Copy neutral loss of heterozygosity is more frequent in older ovarian cancer patients

Loss of heterozygosity (LOH) is a common type of genomic alterations in ovarian cancer. Analyzing 74,415 copy neutral LOH events in 513 serous ovarian adenocarcinomas samples from the Cancer Genome Atlas, we report that the frequency of LOH events increases with age. Similar trend is observed for LOH involving chromosome 17, which is frequently implicated in ovarian cancer. The results are consistent when we analyze data from the Boston high‐grade serous cancer cohort. We further show that germ line and somatic mutations in BRCA1 (in chromosome 17) and BRCA2 (in chromosome 13) loci are not necessary to establish the pattern. We also report significant age‐related changes in expression patterns for several genes in the homologous recombination (HR) pathway, such as BRCA1, RAD50, RAD52, XRCC2, XRCC3, and MRE11A in these patient samples. Furthermore, we develop a metric for pathway‐level imbalance, and show that increased imbalance in the HR pathway, i.e., increase in expression of some HR genes and decrease in expression of others, is common and correlates significantly with the frequency of LOH events in the patient samples. Taken together, it is highly likely that aging and deregulation of HR pathway contribute to the increased incidence of copy‐neutral LOH in ovarian cancer patients. © 2013 Wiley Periodicals, Inc.

[1]  M. Robson,et al.  Impairment of BRCA1-Related DNA Double-Strand Break Repair Leads to Ovarian Aging in Mice and Humans , 2013, Science Translational Medicine.

[2]  K. Yoshihara,et al.  Increased incidence of brain metastases in BRCA1‐related ovarian cancers , 2013, The journal of obstetrics and gynaecology research.

[3]  Peter Donnelly,et al.  Mosaic PPM1D mutations are associated with predisposition to breast and ovarian cancer , 2012, Nature.

[4]  K. Pantel,et al.  Loss of Heterozygosity at Tumor Suppressor Genes Detectable on Fractionated Circulating Cell-Free Tumor DNA as Indicator of Breast Cancer Progression , 2012, Clinical Cancer Research.

[5]  S. Boulton,et al.  Playing the end game: DNA double-strand break repair pathway choice. , 2012, Molecular cell.

[6]  John Quackenbush,et al.  Profiles of Genomic Instability in High-Grade Serous Ovarian Cancer Predict Treatment Outcome , 2012, Clinical Cancer Research.

[7]  Reinhard Schneider,et al.  Bioinformatics Applications Note Systems Biology Pathvar: Analysis of Gene and Protein Expression Variance in Cellular Pathways Using Microarray Data , 2022 .

[8]  Benjamin J. Raphael,et al.  Integrated Genomic Analyses of Ovarian Carcinoma , 2011, Nature.

[9]  Subhajyoti De,et al.  Somatic mosaicism in healthy human tissues. , 2011, Trends in genetics : TIG.

[10]  Jonathan W. Pillow,et al.  POSTER PRESENTATION Open Access , 2013 .

[11]  A. Jemal,et al.  Cancer Statistics, 2010 , 2010, CA: a cancer journal for clinicians.

[12]  L. Ries,et al.  Ovarian cancer: Survival and treatment differences by age , 2010, Cancer.

[13]  David P. Davis,et al.  Diverse somatic mutation patterns and pathway alterations in human cancers. , 2010, Nature.

[14]  M. Babu,et al.  A time-invariant principle of genome evolution , 2010, Proceedings of the National Academy of Sciences.

[15]  D. Melzer,et al.  Human genetic variations: Beacons on the pathways to successful ageing , 2009, Mechanisms of Ageing and Development.

[16]  S. Teichmann,et al.  Patterns of evolutionary constraints on genes in humans , 2008, BMC Evolutionary Biology.

[17]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[18]  D. Gottschling,et al.  Does age influence loss of heterozygosity? , 2008, Experimental Gerontology.

[19]  S. Ozanne,et al.  DNA damage, cellular senescence and organismal ageing: causal or correlative? , 2007, Nucleic acids research.

[20]  D. Whiteman,et al.  Obesity and the risk of epithelial ovarian cancer: a systematic review and meta-analysis. , 2007, European journal of cancer.

[21]  W. Engels,et al.  A Third Link connecting Aging with Double Strand Break Repair , 2007, Cell cycle.

[22]  W. Engels,et al.  Age-Dependent Usage of Double-Strand-Break Repair Pathways , 2006, Current Biology.

[23]  Jan Vijg,et al.  Increased cell-to-cell variation in gene expression in ageing mouse heart , 2006, Nature.

[24]  T. Kirkwood,et al.  Understanding the Odd Science of Aging , 2005, Cell.

[25]  D. Mittelman,et al.  DNA end joining becomes less efficient and more error-prone during cellular senescence. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[26]  D. Gottschling,et al.  An Age-Induced Switch to a Hyper-Recombinational State , 2003, Science.

[27]  R. Jaszewski,et al.  Age-associated loss of heterozygosity of tumor suppressor genes in the gastric mucosa of humans. , 2002, American journal of physiology. Gastrointestinal and liver physiology.

[28]  X. Matías-Guiu,et al.  Loss of Heterozygosity on Chromosome 17q in Epithelial Ovarian Tumors: Association with Carcinomas with Serous Differentiation , 2000, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[29]  L. Balducci,et al.  Antineoplastic chemotherapy of the older cancer patient. , 2000, Hematology/oncology clinics of North America.

[30]  J. Riggs.  Rising ovarian cancer mortality in the elderly: a manifestation of differential survival. , 1995, Gynecologic oncology.

[31]  S. Orsulic,et al.  Ovarian Cancer , 1993, British Journal of Cancer.

[32]  D. Eccles,et al.  Early loss of heterozygosity on 17q in ovarian cancer. The Abe Ovarian Cancer Genetics Group. , 1992, Oncogene.

[33]  J. C. Eissenberg.  Telomeres, cancer & aging: live long & prosper? , 2013, Missouri medicine.

[34]  S. Pignata,et al.  Ovarian cancer in the elderly. , 2004, Critical reviews in oncology/hematology.

[35]  R Yancik,et al.  Ovarian cancer. Age contrasts in incidence, histology, disease stage at diagnosis, and mortality. , 1993, Cancer.