Thousands of High-Risk Cancer Gene Variants Uncovered: A Breakthrough in Cancer Research

In a groundbreaking study, scientists have identified over 5,000 genetic variations that can lead to the growth of certain cancers. This discovery has opened up new possibilities for developing targeted treatments and potentially preventing these cancers from arising in the first place. The research focused on the BAP1 gene, which acts as a “tumour defence” mechanism in the body, protecting against various types of cancer.

The team of researchers from the Wellcome Sanger Institute, The Institute of Cancer Research, London, and the University of Cambridge evaluated the health effects of genetic alterations in the BAP1 gene. They found that nearly one-fifth of these potential mutations were harmful, significantly increasing the risk of developing eye, lung lining, brain, skin, and kidney cancers. These findings are significant because they can be used immediately by doctors to diagnose patients and choose the most effective treatments.

The study, published in Nature Genetics, is a major breakthrough because it assessed all possible variants of the BAP1 gene, including those that are rare and affect individuals from diverse ethnic backgrounds. Historically, genetics research has been limited by a lack of representation from non-European populations. This study addresses this issue by providing a comprehensive profile of BAP1 variants from diverse populations.

The researchers also discovered a link between certain harmful BAP1 variants and higher levels of IGF-1, a hormone and growth factor. This finding has the potential to lead to the development of new drugs that can inhibit these harmful effects, potentially slowing down or preventing the progression of certain cancers.

The BAP1 protein plays a crucial role in protecting against cancer by suppressing tumour growth. However, inherited variants that disrupt the protein can increase a person’s lifetime risk of developing these cancers by up to 50%. Early detection of these variants through genetic screening can guide preventative measures, improve treatment effectiveness, and enhance quality of life for individuals affected.

To achieve this, the researchers used a technique called “saturation genome editing” to artificially alter the genetic code of human cells grown in a dish. This allowed them to identify 5,665 harmful changes in the BAP1 gene that disrupt the protein’s protective effects. Analysis of UK Biobank data confirmed that individuals carrying these harmful variants are over 10% more likely to be diagnosed with cancer than the general population.

The study also found that people with harmful BAP1 variants have elevated levels of IGF-1 in their blood, which is linked to both cancer growth and brain development. Even individuals without cancer showed these elevated levels, suggesting that IGF-1 could be a target for new treatments to slow down or prevent certain cancers. Further analysis revealed that harmful BAP1 variants and higher IGF-1 levels were linked to worse outcomes in uveal melanoma patients, highlighting the potential for IGF-1 inhibitors in cancer therapy.

The researchers believe that this study has the potential to revolutionize our understanding of how genetic variations drive disease. Dr. Andrew Waters, the first author of the study, said, “Our approach provides a true picture of gene behaviour, enabling larger and more complex studies of genetic variation. This opens up new possibilities for understanding how these changes drive disease.”

Professor Clare Turnbull, the clinical lead of the study, added, “This research could mean more accurate interpretation of genetic tests, earlier diagnoses, and improved outcomes for patients and their families.” Dr. David Adams, the senior author of the study, emphasized the importance of making genetic insights accessible and relevant to all people, regardless of their ancestry.

This breakthrough study has the potential to transform our understanding of cancer and improve patient outcomes. As the researchers aim to apply this technique to a wider range of genes, potentially covering the entire human genome in the next decade, we can expect to see significant advancements in the field of genetics and cancer research.

Historical Context:

• The study of genetics and cancer research has a long history, dating back to the discovery of the structure of DNA by James Watson and Francis Crick in 1953.
• In the 1970s and 1980s, researchers began to identify specific genes associated with cancer, such as the BRCA1 and BRCA2 genes, which are linked to breast and ovarian cancer.
• In the 1990s and 2000s, advances in genetic sequencing technology enabled researchers to identify more genes associated with cancer, including the TP53 gene, which is involved in the development of many types of cancer.
• In recent years, there has been a growing focus on personalized medicine and targeted therapies, which involve tailoring treatment to an individual’s specific genetic profile.
• The development of next-generation sequencing (NGS) technology has enabled researchers to analyze large numbers of genes simultaneously, leading to a greater understanding of the genetic basis of cancer.

Summary in Bullet Points:

• Scientists have identified over 5,000 genetic variations in the BAP1 gene that can lead to the growth of certain cancers.
• The study found that nearly one-fifth of these mutations are harmful, increasing the risk of developing eye, lung lining, brain, skin, and kidney cancers.
• The research assessed all possible variants of the BAP1 gene, including rare and diverse ethnic backgrounds, addressing a historical limitation in genetics research.
• The study found a link between certain harmful BAP1 variants and higher levels of IGF-1, a hormone and growth factor, which could lead to the development of new drugs to inhibit these effects.
• The BAP1 protein plays a crucial role in protecting against cancer, and inherited variants can increase a person’s lifetime risk of developing cancer by up to 50%.
• Early detection of these variants through genetic screening can guide preventative measures, improve treatment effectiveness, and enhance quality of life for individuals affected.
• The study used a technique called “saturation genome editing” to artificially alter the genetic code of human cells, identifying 5,665 harmful changes in the BAP1 gene.
• Analysis of UK Biobank data confirmed that individuals carrying these harmful variants are over 10% more likely to be diagnosed with cancer than the general population.
• The study found that people with harmful BAP1 variants have elevated levels of IGF-1 in their blood, which is linked to both cancer growth and brain development.
• The researchers believe that this study has the potential to revolutionize our understanding of how genetic variations drive disease and improve patient outcomes.
• The study’s findings could lead to more accurate interpretation of genetic tests, earlier diagnoses, and improved outcomes for patients and their families.
• The researchers aim to apply this technique to a wider range of genes, potentially covering the entire human genome in the next decade, which could lead to significant advancements in the field of genetics and cancer research.