Previous studies have shown an approximately two-fold elevation in the relative risk of urinary bladder cancer (UBC) among people with a family history that could not be entirely explained by shared environmental exposures, thus suggesting a genetic component in its predisposition. Multiple genome-wide association studies and recent gene panel sequencing studies identified several genetic loci that are associated with UBC risk; however, the list of UBC-associated variants and genes is incomplete.
We exome sequenced eight patients from three multiplex UBC pedigrees and a group of 77 unrelated familial UBC cases matched to 241 cancer-free controls. In addition, we examined pathogenic germline variation in 444 candidate genes in 392 The Cancer Genome Atlas UBC cases.
In the pedigrees, segregating variants were family-specific although the identified genes clustered in common pathways, most notably DNA repair (MLH1 and MSH2) and cellular metabolism (IDH1 and ME1). In the familial UBC group, the proportion of pathogenic and likely pathogenic variants was significantly higher in cases compared with controls (P = .003). Pathogenic and likely pathogenic variant load was also significantly increased in genes involved in cilia biogenesis (P = .001). In addition, a pathogenic variant in CHEK2 (NM_007194.4:c.1100del; p.T367Mfs*15) was over-represented in cases (variant frequency = 2.6%; 95% CI, 0.71 to 6.52) compared with controls (variant frequency = 0.21%; 95% CI, 0.01 to 1.15), but was not statistically significant.
These results point to a complex polygenic predisposition to UBC. Despite heterogeneity, the genes cluster in several biologically relevant pathways and processes, for example, DNA repair, cilia biogenesis, and cellular metabolism. Larger studies are required to determine the importance of CHEK2 in UBC etiology.
JCO precision oncology. 2021 Dec 22*** epublish ***
Alexander Pemov, Talia Wegman-Ostrosky, Jung Kim, Stella Koutros, Brenna Douthitt, Kristine Jones, Bin Zhu, Dalsu Baris, Molly Schwenn, Alison Johnson, Margaret R Karagas, Brian D Carter, Marjorie L McCullough, Maria Teresa Landi, Neal D Freedman, Demetrius Albanes, Debra T Silverman, Nathaniel Rothman, Neil E Caporaso, Mark H Greene, Joseph F Fraumeni, Douglas R Stewart
Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD., Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD., Frederick National Laboratory for Cancer Research, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD., Maine Cancer Registry, Augusta, ME., Vermont Department of Health, Burlington, VT., Department of Epidemiology, Geisel School of Medicine at Dartmouth, Hanover, NH., Department of Population Science, American Cancer Society, Atlanta, GA., Integrative Tumor Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD., Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD., Office of the Director, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.