Ancestry connects non-cancer causing mutations in cancer patients

The cause of cancer as a disease has been partly attributed to genetics across a diverse range of populations. However, it is unclear whether cancer patients carry additional genetic mutations, also known as variants, in non-cancer causing genes and if these variants are evolutionarily related. Because ancestry-specific variants were more recently generated in evolutionary time, they could have been easily missed in analyses where all patients were cumulatively analyzed without consideration for ancestry. A recent concept proposed by geneticists suggests that people are more likely to develop or be protected from diseases based on recently acquired mutations and are less so due to more distant mutations. This is an interesting theory that scientists can now test using genome information from more than 10,000 cancer patients whose ancestries are known. So far, how mutations affect gene expression – whether they completely abolish the expression of gene products (e.g. protein) or result in the creation of a misshapen protein, have only been reported for variants present in patients with European ancestry. The remaining ancestries are yet to be explored.

 

Advances in sequencing technology have made it easier for researchers to access genome sequencing information under clinical settings and for healthcare providers to share personalized diagnoses as part of ‘genomic medicine’ to patients. Using publicly available genome sequencing data for cancer patients, Dr. Xiao Fan and colleagues analyzed the variants in non-cancer causing genes and in “medically actionable” genes in 10,389 cancer patients. The authors found 1.46 billion mutations, which were then filtered through rigorous quality testing of sequencing information followed by expert geneticist review, resulting in a final total reliable set of 2,920 non-cancer related pathogenic and likely pathogenic variants. About 750 of these variants were harbored on average within a quarter of the cancer cases, no matter the heritage. A surprising majority (~27%) of the total variants were displayed in patients with European ancestry, followed sequentially by Latinx/Native American (15%), African American (13%) and East Asian (12%) patients.

 

Because genetic mutations can affect expression of proteins, the authors then dug deep into the variant data to examine whether these variants behaved in an expected manner on a molecular level. When genes contain mutations that cause the protein it encodes to be a shorter version of itself, the mutation is referred to cause a protein “truncation”. Sometimes, a truncating mutation in a gene can trigger a decrease in expression at the messenger RNA (mRNA) level even before the mRNA is used to make the protein. To find out if the variants that produced truncated gene products underwent changes at the mRNA level, the authors measured the gene expression levels of such variants. Of the variants that showed a meaningful difference in gene expression compared to non-cancer patients, a large majority of variants showed a decrease in expression. This result indicated to the authors that truncation-causing variants often work at the mRNA level even before the cells spend energy to make the disease-associated proteins. The authors then examined the behavior of gene variants that do not cause truncations but rather cause just a single swap in the gene sequence, known as “missense” variants. Missense mutations typically only cause a change in one or two building blocks of the protein but do not affect the abundance of the protein itself. Surprisingly, the authors found that the missense variants in their data are unusually regulated in the cancer patients at the mRNA level resulting in a decrease in gene, and therefore, protein expression. This is an uncommon observation, making the authors speculate that missense variants are perhaps controlled by gene-expression independent mechanisms within the cancer patients’ cells.

This study provides a testament to the power of genomic medicine that can be used to complement conventional medical treatment. With a strong sample of ~10,000 cancer patients, this report stands as one of the most comprehensive studies that considers race and ancestry in its analysis. While genomic profiling is becoming more common in medical diagnoses, this study further provides a reason for understanding diseases and invention of medicine based on race, ethnicity and genetic heritage.

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