutation is halfway to cancer, and they have a much higher risk of that than the general population. But relatives of patients with somatic (also called sporadic) cancers do not face higher risk than anyone else. I had 100+ genes tested for my breast cancer and none indicated inherited mutations.
Finding Cancer Clues in Stool, Spit, and Blood
Traditionally scans and biopsies have been the standard trajectory for cancer diagnosis. Biopsies can be extremely distressful and painful. I’d prefer to have had a body fluid tested than my breast harpooned, and I’m sure people having a scope pushed into the bladder feel the same way.
That’s where fluids and waste come into the diagnostic picture.
Stool tests, some DIY at-home, have been available to screen for mutations indicating possible colorectal cancer for years. They check for hemoglobin, indicating bleeding, as well. Different tests for hereditary colorectal cancers are available from physicians. Colorectal cancer begins and progresses with a specific sequence of mutations.
Blood also holds clues to cancer in the form of mutations identified in snippets of DNA called circulating tumor DNA (ctDNA). This type of “liquid biopsy” is useful when tissue is difficult to obtain or not enough cells are sampled, or when cancer has spread and the initial site is unknown.
Blood liquid biopsies have been used for years to detect cancer recurrence and to track response to treatment. If a blood sample taken soon after cancer surgery does not have ctDNA, but two years later a new sample does, then the cancer may be back, perhaps with new mutations. Similarly, if a drug is working, the level of ctDNA will decrease over time, but if cancer cells have mutated in a way that makes them resistant to a drug, ctDNA increases.
CtDNA is also collected from sputum to detect specific mutations that cause lung cancer. One company personalizes spit tests to detect recurrence of lung cancer to the patient’s individual mutations.
Eventually, liquid biopsies will likely be used to screen high-risk populations. These include people with family histories of a particular cancer or those with environmental exposures, such as smokers and the residents of East Palestine, Ohio, where carcinogens billowed into the air following a train derailment on February 3.
Liquid biopsies may one day be useful on anyone, even people without symptoms or risk factors. Detecting ctDNA in a healthy person can suggest follow-up tests to look for very early cancer. Ovarian cancer provides a good example. It sometimes isn’t diagnosed until a late stage because the symptoms – bloating and fatigue – are vague and common, and may be attributed to a change in diet or exercise routine.
The down side is that too-liberal use of liquid biopsy could lead to false positives – finding an oncogene or tumor suppressor variant that doesn’t cause cancer in everyone, due to effects of other genes. Clinical trials on thousands of healthy people at low or average risk of cancer are underway to assess the technology’s predictive value.
Sometimes tumor DNA turns up in the blood of a healthy pregnant woman having a prenatal test, and she finds out she has cancer!
Urine Liquid Biopsy for Bladder Cancer
To develop the predictive urine test for bladder cancer described at the recent meeting, the researchers identified mutations in 60 genes that are associated with bladder cancer, then boiled them down to 10 key genes that indicate the cancer – in patients without symptoms.
The team tested urine samples from more than 50,000 healthy people being followed at the Tehran University of Medical Sciences (the Golestan Cohort Study); all had provided samples at the outset. Over a decade, 40 people developed bladder cancer. The report considered 29 of them, plus samples from 98 other similar participants as controls.
Of the 29 people, the test predicted the cancer in 19 – that’s 66% – even from samples taken up to a dozen years before clinical diagnosis. Of 14 people diagnosed within seven years of providing urine samples, the test predicted cancer in 12 (86%) of them. Plus, the test was negative in 94 of the 98 participants (96%) who didn’t develop cancer. The test also yielded encouraging results in patients from Massachusetts General Hospital and Ohio State University, leading to new diagnoses and detecting recurrence.
“We’ve clearly identified which are the most important acquired genetic mutations that can significantly increase the risk of cancer developing within ten years. Our results were consistent across two very different groups – those with known risk factors undergoing cystoscopy and individuals who were assumed to be healthy,” summed up Dr. Le Calvez-Kelm. If the findings are repeated in many more patients, she foresees routine screening for high-risk groups, such as smokers or those exposed to known bladder carcinogens at work.
“This kind of test could also be used when patients come to their doctors with blood in the urine, to help reduce unnecessary cystoscopies. If we can identify bladder cancer early on, before the disease has advanced, then we can save more lives,” she added.