PMID- 29580810
OWN - NLM
STAT- In-Data-Review
LR  - 20180424
IS  - 1872-7980 (Electronic)
IS  - 0304-3835 (Linking)
VI  - 425
DP  - 2018 Jul 1
TI  - Accurate detection and quantification of epigenetic and genetic second hits in
      BRCA1 and BRCA2-associated hereditary breast and ovarian cancer reveals multiple 
      co-acting second hits.
PG  - 125-133
LID - S0304-3835(18)30223-4 [pii]
LID - 10.1016/j.canlet.2018.03.026 [doi]
AB  - BACKGROUND: This study characterizes the second hit spectrum in BRCA1 and
      BRCA2-associated breast and ovarian cancers at both gene loci to investigate if
      second hit mechanisms are mutually exclusive or able to coincide within the same 
      tumor. METHODS: Loss of heterozygosity, somatic point mutations and copy number
      alterations along with promoter methylation were studied in 56 breast and 15
      ovarian cancers from BRCA1 and BRCA2 germline mutation carriers. A mathematical
      methodology was introduced to quantify the tumor cell population carrying a
      second hit. RESULTS: Copy neutral LOH was the most prevalent LOH mechanism in
      this cohort (BC 69%, OC 67%). However, only 36% of BC and 47% of OC showed LOH in
      all cancerous cells. Somatic intragenic deletions and methylated subclones were
      also found in combination with (partial) loss of heterozygosity. Unequivocal
      deleterious somatic point mutations were not identified in this cohort.
      CONCLUSION: Different mechanisms inactivating the wild type allele are present
      within the same tumor sample at various extents. Results indicate that
      BRCA1/2-linked breast and ovarian cancer cells are predominantly characterized by
      LOH, but harbor a complex combination of second hits at various frequencies.
CI  - Copyright (c) 2018 Elsevier B.V. All rights reserved.
FAU - Van Heetvelde, Mattias
AU  - Van Heetvelde M
AD  - Center for Medical Genetics Ghent, Ghent University Hospital, Medical Research
      Building 1, Corneel Heymanslaan 10, B-9000, Ghent, Belgium; Cancer Research
      Institute Ghent (CRIG), B-9000, Ghent, Belgium; Department of Basic Medical
      Sciences, Ghent University, Entrance 46, De Pintelaan 185, B-9000, Ghent,
      Belgium. Electronic address: mattias.vanheetvelde@ugent.be.
FAU - Van Bockstal, Mieke
AU  - Van Bockstal M
AD  - Department of Pathology, Ghent University Hospital, Entrance 23, Corneel
      Heymanslaan 10, B-9000, Ghent, Belgium. Electronic address:
      mieke.vanbockstal@ugent.be.
FAU - Poppe, Bruce
AU  - Poppe B
AD  - Center for Medical Genetics Ghent, Ghent University Hospital, Medical Research
      Building 1, Corneel Heymanslaan 10, B-9000, Ghent, Belgium; Cancer Research
      Institute Ghent (CRIG), B-9000, Ghent, Belgium. Electronic address:
      bruce.poppe@ugent.be.
FAU - Lambein, Kathleen
AU  - Lambein K
AD  - Department of Pathology, AZ St Lucas Hospital, Groenebriel 1, B-9000, Ghent,
      Belgium; Department of Oncology, KU Leuven, Surgical Oncology, University
      Hospital Leuven Gasthuisberg, Herestraat 49, O&N1 Box 818, B-3000, Leuven,
      Belgium. Electronic address: kathleen.lambein@azstlucas.be.
FAU - Rosseel, Toon
AU  - Rosseel T
AD  - Center for Medical Genetics Ghent, Ghent University Hospital, Medical Research
      Building 1, Corneel Heymanslaan 10, B-9000, Ghent, Belgium. Electronic address:
      toon.rosseel@ugent.be.
FAU - Atanesyan, Lilit
AU  - Atanesyan L
AD  - MRC-Holland, Willem Schoutenstraat 1, 1057 DL, Amsterdam, The Netherlands.
      Electronic address: l.atanesyan@mlpa.com.
FAU - Deforce, Dieter
AU  - Deforce D
AD  - Cancer Research Institute Ghent (CRIG), B-9000, Ghent, Belgium; Faculty of
      Pharmaceutical Sciences, Laboratory of Pharmaceutical Biotechnology, Ghent
      University, Ottergemsesteenweg 460, B-9000, Ghent, Belgium. Electronic address:
      dieter.deforce@ugent.be.
FAU - Van Den Berghe, Ivo
AU  - Van Den Berghe I
AD  - Department of Pathology, AZ Sint Jan Hospital Brugge-Oostend, Ruddershove 10,
      B-8000, Brugge, Belgium. Electronic address:
      anatomopathologie.brugge@azsintjan.be.
FAU - De Leeneer, Kim
AU  - De Leeneer K
AD  - Center for Medical Genetics Ghent, Ghent University Hospital, Medical Research
      Building 1, Corneel Heymanslaan 10, B-9000, Ghent, Belgium; Cancer Research
      Institute Ghent (CRIG), B-9000, Ghent, Belgium. Electronic address:
      kim.deleeneer@ugent.be.
FAU - Van Dorpe, Jo
AU  - Van Dorpe J
AD  - Cancer Research Institute Ghent (CRIG), B-9000, Ghent, Belgium; Department of
      Pathology, Ghent University Hospital, Entrance 23, Corneel Heymanslaan 10,
      B-9000, Ghent, Belgium. Electronic address: jo.vandorpe@ugent.be.
FAU - Vral, Anne
AU  - Vral A
AD  - Cancer Research Institute Ghent (CRIG), B-9000, Ghent, Belgium; Department of
      Basic Medical Sciences, Ghent University, Entrance 46, De Pintelaan 185, B-9000, 
      Ghent, Belgium. Electronic address: anne.vral@ugent.be.
FAU - Claes, Kathleen B M
AU  - Claes KBM
AD  - Center for Medical Genetics Ghent, Ghent University Hospital, Medical Research
      Building 1, Corneel Heymanslaan 10, B-9000, Ghent, Belgium; Cancer Research
      Institute Ghent (CRIG), B-9000, Ghent, Belgium. Electronic address:
      kathleen.claes@ugent.be.
LA  - eng
PT  - Journal Article
DEP - 20180323
PL  - Ireland
TA  - Cancer Lett
JT  - Cancer letters
JID - 7600053
OTO - NOTNLM
OT  - BRCA1
OT  - BRCA2
OT  - Loss of heterozygosity
OT  - Methylation
OT  - Tumor cell percentage
EDAT- 2018/03/28 06:00
MHDA- 2018/03/28 06:00
CRDT- 2018/03/28 06:00
PHST- 2017/12/18 00:00 [received]
PHST- 2018/03/10 00:00 [revised]
PHST- 2018/03/16 00:00 [accepted]
PHST- 2018/03/28 06:00 [pubmed]
PHST- 2018/03/28 06:00 [medline]
PHST- 2018/03/28 06:00 [entrez]
AID - S0304-3835(18)30223-4 [pii]
AID - 10.1016/j.canlet.2018.03.026 [doi]
PST - ppublish
SO  - Cancer Lett. 2018 Jul 1;425:125-133. doi: 10.1016/j.canlet.2018.03.026. Epub 2018
      Mar 23.