Prediction of BRCA2-association in hereditary breast carcinomas using array-CGH.
Germline mutations in BRCA1/2 increase the lifetime risk for breast and ovarian cancer dramatically. Identification of such mutations is important for optimal treatment decisions and pre-symptomatic mutation screening in family members. Although current DNA diagnostics is able to identify many different mutations, it remains unclear, how many BRCA2-associated breast cancer cases remain unidentified as such. In addition, mutation scanning detects many unclassified variants (UV) for which the clinical relevance is uncertain. Therefore, our aim was to develop a test to identify BRCA2-association in breast tumors based on the genomic signature. A BRCA2-classifier was built using array-CGH profiles of 28 BRCA2-mutated and 28 sporadic breast tumors. The classifier was validated on an independent group of 19 BRCA2-mutated and 19 sporadic breast tumors. Subsequently, we tested 89 breast tumors from suspected hereditary breast (and ovarian) cancer (HBOC) families, in which either no BRCA1/2 mutation or an UV had been found by routine diagnostics. The classifier showed a sensitivity of 89% and specificity of 84% on the validation set of known BRCA2-mutation carriers and sporadic tumor cases. Of the 89 HBOC cases, 17 presented a BRCA2-like profile. In three of these cases additional indications for BRCA2-deficiency were found. Chromosomal aberrations that were specific for BRCA2-mutated tumors included loss on chromosome arm 13q and 14q, and gain on 17q. Since we could separate BRCA1-like, BRCA2-like, and sporadic-like tumors, using our current BRCA2- and previous BRCA1-classifier, this method of breast tumor classification could be applied as additional test for current diagnostics to help clinicians in decision making and classifying sequence variants of unknown significance.
Joosse
Simon A
SA
Division of Experimental Therapy, The Netherlands Cancer Institute NKI/AvL, Plesmanlaan 121, 1066CX Amsterdam, The Netherlands. s.joosse@in-silico.net
Brandwijk
Kim I M
KI
Devilee
Peter
P
Wesseling
Jelle
J
Hogervorst
Frans B L
FB
Verhoef
Senno
S
Nederlof
Petra M
PM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D024682:BRCA2 Protein / Q000235:genetics*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D018270:Carcinoma, Ductal, Breast / Q000737:chemistry / Q000145:classification / Q000235:genetics* / Q000473:pathology; D002869:Chromosome Aberrations; D055028:Comparative Genomic Hybridization; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods*; D015972:Gene Expression Regulation, Neoplastic; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing / Q000379:methods*; D040941:Heredity; D006801:Humans; D007150:Immunohistochemistry; D019656:Loss of Heterozygosity; D008875:Middle Aged; D009154:Mutation; D009361:Neoplasm Invasiveness; D009426:Netherlands; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011237:Predictive Value of Tests; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000032:analysis; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity
D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D024682:BRCA2 Protein; C551750:BRCA2 protein, human; D014408:Biomarkers, Tumor; D011960:Receptors, Estrogen