July 27, 2023
Kyoto University
Tokyo Medical and Dental University
Keio University School of Medicine
Cancer is the leading cause of death in many developed countries, including Japan, and is a disease that has a significant impact on our health. In recent years, its incidence has been steadily increasing, and it is estimated that in Japan, one in three men and one in two women will be diagnosed with cancer in their lifetime. Previous research has revealed that cancer is a disease caused by abnormalities in the cell's genome. Against the backdrop of recent innovations in genomic analysis technology, the genomic abnormalities (driver mutations) involved in the development of major human cancers have been identified over the past decade. However, much about its pathophysiology remains to be elucidated. Cancer is thought to begin with a single cell of origin that acquires a driver mutation, and its descendant cells successively acquire new driver mutations, leading to the development of a population of tens to hundreds of billions of cells, the so-called "cancer." However, the overall picture of the course of cancer development—when this first mutation is acquired, and when and what kind of mutations the cell that acquired this first mutation subsequently obtains to ultimately be diagnosed as "cancer"—was not well understood. This time, a research team led by Professor Seishi Ogawa of the Department of Tumor Biology, Kyoto University Graduate School of Medicine; Professor Masakazu Toi of the Department of Breast Surgery at the same university (currently Director of Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital); Project Assistant Professor Tomomi Nishimura of the Department of Next-Generation Clinical Genomics at the same university; and Project Associate Professor Nobuyuki Kakiuchi of the Hakubi Center for Advanced Research, Kyoto University, has succeeded for the first time in the world in clarifying the entire process of breast cancer—which has been steadily increasing in recent years—from the acquisition of the first mutation around puberty to the onset of the disease decades later, by using state-of-the-art genomic analysis technology.
The research team first analyzed the process of mutation accumulation in single mammary gland cells with aging. They found that approximately 20 mutations accumulate annually in all mammary gland cells until menopause, that the accumulation rate decreases to about one-third after menopause, and that a single pregnancy and childbirth reduces the number of mutations by about 50. This suggests that mutation accumulation is dependent on female hormones (estrogen) and that after pregnancy and childbirth, mammary tissue may be newly reconstructed from cells that were previously dormant. Next, based on the mutation acquisition rate determined in this way, the research team estimated the chronological course from the acquisition of initial mutations to the onset of breast cancer by examining the genetic relationships between breast cancer and surrounding benign proliferative lesions and normal epithelium. The results estimated that (1) the origin of "der(1;16) translocation-positive breast cancer," which accounts for about 20% of all breast cancers, is a single cell that acquired this translocation around puberty; (2) this cell repeatedly divided and proliferated, expanding over a wide area within the mammary gland by the time breast cancer developed decades later; and (3) through this expansion process, multiple cells of origin that would later develop into breast cancer emerged by around the age of 30, and carcinogenesis occurred multicentrically from these cells. This study is the first to reveal the entire picture of cancer development from a cell that acquired a mutation very early in life, and it is expected to contribute to the development of breast cancer prevention, early detection, and early treatment in the future. These results were obtained through a collaborative study with Project Professor Satoru Miyano of the M&D Data Science Center, Tokyo Medical and Dental University, and Professor Toshiro Sato of The Sakaguchi Laboratory (Organoid Medicine), Keio University School of Medicine (currently Professor, Department of Biochemistry at the same university). The findings were published online in the British international academic journal Nature on July 26, 2023, at 16:00 local time.
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