PMID- 29447163
OWN - NLM
STAT- MEDLINE
DCOM- 20180718
LR  - 20190416
IS  - 1553-7404 (Electronic)
IS  - 1553-7390 (Linking)
VI  - 14
IP  - 2
DP  - 2018 Feb
TI  - Paternal lineage early onset hereditary ovarian cancers: A Familial Ovarian
      Cancer Registry study.
PG  - e1007194
LID - 10.1371/journal.pgen.1007194 [doi]
AB  - 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.
FAU - Eng, Kevin H
AU  - Eng KH
AD  - Departments of Biostatistics and Bioinformatics, Roswell Park Cancer Institute,
      Buffalo NY, United States of America.
FAU - Szender, J Brian
AU  - Szender JB
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
FAU - Etter, John Lewis
AU  - Etter JL
AD  - Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo NY, United 
      States of America.
FAU - Kaur, Jasmine
AU  - Kaur J
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
FAU - Poblete, Samantha
AU  - Poblete S
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
FAU - Huang, Ruea-Yea
AU  - Huang RY
AD  - Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo NY, United
      States of America.
FAU - Zhu, Qianqian
AU  - Zhu Q
AD  - Departments of Biostatistics and Bioinformatics, Roswell Park Cancer Institute,
      Buffalo NY, United States of America.
FAU - Grzesik, Katherine A
AU  - Grzesik KA
AUID- ORCID: 0000-0002-9176-4684
AD  - Departments of Biostatistics and Bioinformatics, Roswell Park Cancer Institute,
      Buffalo NY, United States of America.
FAU - Battaglia, Sebastiano
AU  - Battaglia S
AD  - Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo NY, United
      States of America.
FAU - Cannioto, Rikki
AU  - Cannioto R
AD  - Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo NY, United 
      States of America.
FAU - Krolewski, John J
AU  - Krolewski JJ
AD  - Cancer Genetics and Genomics, Roswell Park Cancer Institute, Buffalo NY, United
      States of America.
FAU - Zsiros, Emese
AU  - Zsiros E
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
FAU - Frederick, Peter J
AU  - Frederick PJ
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
FAU - Lele, Shashikant B
AU  - Lele SB
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
FAU - Moysich, Kirsten B
AU  - Moysich KB
AD  - Cancer Prevention and Control, Roswell Park Cancer Institute, Buffalo NY, United 
      States of America.
FAU - Odunsi, Kunle O
AU  - Odunsi KO
AD  - Gynecologic Oncology, Roswell Park Cancer Institute, Buffalo NY, United States of
      America.
AD  - Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo NY, United
      States of America.
LA  - eng
GR  - P30 CA016056/CA/NCI NIH HHS/United States
GR  - T32 CA108456/CA/NCI NIH HHS/United States
GR  - P50CA159981 /NH/NIH HHS/United States
GR  - R01 CA188900/CA/NCI NIH HHS/United States
GR  - K01 LM012100/LM/NLM NIH HHS/United States
GR  - K01LM012100 /NH/NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180215
PL  - United States
TA  - PLoS Genet
JT  - PLoS genetics
JID - 101239074
SB  - IM
CIN - PLoS Genet. 2018 Jun 29;14(6):e1007416. PMID: 29958288
MH  - Adult
MH  - Age of Onset
MH  - Breast Neoplasms/complications/epidemiology/genetics
MH  - Family
MH  - Female
MH  - *Genes, X-Linked
MH  - Genetic Predisposition to Disease
MH  - *Heredity
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Models, Genetic
MH  - Ovarian Neoplasms/complications/*epidemiology/*genetics
MH  - Paternal Inheritance/*genetics
MH  - Pedigree
MH  - Registries
PMC - PMC5813894
EDAT- 2018/02/16 06:00
MHDA- 2018/07/19 06:00
CRDT- 2018/02/16 06:00
PHST- 2017/10/25 00:00 [received]
PHST- 2018/01/09 00:00 [accepted]
PHST- 2018/02/16 06:00 [entrez]
PHST- 2018/02/16 06:00 [pubmed]
PHST- 2018/07/19 06:00 [medline]
AID - 10.1371/journal.pgen.1007194 [doi]
AID - PGENETICS-D-17-02112 [pii]
PST - epublish
SO  - PLoS Genet. 2018 Feb 15;14(2):e1007194. doi: 10.1371/journal.pgen.1007194.
      eCollection 2018 Feb.