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HCI researchers design new use for pedigrees and discover 2 potentially cancer-causing genes along the way

 

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Huntsman Cancer Institute researchers Nicola Camp and Rosalie Waller have created a new way to use family trees in the search for cancer-causing genes. In testing their new method, they pinpointed two genes that may contribute to multiple myeloma, a rare and deadly form of cancer which affects the bone marrow.

 As we’ve explained a few times in the past, cancer is the result of changes in human DNA. DNA is the instruction manual for life. A genome is the complete set of DNA in a person’s cells. A gene is just a subset of the genome—a portion of the DNA. Genes consist of chemicals nicknamed As, Ts, Cs, and Gs in an order that eventually leads to a specific function. A change—or mutation—in those chemicals may lead to a gene that does something different or doesn’t function at all.

Pedigree

 For years, geneticists have used a form of family trees called pedigrees to track diseases in families and discover the genetic mutations that cause the disease. They choose what are called high-risk pedigrees: pedigrees of large, multi-generational families with more disease than researchers would expect if the diseases weren’t inherited in families. For diseases caused by a mutation in a single gene—like cystic fibrosis, sickle-cell anemia, and Huntington’s disease—this is relatively straightforward. Until now, pedigrees have been used very infrequently for studying complicated diseases that involve multiple genes,.

Camp and Waller’s new method allows them to look at multiple potential causes of disease among the pedigree and thus identify shared DNA segments that might be causing complicated diseases. They say it could help discover “the genetic basis” of complex diseases.

Plasmozytom_multiple_Osteolysen_UnterarmThe two put the method to use with 11 Utah pedigrees from the Utah Population Database. Those families contained 1,063 people who had either multiple myeloma or a precursor to it, and 964 people who did not. Multiple myeloma is known to be genetically passed because it clusters in families, but the exact details of how children inherit it from parents remain foggy.
 

As a side note, the researchers said that the Utah Population Database is a unique resource for their work. Because multiple myeloma is relatively rare and has low survival rates, not many high-risk pedigrees for the disease exist. They say, “The Utah MM [high-risk pedigrees] are one of only a few pedigree resources worldwide and contains unparalleled multi-generational high-risk pedigrees.”

In their testing, Camp and Waller found two genes that might be involved in the development of the disease. One—a gene called USP45—is involved in fixing DNA mutations. The other, named ARID1A, is part of the process to properly package DNA include the cell’s nucleus, where it belongs.

Camp and Waller say that future work is heading in multiple directions. The two genes which might be contributing to development of multiple myeloma need to be investigated further. The method itself is also moving forward. They say it could be used in research into other complex diseases, not just cancer. Camp explains, “We are already pursuing large pedigrees in several other domains, including other cancers, psychiatric disorders, birth defects, and pre-term birth phenotypes, with several more genome-wide significant regions found. We’re excited about the potential.”


Sources

“Changes in Genes Involved in DNA Repair and Packaging Linked to Risk of Multiple Myeloma.” University of Utah Health, 1 Feb. 2018, https://healthcare.utah.edu/huntsmancancerinstitute/news/2018/02/changes-in-genes-involved-in-dna-repair.php

Chial, Heidi. “Mendelian Genetics: Patterns of Inheritance and Single-Gene Disorders.” Nature News, Nature Publishing Group, 2008, www.nature.com/scitable/topicpage/mendelian-genetics-patterns-of-inheritance-and-single-966

Hellerhoff. Plasmozytom Multiple Osteolysen Unterarm. 13 May 2010.

Waller, Rosalie G., et al. “Novel Pedigree Analysis Implicates DNA Repair and Chromatin Remodeling in Multiple Myeloma Risk.” PLOS Genetics, 1 Feb. 2018, doi:10.1101/137000.

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