Multiethnic PDX models predict a possible immune signature associated with TNBC of African ancestry.

PURPOSE: Triple-negative breast cancer (TNBC) is an aggressive subtype most prevalent among women of Western Sub-Saharan African ancestry. It accounts for 15-25% of African American (AA) breast cancers (BC) and up to 80% of Ghanaian breast cancers, thus contributing to outcome disparities in BC for black women. The aggressive biology of TNBC has been shown to be regulated partially by breast cancer stem cells (BCSC) which mediate tumor recurrence and metastasis and are more abundant in African breast tumors. METHODS: We studied the biological differences between TNBC in women with African ancestry and those of Caucasian women by comparing the gene expression of the BCSC. From low-passage patient derived xenografts (PDX) from Ghanaian (GH), AA, and Caucasian American (CA) TNBCs, we sorted for and sequenced the stem cell populations and analyzed for differential gene enrichment. RESULTS: In our cohort of TNBC tumors, we observed that the ALDH expressing stem cells display distinct ethnic specific gene expression patterns, with the largest difference existing between the GH and AA ALDH+ cells. Furthermore, the tumors from the women of African ancestry [GH/AA] had ALDH stem cell (SC) enrichment for expression of immune related genes and processes. Among the significantly upregulated genes were CD274 (PD-L1), CXCR9, CXCR10 and IFI27, which could serve as potential drug targets. CONCLUSIONS: Further exploration of the role of immune regulated genes and biological processes in BCSC may offer insight into developing novel approaches to treating TNBC to help ameliorate survival disparities in women with African ancestry.

A genome-wide scan for naevus count: linkage to CDKN2A and to other chromosome regions.

High numbers of melanocytic naevi (moles), and mutations in the p16 gene (CDKN2A), are two strong risk factors for cutaneous malignant melanoma. We have previously reported linkage of mole count to the CDKN2A locus. Here, we report genome-wide scans for mole counts (differentiated into flat, raised and atypical subtypes) with a total of 796 microsatellite markers for 424 families with 1024 twins and siblings, plus genotypes for 690 parents. Inclusion of 221 pairs of MZ twins enabled separation of shared environmental and polygenic influences, so placing an upper limit to estimates of QTL variance. Maximum likelihood multipoint variance component methods were used to assess linkage of naevus count. Sex, age, body surface area, skin colour, hair colour, sunburn and facial freckles were included as covariates. Peak linkage of flat mole count was to regions on chromosomes 2, 9, 8 and 17 with lod scores 2.95, 2.95, 2.50 and 2.15, respectively. The support for linkage to the CDKN2A gene region (9p21) increased to 3.42 when additional fine mapping markers were added. For raised mole count, there was suggestive evidence of linkage in our sample to chromosome 16 (lod=1.87), and for atypical mole count on chromosomes 1, 6 and X with lod scores of 2.20, 2.00 and 2.00, respectively. The multivariate linkage peaks generally match those from individual trait analyses, with the exception of a new peak on chromosome 4 (point-wise empirical P-value=0.001). We replicate our earlier finding of linkage to CDKN2A and discovering linkage to several novel regions that may also influence risk of the development of malignant melanoma.