Abstract：
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.
journal_name
Cancer Lettjournal_title
Cancer lettersauthors
Van Heetvelde M,Van Bockstal M,Poppe B,Lambein K,Rosseel T,Atanesyan L,Deforce D,Van Den Berghe I,De Leeneer K,Van Dorpe J,Vral A,Claes KBMdoi
10.1016/j.canlet.2018.03.026subject
Has Abstractpub_date
2018-07-01 00:00:00pages
125-133eissn
0304-3835issn
1872-7980pii
S0304-3835(18)30223-4journal_volume
425pub_type
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