Written by: Maddi Langweil
Medically Reviewed By: Alan D’Andrea, MD
Alan D’Andrea, MD
Rare genetic cancers may affect few people, but their complexity makes them powerful windows into how even the most common cancers develop and behave.
Delving into understanding how DNA is damaged and repaired in rare genetic conditions is how physician-scientist Alan D’Andrea, MD, built a foundation of knowledge about Fanconi anemia (FA) – a rare genetic disease of the bone marrow that significantly increases the risk of certain cancers.
In people with rare genetic diseases, the body’s ability to repair damaged DNA is affected. Mutations – or changes – in one or more genes hinder a cell’s ability to control abnormal cell growth, allowing cancer cells to grow more rapidly.
“By understanding rare diseases, we can learn the fundamentals of oncogenesis, or how a normal cell turns into a cancer cell,” says D’Andrea, director of the Center for DNA Damage and Repair and the Susan F. Smith Center for Women’s Cancers at Dana-Farber.
The Maine start
Since joining Dana-Farber more than 35 years ago. D’Andrea and his team have made notable discoveries that advanced cancer care and research. One of these breakthroughs is understanding the relationship between FA and the tumor-suppressing BRCA gene, which mutates in a similar manner to DNA damage and repair.
In his more recent research on FA, a breakthrough discovery first emerged during a family retreat in Maine hosted by the Fanconi Cancer Foundation and The Painted Turtle, a foundation that supports children with medical needs through camp experiences and connects researchers and physicians with families affected by FA.
“Every year, I go to the family retreat in Maine and collect blood samples from children who have this disease and from their family members who volunteer to contribute to FA research,” explains D’Andrea. “While studying FA, my colleagues and I discovered an entire biological pathway – or a series of unique molecular interactions in a cell – in which these children had a mutation.”
In what is now called the Fanconi anemia/BRCA pathway, D’Andrea and his colleagues identified 23 genes and 23 encoding proteins that work together for DNA repair. Children with Fanconi anemia, however, are born with a mutation in one of these 23 genes, which causes physical and neurodevelopmental differences and an increased cancer risk.
This discovery has allowed D’Andrea and his team to identify a biological mechanism of DNA repair, which is fundamental in advancing scientific understanding about the connection between rare genetic diseases and cancer. One gene in the Fanconi pathway is the tumor-suppressing BRCA2 gene, the discovery of which has helped expand current understanding of breast, ovarian, prostate, pancreatic, and other cancers.
As one door opened in research with the identification of the biological mechanism related to DNA repair, D’Andrea and his colleagues soon found another to unlock.
From one breakthrough to another
Five years ago, D’Andrea and his team learned that when one of the Fanconi pathway proteins was isolated, it would bind to another protein – a phenomenon of which they had no prior knowledge.
“The protein was called CHAMP1,” D’Andrea says. “We suspected that it had something to do with DNA damage and repair because it was so tightly bound to the Fanconi proteins.”
The researchers then used CRISPR, a gene-editing technique, to remove CHAMP1 from the cells. This confirmed that the protein indeed plays a role in providing structural support for DNA during cell division and is essential for DNA repair. The team then learned that the mutation was also responsible for genetic diseases such as CHAMP1-related intellectual disability syndrome – a neurodevelopmental disorder that causes speech challenges and some developmental delays similar to those seen in children with FA.
D’Andrea also noticed that children with CHAMP1-related conditions had an intellectual disability and an increased risk of developing cancer – especially a type of blood cancer called leukemia. Additionally, many shared a diagnosis of autism.
This was “a striking discovery,” says D’Andrea, because the mutation affects how CHAMP1 connects with other proteins that help repair DNA, similar to the Fanconi pathway. This may help explain the increased risk of cancer. “I find this work fascinating,” remarks D’Andrea.
“Now we have a molecular understanding that CHAMP1 is a DNA repair disorder similar to FA. This sets the stage for experts to advance this work and to support these families because this disease has not been studied before.”
Despite its rarity, D’Andrea says learning about the CHAMP1 mutation at the molecular level can broaden current understanding of neurodevelopmental, genetic, and other disorders, and may also provide insight into how other diseases occur.
“The study of rare diseases is so directional,” D’Andrea says. “CHAMP1 is an irreversible mutation, but what we’ve learned from its discovery has the potential to expand our current understanding about the connection between rare genetic diseases and cancer, and it can bring new opportunities for targeted therapies in the future.”