Inherited DNA Repair Gene Mutations in Men with Lethal Prostate Cancer

Germline variants in DNA repair genes are associated with aggressive prostate cancer (PrCa). The aim of this study was to characterize germline variants in DNA repair genes associated with lethal PrCa in Finnish and Swedish populations. Whole-exome sequencing was performed for 122 lethal and 60 unselected PrCa cases. Among the lethal cases, a total of 16 potentially damaging protein-truncating variants in DNA repair genes were identified in 15 men (12.3%). Mutations were found in six genes with CHEK2 (4.1%) and ATM (3.3%) being most frequently mutated. Overall, the carrier rate of truncating variants in DNA repair genes among men with lethal PrCa significantly exceeded the carrier rate of 0% in 60 unselected PrCa cases (p = 0.030), and the prevalence of 1.6% (p < 0.001) and 5.4% (p = 0.040) in Swedish and Finnish population controls from the Exome Aggregation Consortium. No significant difference in carrier rate of potentially damaging nonsynonymous single nucleotide variants between lethal and unselected PrCa cases was observed (p = 0.123). We confirm that DNA repair genes are strongly associated with lethal PrCa in Sweden and Finland and highlight the importance of population-specific assessment of variants contributing to PrCa aggressiveness.

[1]  Nicholas J. Roberts,et al.  ATM Serine/Threonine Kinase and its Role in Pancreatic Risk , 2020, Genes.

[2]  Young Kee Shin,et al.  Loss of Tumor Suppressor Gene Function in Human Cancer: An Overview , 2018, Cellular Physiology and Biochemistry.

[3]  The UniProt Consortium,et al.  UniProt: a worldwide hub of protein knowledge , 2018, Nucleic Acids Res..

[4]  R. Eeles,et al.  Rare germline variants in DNA repair genes and the angiogenesis pathway predispose prostate cancer patients to develop metastatic disease , 2018, British Journal of Cancer.

[5]  K. D. Sørensen,et al.  Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci , 2018, Nature Genetics.

[6]  K. Cooney,et al.  A comprehensive evaluation of CHEK2 germline mutations in men with prostate cancer , 2018, The Prostate.

[7]  J. Lindberg,et al.  Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis , 2018, Genome Medicine.

[8]  M. Teixeira,et al.  Targeted next generation sequencing identifies functionally deleterious germline mutations in novel genes in early-onset/familial prostate cancer , 2018, PLoS genetics.

[9]  K. Cooney,et al.  Germline Mutations in ATM and BRCA1/2 Distinguish Risk for Lethal and Indolent Prostate Cancer and are Associated with Early Age at Death. , 2017, European urology.

[10]  Trevor Hastie,et al.  REVEL: An Ensemble Method for Predicting the Pathogenicity of Rare Missense Variants. , 2016, American journal of human genetics.

[11]  T. Kipps,et al.  ATM Mutations in Cancer: Therapeutic Implications , 2016, Molecular Cancer Therapeutics.

[12]  Ahmet Zehir,et al.  Inherited DNA-Repair Gene Mutations in Men with Metastatic Prostate Cancer. , 2016, The New England journal of medicine.

[13]  Krishna R. Kalari,et al.  Determining the frequency of pathogenic germline variants from exome sequencing in patients with castrate-resistant prostate cancer , 2016, BMJ Open.

[14]  S. Chandna,et al.  ATM kinase: Much more than a DNA damage responsive protein. , 2016, DNA repair.

[15]  G. Parmigiani,et al.  Familial Risk and Heritability of Cancer Among Twins in Nordic Countries. , 2016, JAMA.

[16]  P. Jeggo,et al.  DNA repair, genome stability and cancer: a historical perspective , 2015, Nature Reviews Cancer.

[17]  James Y. Zou.  Analysis of protein-coding genetic variation in 60,706 humans , 2015, Nature.

[18]  Wei Yuan,et al.  DNA-Repair Defects and Olaparib in Metastatic Prostate Cancer. , 2015, The New England journal of medicine.

[19]  T. Sellers,et al.  Genome-Wide Association Study of Prostate Cancer–Specific Survival , 2015, Cancer Epidemiology, Biomarkers & Prevention.

[20]  A. Quinlan.  BEDTools: The Swiss‐Army Tool for Genome Feature Analysis , 2014, Current protocols in bioinformatics.

[21]  J. Shendure,et al.  A general framework for estimating the relative pathogenicity of human genetic variants , 2014, Nature Genetics.

[22]  Mauricio O. Carneiro,et al.  From FastQ Data to High‐Confidence Variant Calls: The Genome Analysis Toolkit Best Practices Pipeline , 2013, Current protocols in bioinformatics.

[23]  L. Aaltonen,et al.  HOXB13 G84E Mutation in Finland: Population-Based Analysis of Prostate, Breast, and Colorectal Cancer Risk , 2013, Cancer Epidemiology, Biomarkers & Prevention.

[24]  A. Whittemore,et al.  HOXB13 is a susceptibility gene for prostate cancer: results from the International Consortium for Prostate Cancer Genetics (ICPCG) , 2012, Human Genetics.

[25]  J. Carpten,et al.  Germline mutations in HOXB13 and prostate-cancer risk. , 2012, The New England journal of medicine.

[26]  M. DePristo,et al.  A framework for variation discovery and genotyping using next-generation DNA sequencing data , 2011, Nature Genetics.

[27]  R. Wood,et al.  DNA polymerases and cancer , 2011, Nature Reviews Cancer.

[28]  M. DePristo,et al.  The Genome Analysis Toolkit: a MapReduce framework for analyzing next-generation DNA sequencing data. , 2010, Genome research.

[29]  H. Hakonarson,et al.  ANNOVAR: functional annotation of genetic variants from high-throughput sequencing data , 2010, Nucleic acids research.

[30]  J. Morrison,et al.  A recurrent truncating germline mutation in the BRIP1/FANCJ gene and susceptibility to prostate cancer , 2009, British Journal of Cancer.

[31]  Olga Anczuków,et al.  Does the nonsense‐mediated mRNA decay mechanism prevent the synthesis of truncated BRCA1, CHK2, and p53 proteins? , 2008, Human mutation.

[32]  B. Friedenson,et al.  The BRCA1/2 pathway prevents hematologic cancers in addition to breast and ovarian cancers , 2007, BMC Cancer.

[33]  Tomas Lindahl,et al.  Human DNA repair genes, 2005. , 2005, Mutation research.

[34]  Pär Stattin,et al.  H6D polymorphism in macrophage-inhibitory cytokine-1 gene associated with prostate cancer. , 2004, Journal of the National Cancer Institute.

[35]  J. Schleutker,et al.  CHEK2 variants associate with hereditary prostate cancer , 2003, British Journal of Cancer.

[36]  J. Schleutker,et al.  BRCA1 and BRCA2 mutations have no major role in predisposition to prostate cancer in Finland , 2003, Journal of medical genetics.

[37]  Richard D. Wood,et al.  Human DNA Repair Genes , 2001, Science.

[38]  J. Carpten,et al.  A genetic epidemiological study of hereditary prostate cancer (HPC) in Finland: frequent HPCX linkage in families with late-onset disease. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[39]  A. Knudson.  Mutation and cancer: statistical study of retinoblastoma. , 1971, Proceedings of the National Academy of Sciences of the United States of America.

[40]  C. Liang,et al.  ATM deficiency promotes progression of CRPC by enhancing Warburg effect. , 2019, Endocrine-related cancer.

[41]  A. Jemal,et al.  Cancer statistics, 2019 , 2019, CA: a cancer journal for clinicians.

[42]  T. Tammela,et al.  Screening and prostate cancer mortality: results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up , 2014, The Lancet.

[43]  B. G. Blijenberg,et al.  Screening and prostate-cancer mortality in a randomized European study. , 2009, The New England journal of medicine.

[44]  Claude-Alain H. Roten,et al.  Fast and accurate short read alignment with Burrows–Wheeler transform , 2009, Bioinform..

[45]  N. Dubrawsky.  Cancer statistics , 2022 .