Largest genetic study to date uncovers DNA profiles that lead to cancer

Cancers are like malevolent snowflakes. Each harbors a unique set of mutations in their genes, gradually turning them to the dark side. Eventually, without regard for their neighbors, the mutated cells destroy tissues, organs and life.

But their set of genetic mutations – a signature – may also be their downfall. Like fingerprints or DNA left at a crime scene, we can use these signatures to hunt down cancer cells, nailing the culprits with drugs while leaving innocent, healthy cells alone.

The key is a database documenting these signatures. Fingerprints are useless if there is nothing to compare them to. Researching family trees would not be possible without open source genealogy sites. Similarly, to hunt biological terrorists like cancer, we need a whole registry of genetic mutation culprits as a benchmark.

We just received it. In a massive study covering more than 12,000 tumours, a team from the UK mapped the genetic changes that lead normal cells to develop into cancer cells. A treasure trove, the dataset captured unique genetic “fingerprints” of common types of cancer, but also of rare individual mutations that reflect a person’s history.

The study and its resulting catalog is the largest of its kind. By comparing the new mutation atlas to previous studies, the team found 58 new ones, which informed them of potential genetic changes and lifestyle factors that lead to cancer. They then developed an algorithm to match mutational signatures from the database to new tissue samples, creating a comprehensive crime scene investigation system for cancer screening.

“The reason it’s important to identify mutational signatures is that they’re like fingerprints at a crime scene – they help identify the culprits of cancer,” said the study’s lead author, Dr Serena Nik-Zainal from the University of Cambridge. “Certain mutational signatures have clinical or therapeutic implications – they may highlight abnormalities that can be targeted by specific drugs or may indicate a potential ‘Achilles heel’ in individual cancers.”

Turning

We have about 30 billion cells in our body. With age, the genome of each cell slowly changes its DNA letters.

“Right now, every cell in my body is accumulating mutations, so if they live long enough, it will be inevitable that they will eventually develop into a tumor,” Nik-Zainal said. “Having said that, let’s remember that a human being is made up of 30 billion cells, all accumulating mutations, and only one of them will trigger cancer throughout my life. This is amazing.”

So why do some normal cells deteriorate?

We have known for decades that DNA copy changes can activate oncogenic or pro-cancer genes, while blocking genes that normally protect against this process. Cancer cells also divide more often than normal cells. These discoveries have led to powerful treatments, including chemotherapy and immunotherapies.

But these ideas are relatively crude, like painting the genomic landscape of cancer with a broad brushstroke; little individuality seeps through. And with cancer, the uniqueness of the host and the pattern of genetic mutations are important.

Enter mutational signatures.

Here, the focus is on the changes in the precise DNA lettering when a cell becomes cancerous. Different types of cancer have distinct mutations while sharing some commonalities. These signatures capture both the habits of the host – for example, if they smoke – and the cancer itself, such as its inability to repair damaged DNA.

In other words, a mutational signature captures a specific pattern of DNA letter changes and repairs into a highly personalized fingerprint of a person’s cancer. As with actual fingerprints, there are similarities between different people and cancers. The study followed a clever route: First, they looked for common signatures in cancers from different organs and people. They then cross-examined the signatures between the organs, ultimately identifying 120 key mutational signatures common to all cancers in the study.

The process is like taking photos of different faces, but eventually mixing them together to find commonalities in features, while highlighting the differences.

The team lucked out with a huge asset: Genomics England’s 100,000 Genomes Project, which sequenced the entire genome of tens of thousands of people. It “has a greater number of whole-genome sequences than previous major cancer sequencing projects combined,” said Dr Dávid Szüts from the Center for Natural Science Research in Budapest, who was not involved in the study. . “Because the mechanism behind many signatures is still unknown, the study … also provides fertile ground for further investigation.”

A rainbow of mutations

In total, the team looked for single or double DNA letter changes in 12,222 cancer samples. The resulting dataset was a beast to kill. To fish out mutational signatures, they developed a computational method that analyzes common mutations from rarer ones. To verify integrity, the team validated their findings by comparing their data from two open-source databases, each containing around 3,000 cancer samples.

[We looked at] “Thousands and thousands of mutations, and that gives us a lot of power to be able to look at patterns across patient samples,” Nik-Zainal said.

For each organ, the team found only 5 to 10 common signatures, suggesting a common thread in cancers that could be co-opted for better treatment. By matching signatures between organs, they found 58 new fingerprints, which were compared to a previous global attempt to document cancer mutations. Some were common to all patients; others more unique, teasing the “snowflake” character of Cancers.

With additional detective work, they searched for potential causes of the mutation signatures. Some culprits were already well known: nip-tucks that compromise DNA’s ability to repair itself after a break.

Others revealed more enigmatic damage. A signature for brain tumors, for example, was strikingly similar to samples blasted with UV light. Platinum exposure was correlated with several types of cancers, including ovarian, stomach, and breast cancers. Another signature, dubbed SBS4 (yes, they don’t have the catchiest names) is strongly associated with tobacco use, but with a surprising correspondence to breast and colon cancer – potentially, a target for the development of drugs to kill several birds with one stone.

Similar to colors, mutational signatures can be combined into a spectrum, a rainbow of different mutation profiles. If that sounds complex, it’s because cancer is extremely complex. Different signatures can help us deconstruct a complex and cancerous genetic recipe so that we can understand it and thus know how to control it.

After that ?

Fingerprinting cancer genomes isn’t exactly eye-catching, but the database could power the next generation of cancer treatments.

The amount of information is staggering – even the authors admitted to abandoning further analyses. Instead, they developed and published an algorithm that fits the new genetic cancer data to the dataset. Dubbed FitMS, or Signature Fit Multi-Step, the software takes the same approach as the study: first fitting signatures to common signatures, then expanding the scope to identify other rare signatures.

The tool is available free of charge so doctors can match a new tissue sample to the database. This “signature fitting” process can, in theory, diagnose and tailor the patient’s cancer treatment to their particular set of mutations.

“This study shows how powerful whole genome sequencing tests can be in giving clues about how the cancer may have developed, how it behaved, and which treatment options would work best,” said Michelle Mitchell of Cancer Research UK.

Image Credit: Zita / Shutterstock.com

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