Genomic Data Offers Insight into Colon Cancer, Alzheimer’s Disease

For organizations that want to deepen their knowledge of disease risk and health outcomes, genomic data has emerged as a comprehensive resource that can provide clinicians with new insights.

While the healthcare industry is working to bring this information into routine clinical care, health systems still have to find ways of managing these massive datasets, interpreting genomic test results, and leveraging this data to make more informed decisions.

In two new studies conducted by researchers at Mayo Clinic, the institution demonstrated the critical role of this information in disease research, as well as the value of integrating genomics with everyday care delivery.

In an analysis published in Clinical Gastroenterology and Hepatology, a team from the Mayo Clinic Center for Individualized Medicine found that one in six patients with colorectal cancer had an inherited cancer-related gene mutation that likely predisposed them to the disease.

Researchers also found that 60 percent of these cases would have gone undetected if they relied on a standard guideline-based approach.

"We found that 15.5 percent of the 361 patients with colorectal cancer had an inherited mutation in a gene associated with the development of their cancer," said Niloy Jewel Samadder, MD, a Mayo Clinic gastroenterologist and hepatologist, who is the study's senior author.

"We also found that over one in ten of these patients had modifications in their medical or surgical therapy based on the genetic findings."

Researchers tested the patients using a sequencing panel that included more than 80 cancer-causing or predisposing genes. In comparison, standard panels for colorectal cancer include only 20 or fewer genes.

The study highlights the benefits of using universal testing approaches and broader gene panels to uncover hidden inherited genetic mutations. These methods could lead to opportunities for cancer management in families, as well as targeted cancer therapies.

"Colorectal cancer screening is an important modality to prevent this deadly disease and many resultant unnecessary deaths," Samadder said. "Screening can be performed with a colonoscopy, stool tests or even specialized CT scans."

While many mutations that cause colon cancer happen by chance in a single cell – from environmental factors, diet, smoking and alcohol use – the study confirmed that many are inherited mutations that set off a cycle of events that can lead to cancer.

"Though the most common mutations were found in genes typically associated with colorectal cancer, we found that a substantial number of mutations were present in genes typically associated with breast and ovarian cancer," said Samadder.

"This may lead to novel targeted therapies based on the cancer's unique genetic basis. For example, where a breast cancer drug can be used in a patient with colon cancer."

Genomic data analyses can also allow patients to share the heritable cause of their disease with their blood relatives, leading to earlier disease detection and management.

"The power of genetics is that we can foresee the cancer that will develop in other family members," Samadder said. "This can allow us to target cancer screening to those high-risk individuals and hopefully prevent cancer altogether in the next generation of the family."

The researchers are currently aiming to incorporate the study results into the care of patients with cancer at Mayo Clinic.

"Steps are being taken to ensure all patients are offered genomic sequencing to better understand the genes that led to the development of their cancer, and how to precisely target treatment and improve survival," Samadder said.

In a separate study published in Nature Communications, Mayo Clinic researchers combined clinical expertise, brain tissue samples, and machine learning to clarify and validate the relevance of the SERPINA5 protein-coding gene to Alzheimer’s disease.

Using brain tissue samples from brains donated to the Mayo Clinic Brain Bank, the team classified the pattern of protein tangles associated with Alzheimer’s. Researchers then used digital pathology and RNA sequencing to identify gene expression in the samples, effectively measuring gene changes responsible for instructing proteins.

"We were able to look at an entire disease spectrum and find gene changes that may really influence the hippocampus, the brain's memory center," said Melissa Murray, PhD, a Mayo Clinic translational neuropathologist and lead author on the paper.

"That means we may have targets that indicate why some people have relative preservation and some people have relative exacerbation of memory loss symptoms."

The group used a machine learning algorithm to narrow the genes of interest from about 50,000 to five. SERPINA5, the top candidate, was found to be strongly associated with tau tangle progression in the hippocampus and cortex of the samples.

Researchers plan to explore how SERPINA5 interacts with tau protein to develop an inhibitor.

"Much of the focus of therapeutics is on abnormal proteins ― amyloid and tau ― used to biologically define Alzheimer's disease," said Murray. "But we hope to take a step back to look at a new interacting partner that may be actually accelerating tau or pushing tau accumulation past the tipping point."

The findings could help provide a deeper level of understanding to advance results to clinical trials faster.

“While we have direct evidence of SERPINA5 in the context of Alzheimer's disease, SERPINA3 in this same family of genes has also been looked at in Alzheimer's, and SERPINA1 in ALS. So I think it's about collective awareness and paying attention to this group of proteins," Murray stated.