DNA Study Reveals the Personal Pathways Behind Different Tumors

Why do two individuals with the identical cancer diagnosis, the same cell type, the same stage, and the same clinical profile often experience very different outcomes? Scientists have been researching acquired mutations in cancer for decades in an effort to uncover solutions, but mutations only account for part of the problem.

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A new study published in Genome Medicine helps to address that question, revealing that each cancer is caused by a unique mix of hereditary and acquired disruptions across biological pathways.

Each cancer is as unique as the individual who suffers from it.

Lajos Pusztai, MD, DPhil, Study Senior Author and Professor, Medicine (Medical Oncology), Yale School of Medicine

He believes that the disparities among patients are driven by patient-specific disturbances that make each tumor biologically distinct, rather than by the fundamental set of pathways that all cancers share.

Developing a Score for Genetic Mutation Impact

In previous research, Pusztai’s study examined thousands of cancer patients and found a pattern: individuals who were born with higher genetic vulnerabilities in cancer-relevant genes were more likely to acquire cancer at a younger age. Those who had cancer later in life, however, experienced greater DNA damage throughout the course of their lives, but were born with fewer of those inherited vulnerabilities.

That negative association prompted his team to ask a deeper question: Could the total effect of inherited and acquired disruptions be quantified for each individual patient, and would it result in biologically diverse tumors?

To address this, the research team developed CanSys, an open-access platform that generates a tailored biological damage assessment for each disease.

According to Pusztai, CanSys asks two essential questions about each gene in a patient's genome: how destructive the mutation is, and how vital that gene is to keeping a cancer cell alive.

To answer the first question, the scientists employed a computational metric that provides a damage score to each conceivable DNA variation, estimating how severely it affects the protein encoded by the gene. For the second, they went to DepMap, a platform that has collected data on the effect of silencing specific genes on cancer cell survival across about 600 cancer cell lines.

Using these two measurements, Pusztai and his team generated a gene-level impact score for each gene in a patient’s tumor, which was then assigned to cancer-relevant biological pathways and aggregated to produce pathway disturbance scores. The researchers referred to the sum of these disturbances as the CanSys score.

The CanSys score measures the overall damage to a biological system, whereas the gene-level score indicates how poorly one single piece of the cell’s machinery is destroyed.

Researchers can upload their data, and it can show you that in this particular individual cancer, what pathways are affected.

Lajos Pusztai, MD, DPhil, Study Senior Author and Professor, Medicine (Medical Oncology), Yale School of Medicine

The tool is accessible for free at cansysplot.com.

Rethinking Cancer Risk

When the team applied CanSys to more than 9,000 tumor samples across 31 cancer types in the Cancer Genome Atlas, the largest cancer genomics database, they found that a substantial proportion of cancer patients carried inherited disruptions in DNA repair, cell cycle regulation, and telomere maintenance pathways. These are the biological processes that keep genetic errors in check and regulate how long cells survive.

However, when they did the same study on 2,504 healthy individuals (no cancer diagnosis) from another open tool, the 1000 Genomes Project, the same hereditary pathway vulnerabilities were found.

“Many of us are born with subtle pathway abnormalities. Each individual carries a different abnormality, but they converge at the pathway level,” Pusztai added.

The more inherited pathway disruptions a person has, the fewer DNA modifications are required before a cell turns cancerous, according to the study team.

“The more inherited impairment, the sooner people would actually develop cancer,” Pusztai noted.

For the time being, those with a high genetic risk should strictly adhere to cancer screening guidelines and limit their exposure to carcinogens.

Pusztai's team is currently attempting to gain access to the UK Biobank, a dataset of around 500,000 people, with the objective of developing a cancer risk score based on the overall number of hereditary pathway disruptions a person is born with. They intend to use artificial intelligence to discover gene connections that previous statistical approaches could not capture.

Why some individuals develop cancer is a mystery to so many people. I really hope that in the next 10 to 20 years we are able to solve that mystery.

Lajos Pusztai, MD, DPhil, Study Senior Author and Professor, Medicine (Medical Oncology), Yale School of Medicine