Revolutionary DNA Method Could Save Thousands from Ineffective Cancer Treatments

CAMBRIDGE, England — Cancer patients across the country could soon benefit from a game-changing breakthrough in how doctors identify who will respond to immunotherapy. Researchers have discovered a new way to read cancer’s genetic fingerprints that reveals crucial details conventional methods miss.

This discovery could save countless lives by helping doctors match patients with the treatments most likely to work for them, while sparing others from unnecessary side effects.

Researchers at the University of Cambridge have developed a refined method for categorizing small DNA mutations in cancer that provides deeper insights into the molecular processes driving cancer development. Their findings, published in Nature Genetics, reveal that by simply changing how these mutations are classified, scientists can uncover previously hidden patterns that better distinguish different types of cancer.

Most people don’t realize that cancer isn’t just one disease but hundreds of different conditions with unique genetic traits. When your cells copy their DNA during division, errors sometimes occur. Normally, your body has mechanisms to fix these mistakes, but when those repair systems break down, cancer can develop.

These broken repair systems leave distinctive patterns of DNA damage, like genetic fingerprints that can help doctors choose the right treatments. But until now, we’ve been missing important clues.

Reading Between the Genetic Lines

The Cambridge researchers discovered the current system for classifying small DNA mutations was like trying to identify someone by their height alone, rather than looking at their entire appearance. Their improved method incorporates more details about the surrounding genetic sequences – like considering someone’s facial features, hair color, and clothing instead of just how tall they are.

To test their theory, the team first created lab cells with specific genetic defects that mimic cancer. They allowed these cells to grow and accumulate mutations for about 45-50 days, then sequenced their DNA to see what patterns emerged.

With the traditional classification method, different mutation patterns appeared about 89% similar to each other – making them nearly impossible to distinguish. But with the new method, that similarity dropped to just 68%, making the differences much clearer.

The paper notes that the previous classification system “was unable to discriminate these InDel signatures from background mutagenesis and from each other,” highlighting how the new approach solves a fundamental problem in cancer genetics.

Uncovering Hidden Cancer Signatures

When the team applied their improved classification system to tumor samples from seven cancer types in the 100,000 Genomes Project, they discovered 37 unique mutation patterns, called “signatures.” Remarkably, 27 of these had never been seen before.

Some signatures reveal damage from environmental factors like tobacco smoke or ultraviolet radiation, while others show internal cellular defects in DNA repair mechanisms.

The team created a new diagnostic tool called PRRDetect that can analyze a tumor’s genetic information and determine if it has specific DNA repair deficiencies that make it more likely to respond to immunotherapy drugs. When tested, PRRDetect demonstrated extraordinary accuracy, outperforming existing diagnostic methods by correctly identifying cases that current tests miss.

Why This Matters for Patients

Currently, many patients receive immunotherapy based on a measure called “tumor mutation burden” (TMB) – essentially a count of the total mutations in a tumor. High TMB is thought to predict which patients will respond to immunotherapy. However, this Cambridge study reveals a serious problem with this approach.

The researchers found that only about 10% of patients with high TMB actually had the specific repair deficiencies that respond best to immunotherapy. This means many patients are receiving treatments unlikely to help them, while experiencing potentially severe side effects.

Even more concerning, current diagnostic methods miss many patients who could benefit. The study found that roughly half of all tumors with repair deficiencies lacked the genetic markers typically used to identify them.

As the paper states, “If PRRDetect predictions were all true and sequencing approaches focused exclusively on identifying driver events associated with these deficiencies were used, a significant proportion of cases (66%) could be missed.”

This explains why some cancer patients respond unexpectedly well to immunotherapy while others with seemingly similar cancers see no benefit – their cancers appear the same using current classification systems but have fundamentally different mechanisms driving them.

Beyond Colorectal Cancer

While certain repair deficiencies are well-known in colorectal and uterine cancers, the researchers found them in other cancer types too. Their tool identified these deficiencies in a small but significant number of stomach, bladder, brain, and lung cancers.

This suggests that repair deficiencies aren’t limited to the cancer types where doctors typically look for them. Patients with various cancer types might benefit from immunotherapy if we can accurately identify these genetic patterns.

“Genomic sequencing is now far faster and cheaper than ever before. We are getting closer to the point where getting your tumour sequenced will be as routine as a scan or blood test,” says lead researcher Serena Nik-Zainal, a professor of genomic medicine and bioinformatics at Cambridge, in a statement “To use genomics most effectively in the clinic, we need tools which give us meaningful information about how a person’s tumour might respond to treatment. This is especially important in cancers where survival is poorer, like lung cancer and brain tumors.”

The breakthrough demonstrates how changing the way we classify genetic information can transform cancer care. By looking at the same data differently, doctors can make more informed treatment decisions tailored to each patient’s unique cancer.

“Cancers with faulty DNA repair are more likely to be treated successfully,” adds Nik-Zainal. “PRRDetect helps us better identify those cancers and, as we sequence more and more cancers routinely in the clinic, it could ultimately help doctors better tailor treatments to individual patients.”