Irvine, Calif., Aug. 10, 2022 — In a new University of California, Irvine-led study, researchers define how the circadian clock influences cell growth, metabolism and tumor progression. Their research also reveals how disruption of the circadian clock impacts genome stability and mutations that can further drive critical tumor promoting pathways in the intestine.
The study, titled, “Disruption of the Circadian Clock drives Apc Loss of Heterozygosity to Accelerate Colorectal Cancer,” was published today in Science Advances.
In this study, researchers found that both genetic disruption and environmental disruption of the circadian clock contribute to the mutation of the adenomatous polyposis coli (APC) tumor suppressor, which is found in the vast majority of human colorectal cancers (CRC). APC point mutations, deletions, and loss of heterozygosity (LOH) events have been reported in ~80 percent of human CRC cases, and it is these mutations that drive the initiation of intestinal adenoma development.
“As a society, we are exposed to several environmental factors that influence our biological clock, including night shift work, extended light exposure, changes in sleep/wake cycles and altered feeding behavior,” said Selma Masri, PhD, assistant professor of biological chemistry at UCI School of Medicine. “Strikingly, we have seen an alarming increase in several young-onset cancers, including colorectal cancer. The underlying cause of this increased incidence of cancer in adults in their 20s and 30s remains undefined. However, based on our findings, we now believe that disruption of the circadian clock plays an important role.”
According to the National Institutes of Health, there has been an alarming rise in early-onset colorectal cancer among young individuals. Today, nearly 10 percent of CRC cases are now diagnosed in people younger than 50 years, and this trend is on a steady rise. Suspected risk factors include environmental aspects, such as lifestyle and dietary factors, which are known to affect the circadian clock.
APC mutations are also associated with second hits in key oncogenic pathways, including Kras, Braf, p53, and Smad4, and these mutations drive progression to adenocarcinoma, collectively contributing to disease progression. Our findings now implicate circadian clock disruption in driving additional genomic mutations that are critical for accelerating colorectal cancer.
The circadian clock is an internal biological pacemaker that governs numerous physiological processes. Research in the Masri Lab is primarily focused on how disruption of the circadian clock is involved in the development and progression of certain cancer types. Researchers in the Masri Lab are actively pursuing further research aimed at defining how the circadian clock impacts other cancer types.
Financial support for this study was provided by the National Institutes of Health/National Cancer Institute, the Concern Foundation, the V Foundation for Cancer Research, the Care Research Coordinating Committee, Johnson and Johnson, and the UCI Chao Family Comprehensive Cancer Center’s Anti-Cancer Challenge.
About the UCI School of Medicine: Each year, the UCI School of Medicine educates more than 400 medical students, and nearly 150 doctoral and master’s students. More than 700 residents and fellows are trained at UCI Medical Center and affiliated institutions. The School of Medicine offers an MD; a dual MD/PhD medical scientist training program; and PhDs and master’s degrees in anatomy and neurobiology, biomedical sciences, genetic counseling, epidemiology, environmental health sciences, pathology, pharmacology, physiology and biophysics, and translational sciences. Medical students also may pursue an MD/MBA, an MD/master’s in public health, or an MD/master’s degree through one of three mission-based programs: the Health Education to Advance Leaders in Integrative Medicine (HEAL-IM), the Leadership Education to Advance Diversity-African, Black and Caribbean (LEAD-ABC), and the Program in Medical Education for the Latino Community (PRIME-LC). The UCI School of Medicine is accredited by the Liaison Committee on Medical Accreditation and ranks among the top 50 nationwide for research. For more information, visit som.uci.edu.
Disruption of the circadian clock drives Apc loss of heterozygosity to accelerate colorectal cancer
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The authors declare that they have no competing interests.