| Autor: |
Kondrashova O; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia., Shamsani J; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia., O'Mara TA; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia., Newell F; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia., McCart Reed AE; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia., Lakhani SR; UQ Centre for Clinical Research, Faculty of Medicine, The University of Queensland, Brisbane 4029, Australia.; Anatomical Pathology, Pathology Queensland, Brisbane 4029, Australia., Kirk J; Familial Cancer Service, Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney 2145, Australia.; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney Medical School, University of Sydney, Sydney 2145, Australia., Pearson JV; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia., Waddell N; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia., Spurdle AB; Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane 4006, Australia. |
| Abstrakt: |
Risk of endometrial cancer (EC) is increased ~2-fold for women with a family history of cancer, partly due to inherited pathogenic variants in mismatch repair (MMR) genes. We explored the role of additional genes as explanation for familial EC presentation by investigating germline and EC tumor sequence data from The Cancer Genome Atlas ( n = 539; 308 European ancestry), and germline data from 33 suspected familial European ancestry EC patients demonstrating immunohistochemistry-detected tumor MMR proficiency. Germline variants in MMR and 26 other known/candidate EC risk genes were annotated for pathogenicity in the two EC datasets, and also for European ancestry individuals from gnomAD as a population reference set ( n = 59,095). Ancestry-matched case-control comparisons of germline variant frequency and/or sequence data from suspected familial EC cases highlighted ATM , PALB2 , RAD51C , MUTYH and NBN as candidates for large-scale risk association studies. Tumor mutational signature analysis identified a microsatellite-high signature for all cases with a germline pathogenic MMR gene variant. Signature analysis also indicated that germline loss-of-function variants in homologous recombination ( BRCA1 , PALB2 , RAD51C ) or base excision ( NTHL1 , MUTYH ) repair genes can contribute to EC development in some individuals with germline variants in these genes. These findings have implications for expanded therapeutic options for EC cases. |
