HNSSC tumor

Research on rare genetic diseases sheds light on common head and neck cancer

Cross section of an HNSSC tumor from a Fanconi anemia patient.

Like the New York City subway system, the DNA in our cells needs to run around the clock and needs to be constantly repaired. In any cell, at any time, molecular processes are underway to close cracks in the double helix or reread the genetic code; it’s all part of an ongoing maintenance program that maintains the current state of the body and prevents disease.

Patients with Fanconi anemia, a rare genetic disorder, lack certain elements of this repair system, making their cells unable to heal lesions created by DNA-damaging chemicals called aldehydes. And for reasons that were unclear until now, their risk of developing highly aggressive head and neck tumors is hundreds of times greater than other people’s.

Now, Rockefeller physician-scientist-led research Agata Smogorzewska It explains why patients with Fanconi anemia are vulnerable to this cancer, known as head and neck squamous cell carcinoma (HNSCC), and leads the development of new treatments. Posted in natureThe findings also shed new light on the mechanisms by which smoking and drinking can increase anyone’s risk of cancer, and suggest that people in this category may benefit from similar therapeutic approaches.

Gene duplication chaos

People born with Fanconi anemia may suffer from numerous medical problems, including bone marrow failure, congenital malformations, and an increased risk of certain cancers, including HNSCC with highly metastatic tumors that arise in the mucous membranes of the mouth, nose, throat, or esophagus. There is a strong need for new cancer treatment approaches for this subset of patients who cannot withstand standard chemotherapy due to their inability to repair DNA.

To understand how Fanconi anemia may trigger the development of these tumors, Smogorzewska’s Genome Maintenance Laboratory analyzed HNSCC tumor tissues isolated from more than 50 Fanconi anemia patients and compared them to HNSCC tumors sampled from the general population. After sequencing the tumor genomes, they found that Fanconi anemia tumor cells often have genes that are in too many or too few copies.

This phenomenon, known as copy number variation, was previously detected in HNSCC tumors from people without the genetic condition. Still, the difference between the two groups was significant: Patients with Fanconi anemia had much greater copy number variation in their tumors than individuals without the disease.

Smogorzewska says these findings may explain why HNSCCs of Fanconi anemia patients tend to be particularly fatal, with patients surviving an average of just 17 months after diagnosis.

«You have complete genomic destruction that simultaneously disrupts many different systems that normally prevent our cells from developing into cancer,» he says. «We think this is one of the reasons for the aggressiveness of these tumors.» Smogorzewska adds that Fanconi anemia patients may need multifaceted interventions, and her team’s findings may point the way to certain drug combinations that may help. He and his collaborators are now testing such combination therapies using mouse models and patient-derived tumors growing in mice.

The research also suggests that the high copy number variations are due to structural rearrangements in the genomes of Fanconi anemia patients, which occur when cells are unable to properly repair aldehyde-damaged DNA during cell division. The scientists observed that these patients’ tumors often exhibited such structural variants, with stretches of DNA appearing in the wrong places or missing altogether.

The team also designed a mouse model that lacks one of the Fanconi anemia genes required for DNA repair of tumors. They found that these tumors had an increasing number of structural variants, confirming that the lack of DNA repair functions makes cells vulnerable to acquiring structural variants and consequent copy number changes.

While conducting these experiments, the team found a surprise: Tumors that were unable to repair DNA grew significantly. Careful analysis of tumor cells revealed that they are potentially more mobile, another clue to why cells from Fanconi anemia patients are more prone to metastasis from their source tissue. Smogorzewska believes that some of these features, which still need to be better understood, could be used in the development of new therapeutic approaches to treat cancer patients with Fanconi anemia.

Smoking and alcohol connection

Things got even more interesting when the researchers asked how the findings from Fanconi anemia could be used to understand sporadic cancers in the general population. They took genomic data on sporadic HNSCCs from the Cancer Genome Atlas (TCGA), a large public database, and showed that these tumors also have a number of structural variants in their genomes. There was also a correlation between smoking history and the number of structural variants: The more patients smoked, the more variants were detected in their tumors. Smogorzewska says the tumors with the highest numbers also have signs of high alcohol exposure.

“We propose that smoking and alcohol consumption partially lead to HNSCC tumors because they create more aldehyde-induced DNA damage than cells can repair,” he says. «As a result, cells from people without Fanconi anemia behave as if they have a DNA repair defect, causing the same spectrum of mutations.»

Smogorzewska also emphasizes that these studies cannot be done without collaboration with Fanconi anemia patients, their families, multiple doctors, and many researchers who collect, sequence and analyze the complex genomes of patients’ tumors. “Patient participation in research work, collaborations, and the support of many foundations have allowed us to make fundamental discoveries that are changing how we think about head and neck cancer and how we can prevent or treat it in the future,” he says.

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