Harvard Researchers Discover Some Cancers May Originate Decades Earlier Than Previously Believed

Some cancers may originate from a harmful mutation several decades before a diagnosis is made, with the cancerous cells multiplying in number over the years without the patient’s knowledge, a new study published this month by Harvard researchers suggests.

Researchers at Harvard University, Boston Children’s Hospital, Dana-Farber Cancer Institute, Massachusetts General Hospital, and the European Bioinformatics Institute studied the development of myeloproliferative neoplasms, or MPNs, a type of blood cancer or leukemia caused by a single change in a DNA nucleotide, one of the building blocks of DNA.

The peer-reviewed study — published March 4 in Cell Stem Cell — suggests that cancer development is more gradual than scientists had expected. Utilizing cutting-edge techniques, the researchers calculated that the MPN mutation first occurred at around age nine in a 34-year-old cancer patient and age 19 in a 63-year-old patient. Thus, what doctors had previously believed to be adult leukemia was, in fact, childhood cancer.

Sahand Hormoz, the corresponding author of the paper and an assistant professor of Systems Biology at Harvard Medical School, said traditional diagnostic techniques for cancer do not detect these mutations early enough.

“For the first 10, 15 years, the number of cancer cells [are] very small, on the order of 10 to 100 cells out of 100,000 stem cells,” Hormoz said. “Certainly, none of our routine diagnostic tests would have picked that up.”

Doctors typically do not administer most diagnostic tests for cancer until symptoms, such as fatigue or pain, develop. Mammograms, pap smears, and colonoscopies in routine checkups may find cancer before an individual begins to feel ill, but at that point, the cancer may have been developing for years, according to Hormoz.

“For a while now, the scientific community has qualitatively understood that certain cancers could form in the human body long before the cancer manifests itself as a tangible disease, potentially years in advance,” Maximilian Nguyen, a graduate student at Princeton and a member of the research team, wrote in an emailed statement. “But up until now, we have not had access to the technology and methods that could put an actual number on it.”

Using a new technique, the team of researchers traced the lineage history of cancerous cells, much like comparing related species, such as humans and chimpanzees, to find a common ancestor. Coupled with information regarding the cancer’s replication rate, the scientists determined the age at which the mutation manifested.

Tracing the cells’ history required amplifying enough DNA in a culture outside of the body to be able to study. The team used a slow procedure favored for its accuracy to promote a single cancerous cell to exponentially divide, producing many genetically identical cells. It took “closer to three months” for Hormoz and his team to amplify enough DNA to study, he said. Bulk sequencing was then performed to read and analyze the DNA.

Hormoz noted that these are “not cheap procedures.” Twenty years ago, whole-genome sequencing cost around $1 billion per cell. Though this price “has come down significantly,” sequencing the genome of one cell remains a costly $1,000, he said.

Ann Mullally, another member of the research team and a physician-scientist at Dana-Farber Cancer Institute and Brigham and Women’s Hospital, stressed the importance of better understanding MPN and other cancers before focusing on intervention and diagnostic techniques.

“There are people who will develop this mutation, but will not go on to develop the disease,” Mullally said. “Right now, we don’t really have a good way to understand, or we don’t really know, what are the predictors.” Therefore, “before we start doing widespread testing on people” and “labeling them with potential diagnoses, we need to have a good understanding of what we're going to do with that information.”

The study's authors also addressed the impact their work may have on cancer research and health care.

“We now have the means to follow the evolution of the cancer in patients at the level of the precision of individual cells, which I think will lead to new biology down the road,” Nguyen wrote. “Clinically, I think it potentially impacts physicians by more clearly outlining the time window they have to provide early detection, prevention, and intervention for their patients.”

Hormoz said the study opens the door to future research that could develop early intervention techniques for cancer.

“[The study] raises the possibility that you can go and intervene and treat these patients before you ever have overt cancer,” he said. “That’s where the ultimate dream is.”