Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian Cancer Registry study

Given prior evidence that an affected woman conveys a higher risk of ovarian cancer to her sister than to her mother, we hypothesized that there exists an X-linked variant evidenced by transmission to a woman from her paternal grandmother via her father. We ascertained 3,499 grandmother/granddaughter pairs from the Familial Ovarian Cancer Registry at the Roswell Park Cancer Institute observing 892 informative pairs with 157 affected granddaughters. We performed germline X-chromosome exome sequencing on 186 women with ovarian cancer from the registry. The rate of cancers was 28.4% in paternal grandmother/granddaughter pairs and 13.9% in maternal pairs consistent with an X-linked dominant model (Chi-square test X2 = 0.02, p = 0.89) and inconsistent with an autosomal dominant model (X2 = 20.4, p<0.001). Paternal grandmother cases had an earlier age-of-onset versus maternal cases (hazard ratio HR = 1.59, 95%CI: 1.12–2.25) independent of BRCA1/2 status. Reinforcing the X-linked hypothesis, we observed an association between prostate cancer in men and ovarian cancer in his mother and daughters (odds ratio, OR = 2.34, p = 0.034). Unaffected mothers with affected daughters produced significantly more daughters than sons (ratio = 1.96, p<0.005). We performed exome sequencing in reported BRCA negative cases from the registry. Considering age-of-onset, one missense variant (rs176026 in MAGEC3) reached chromosome-wide significance (Hazard ratio HR = 2.85, 95%CI: 1.75–4.65) advancing the age of onset by 6.7 years. In addition to the well-known contribution of BRCA, we demonstrate that a genetic locus on the X-chromosome contributes to ovarian cancer risk. An X-linked pattern of inheritance has implications for genetic risk stratification. Women with an affected paternal grandmother and sisters of affected women are at increased risk for ovarian cancer. Further work is required to validate this variant and to characterize carrier families.

[1]  C. Morrison,et al.  NY-ESO-1 expression predicts an aggressive phenotype of ovarian cancer. , 2017, Gynecologic oncology.

[2]  Andrew J. Dunford,et al.  Tumor suppressor genes that escape from X-inactivation contribute to cancer sex bias , 2016, Nature Genetics.

[3]  B. Weir,et al.  Testing for Hardy–Weinberg equilibrium at biallelic genetic markers on the X chromosome , 2016, Heredity.

[4]  S. Friedman,et al.  Genetic/Familial High-Risk Assessment: Breast and Ovarian, Version 2.2015. , 2016, Journal of the National Comprehensive Cancer Network : JNCCN.

[5]  J. Weon,et al.  The MAGE protein family and cancer. , 2015, Current opinion in cell biology.

[6]  Mitchell J. Machiela,et al.  LDlink: a web-based application for exploring population-specific haplotype structure and linking correlated alleles of possible functional variants , 2015, Bioinform..

[7]  Jun S. Liu,et al.  The Genotype-Tissue Expression (GTEx) pilot analysis: Multitissue gene regulation in humans , 2015, Science.

[8]  L. Maeng,et al.  Dysregulation of X Chromosome Inactivation in High Grade Ovarian Serous Adenocarcinoma , 2015, PloS one.

[9]  C. Morrison,et al.  Expression and Immune Responses to MAGE Antigens Predict Survival in Epithelial Ovarian Cancer , 2014, PloS one.

[10]  Terry M Therneau,et al.  The kinship2 R Package for Pedigree Data , 2014, Human Heredity.

[11]  Nikki A. Hawkins,et al.  Characteristics associated with genetic counseling referral and BRCA1/2 testing among women in a large integrated health system , 2014, Genetics in Medicine.

[12]  Manolis Kellis,et al.  Systematic discovery and characterization of regulatory motifs in ENCODE TF binding experiments , 2013, Nucleic acids research.

[13]  I. Adzhubei,et al.  Predicting Functional Effect of Human Missense Mutations Using PolyPhen‐2 , 2013, Current protocols in human genetics.

[14]  Jian Peng,et al.  Template-based protein structure modeling using the RaptorX web server , 2012, Nature Protocols.

[15]  Hongtao Yu,et al.  The Smc complexes in DNA damage response , 2012, Cell & Bioscience.

[16]  Manolis Kellis,et al.  HaploReg: a resource for exploring chromatin states, conservation, and regulatory motif alterations within sets of genetically linked variants , 2011, Nucleic Acids Res..

[17]  Maojun Yang,et al.  When MAGE meets RING: insights into biological functions of MAGE proteins , 2011, Protein & Cell.

[18]  T. Hupp,et al.  Mage-A cancer/testis antigens inhibit p53 function by blocking its interaction with chromatin. , 2010, Cancer research.

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

[20]  R. Cooper,et al.  Complex Segregation Analysis of Pedigrees from the Gilda Radner Familial Ovarian Cancer Registry Reveals Evidence for Mendelian Dominant Inheritance , 2009, PloS one.

[21]  Gonçalo R. Abecasis,et al.  The Sequence Alignment/Map format and SAMtools , 2009, Bioinform..

[22]  Robert C. Bast,et al.  The biology of ovarian cancer: new opportunities for translation , 2009, Nature Reviews Cancer.

[23]  L. Aragón,et al.  The unnamed complex: what do we know about Smc5-Smc6? , 2009, Chromosome Research.

[24]  G. Kay,et al.  Skewed X chromosome inactivation and breast and ovarian cancer status: evidence for X-linked modifiers of BRCA1. , 2008, Journal of the National Cancer Institute.

[25]  Kevin M. Bradley,et al.  A haplotype at chromosome Xq27.2 confers susceptibility to prostate cancer , 2008, Human Genetics.

[26]  A. Whittemore,et al.  Contribution of BRCA1 and BRCA2 mutations to inherited ovarian cancer , 2007, Human mutation.

[27]  A. Simpson,et al.  MAGE-A, mMage-b, and MAGE-C proteins form complexes with KAP1 and suppress p53-dependent apoptosis in MAGE-positive cell lines. , 2007, Cancer research.

[28]  J. Lawrence,et al.  The disappearing Barr body in breast and ovarian cancers , 2007, Nature Reviews Cancer.

[29]  C. V. Jongeneel,et al.  Rapid evolution of cancer/testis genes on the X chromosome , 2007, BMC Genomics.

[30]  J. Lawrence,et al.  BRCA1 does not paint the inactive X to localize XIST RNA but may contribute to broad changes in cancer that impact XIST and Xi heterochromatin , 2007, Journal of cellular biochemistry.

[31]  U. P. S. T. Force.  Genetic Risk Assessment and BRCA Mutation Testing for Breast and Ovarian Cancer Susceptibility: Recommendation Statement , 2005, Annals of Internal Medicine.

[32]  L. Kolonel,et al.  Aggregation of ovarian cancer with breast, ovarian, colorectal, and prostate cancer in first-degree relatives. , 2004, American journal of epidemiology.

[33]  C. Deng,et al.  BRCA1 Supports XIST RNA Concentration on the Inactive X Chromosome , 2002, Cell.

[34]  M. Piver.  Hereditary ovarian cancer. Lessons from the first twenty years of the Gilda Radner Familial Ovarian Cancer Registry. , 2002, Gynecologic oncology.

[35]  A. Sood,et al.  Association between nonrandom X-chromosome inactivation and BRCA1 mutation in germline DNA of patients with ovarian cancer. , 1999, Journal of the National Cancer Institute.

[36]  D. Easton,et al.  A systematic review and meta‐analysis of family history and risk of ovarian cancer , 1998, British journal of obstetrics and gynaecology.

[37]  A. Berchuck,et al.  Loss of heterozygosity at chromosome segment Xq25‐26.1 in advanced human ovarian carcinomas , 1997, Genes, chromosomes & cancer.

[38]  W. Thompson,et al.  The genetic attributable risk of breast and ovarian cancer , 1996, Cancer.

[39]  J. Felix,et al.  Potential role of the inactivated X chromosome in ovarian epithelial tumor development. , 1996, Journal of the National Cancer Institute.

[40]  A. Whittemore,et al.  Rates and Risks of Ovarian Cancer in Subgroups of White Women in the United States , 1994, Obstetrics and gynecology.

[41]  P. Humphrey,et al.  Clonal origin of epithelial ovarian carcinoma: analysis by loss of heterozygosity, p53 mutation, and X-chromosome inactivation. , 1992, Journal of the National Cancer Institute.

[42]  Shibo Li,et al.  Frequent loss of heterozygosity on chromosomes Xp and 13q in human ovarian cancer , 1992, International journal of cancer.

[43]  N. Morton,et al.  Genetic epidemiology of ovarian cancer: segregation analysis , 1991, Annals of human genetics.

[44]  H. Lynch,et al.  Hereditary ovarian cancer. Pedigree studies, Part II. , 1991, Cancer genetics and cytogenetics.

[45]  N. Risch,et al.  Evaluating genetic association among ovarian, breast, and endometrial cancer: evidence for a breast/ovarian cancer relationship. , 1989, American journal of human genetics.

[46]  D. Seminara,et al.  Cancer risk estimates for family members of a population-based family registry for breast and ovarian cancer. , 2000, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[47]  J. Higginson.  International Agency for Research on Cancer. , 1968, WHO chronicle.

[48]  M. Feldman,et al.  Open Access Research Characterization of X-linked Snp Genotypic Variation in Globally Distributed Human Populations , 2022 .

[49]  J. J. Gordon,et al.  Bioinformatics Original Paper Improved Prediction of Bacterial Transcription Start Sites , 2022 .