SCIENCE NEWS | Research On Rare Genetic Disease Sheds Light On A Common Head And Neck Cancer

The DNA in our cells needs to operate around the clock—and it’s in constant need of repair.

In any given cell at any given time, molecular processes are underway to seal cracks in the double helix or proofread the genetic code, all part of a perpetual upkeep program that maintains the body’s status quo and prevents disease.


Patients with the rare genetic disorder Fanconi anemia lack certain elements of this repair system, making their cells incapable of removing lesions created by DNA-damaging chemicals, called aldehydes. And for reasons that have thus far been unclear, their risk for developing highly aggressive head-and-neck tumors is hundreds of times higher than that of other people.

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

Gene-copy chaos

People born with Fanconi anemia may suffer from numerous medical problems including bone marrow failure, congenital malformations, and an increased risk of some cancers including HNSCC, with highly metastatic tumors arising in the mucous membranes of the mouth, nose, throat, or esophagus.

To understand how Fanconi anemia might spur the development of these tumors, Smogorzewska’s Laboratory of Genome Maintenance analyzed HNSCC tumor tissues isolated from more than 50 Fanconi anemia patients and compared them with HNSCC tumors sampled from the general population. Upon sequencing the tumor genomes they found that Fanconi anemia tumor cells often had genes present 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. Yet the difference between the two groups was meaningful: Fanconi anemia patients had many more copy-number variations in their tumors than individuals without the disorder.

Smogorzewska says these findings might explain why Fanconi anemia patients’ HNSCCs tend to be particularly deadly, with patients surviving for only 17 months on average after they’ve been diagnosed. “You have complete genomic havoc, which simultaneously perturbs many different systems that normally keep our cells from developing into cancers,” she says. “We think that this is one of the reasons for the aggressiveness of these tumors.”

The researcher adds that Fanconi anemia patients might need multi-pronged interventions, and that her team’s findings might point the way to specific drug combinations that could be helpful. She and her collaborators are now testing such combination therapies using mouse models and patient-derived tumors grown in mice.

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