White matter lesions in multiple sclerosis are enriched for CD20dim CD8+ tissue-resident memory T cells.

Brain CD8+ CD69+ tissue-resident memory T (TRM ) cells comprise a CD20dim subset, which is proportionally larger in CD103-negative TRM cells. In multiple sclerosis (MS) lesions, CD20dim TRM -cell proportions are increased. CD20-expression is associated with higher levels of CXCR6, Ki-67, and granzyme B, supporting CD20dim TRM cells as a relevant subset in MS.

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.

Genomic signature of BRCA1 deficiency in sporadic basal-like breast tumors.

About 10-20% of all breast carcinomas show a basal-like phenotype, while ∼ 90% of breast tumors from BRCA1-mutation carriers are of this subtype. There is growing evidence that BRCA1-mutated tumors are not just a specific subset of the basal-like tumors, but that (the majority of) basal-like tumors show a dysfunctional BRCA1 pathway. This has major treatment implications, because emerging regimens specifically targeting DNA repair mechanisms would then be most effective against these tumors. To further understand the involvement of BRCA1 deficiency in sporadic basal-like tumors, we investigated 41 basal-like tumors for BRCA1 mRNA expression by quantitative real-time polymerase chain reaction, BRCA1 promoter methylation, their genomic profile by array-CGH, and gene expression levels by whole genome expression arrays. Array-CGH results were compared to those of 34 proven BRCA1-mutated tumors. Basal-like tumors were subdivided into two equal groups: deficient and proficient in BRCA1 gene expression. The chromosomal makeup of BRCA1 deficient sporadic basal-like tumors was similar to that of BRCA1-mutated tumors. BRCA1 proficient sporadic basal-like tumors were more similar to nonbasal-like tumors. Only half of the basal-like breast tumors are actually deficient in BRCA1 expression. Gain of chromosome arm 3q is a marker for BRCA1 deficiency in hereditary and sporadic breast tumors.