High VEGF-A expression distinguishes basal-like human breast cancer.

Patients diagnosed with basal-like breast cancer face a more aggressive disease course and more dismal prognosis than patients diagnosed with luminal A and luminal B breast cancer molecular subtypes (1-4). We mined published microarray data (5, 6) to understand in an unbiased fashion the most distinguishing transcriptional features of tumors from patients with basal or basal-like subtype breast cancer. We observed transcriptome-wide differential expression of the vascular endothelial growth factor A, VEGFA, when comparing tumors of patients with basal-like breast cancer with that of other PAM50 molecular subtypes. VEGF-A mRNA was present at significantly higher quantities in the tumors of patients with basal-like breast cancer. Analysis of patient survival data revealed that VEGF-A primary tumor expression was correlated with recurrence-free survival, with higher VEGF-A associated with inferior outcomes - in basal-like patients but not in luminal A, luminal B, HER2+, or normal-like patients. High VEGF-A expression appears to distinguish basal-like human breast cancer from the other molecular subtypes.

A single nucleotide variant on chromosome 10 residing within nebulette (C10orf113) distinguishes patients with basal-like human breast cancer.

Patients diagnosed with basal-like breast cancer face a more aggressive disease course and more dismal prognosis than patients diagnosed with luminal A and luminal B breast cancer molecular subtypes (1-4). We mined published microarray data (5, 6) to understand in an unbiased fashion the most distinguishing genetic and transcriptional features of tumors from patients with basal or basal-like subtype breast cancer. We identified a single nucleotide polymorphism (rs625223) residing within NEBL (C10orf113) as among the most significant genetic differences in the tumors of patients with basal-like breast cancer. In a separate cohort of patients with basal subtype breast cancer, we observed transcriptome-wide differential tumor expression of a C10orf113 transcript. Analysis of patient survival data revealed that C10orf113 primary tumor expression was correlated with recurrence-free survival and distant metastasis-free survival in patients with basal-like breast cancer, but in a contrary manner. Thus, single nucleotide variants on both chromosome 5 (7) and chromosome 10 are fundamental differences that define the genetic composition of basal-like breast cancer in humans.

SMAD3 Host and Tumor Profiling to Identify Locally Advanced Rectal Cancer Patients at High Risk of Poor Response to Neoadjuvant Chemoradiotherapy

Identifying patients at risk of poor response to neoadjuvant chemoradiotherapy (nCRT) is an emerging clinical need in locally advanced rectal cancer (LARC). SMAD3 is a key player in the chemoradio-resistance phenotype and its expression is both constitutive and locally induced. The aim was to investigate both host (genetic polymorphisms) and tumor SMAD3 profiling to predict response to nCRT. In a group of 76 LARC patients, SMAD3 and phosphorylated-SMAD3 expression was assessed by immunohistochemistry in preoperative tumor tissue. In an expanded study group (n = 378), a set of SMAD3 polymorphisms (rs35874463, rs1065080, rs1061427, rs17228212, rs744910, and rs745103) was analyzed. Association with tumor regression grade (TRG) and patient prognosis (progression-free survival [PFS] and overall survival [OS]) was assessed. Patients with high tumor expression of SMAD3 had a significantly increased risk of poor response (TRG≥2) [cellularity >55% (OR:10.36, p = 0.0004), or moderate/high intensity (OR:5.20, p = 0.0038), or an H-score≥1 (OR:9.84, p = 0.0004)]. Patients carrying the variant SMAD3 rs745103-G allele had a poorer response (OR:0.48, p = 0.0093), a longer OS (HR:0.65, p = 0.0307), and a trend for longer PFS (HR:0.75, p = 0.0944). Patients who carried both high SMAD3 tumor expression and the wild-type rs745103-A allele had an extremely high risk of not achieving a complete response (OR:13.45, p = 0.0005). Host and tumor SMAD3 status might be considered to improve risk stratification of LARC patients to facilitate selection for alternative personalized neoadjuvant strategies including intensified regimens.

An allele on chromosome 5 residing within the ZSWIM6 region distinguishes patients with basal-like human breast cancer.

Patients diagnosed with basal-like (also known as basal) subtype breast cancer face a more aggressive disease course and more dismal prognosis than patients diagnosed with luminal A and luminal B breast cancer molecular subtypes (1-4). We mined published microarray data (5, 6) to understand in an unbiased fashion the most distinguishing genetic and transcriptional features of tumors from patients with basal or basal-like subtype breast cancer. We identified a single nucleotide polymorphism, rs6449531 in ZSWIM6 as among the most significant genetic differences in the tumors of patients with basal-like breast cancer. In a separate cohort of patients with basal subtype breast cancer, we observed transcriptome-wide differential expression of a ZSWIM6 transcript. Analysis of patient survival data revealed that ZSWIM6 primary tumor expression was correlated with overall survival in patients with basal subtype breast cancer. Sequence variation in the ZSWIM6 gene may be important in understanding differences in genetic background that favor development of basal subtype human breast cancer.

Differential expression of spexin hormone in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding spexin hormone, SPX, when comparing primary tumors of the breast to the tissue of origin, the normal breast. SPX mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of SPX in primary tumors of the breast was correlated with distant metastasis-free survival in patients with basal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. SPX may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Differential expression of sarcoglycan gamma in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding sarcoglycan gamma, SGCG, when comparing primary tumors of the breast to the tissue of origin, the normal breast. SGCG mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of SGCG in primary tumors of the breast was correlated with distant metastasis-free survival in patients with basal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. SGCG may be of relevance to initiation, maintenance or progression of cancers of the female breast.

PD-L1 Expression in Different Segments and Histological Types of Ovarian Cancer According to Lymphocytic Infiltrate

Background and Objectives: Ovarian cancer is the leading cause of death among gynecological tumors. PD-1/PD-L1 immunoregulatory mechanism is activated in ovarian cancers. Lymphocyte infiltration is a significant factor that affects its expression. We analyzed the correlation between localization of lymphocytic infiltrate and PD-L1 expression in epithelial ovarian tumors. Materials and Methods: PD-L1 expression was analyzed in 328 subjects, 122 with epithelial ovarian carcinoma, 42 with atypical proliferative tumor, and 164 with benign epithelial ovarian tumor. Expression in central and invasive tumor parts in epithelial ovarian carcinoma was combined with the most pronounced lymphocyte reaction. Immunohistochemical analysis was performed using the tissue microarray and correlated with a set of histopathology parameters. Results: PD-L1 expression was most prominent in epithelial ovarian carcinoma with different levels of expression observed between invasive and central tumor segments. A high level of PD-L1 expression on tumor cells was more frequently present in the invasive than in the central tumor parts (p < 0.001) only in high-grade serous ovarian carcinoma (HGSC). There was no significant correlation between peritumoral lymphocytic infiltrate and PD-L1 expression regardless of tumor segment. In the central tumor parts of HGSC, there was a correlation of intratumoral lymphocytic infiltrate with a higher level of PD-L1 expression (p = 0.003). Conclusions: The most prominent PD-L1 expression was observed in the invasive tumor parts of HGSC. Only the central parts of the HGSC exhibited significant PD-L1 expression in association with considerable intratumoral lymphocytic infiltrate.

Differential expression of calsequestrin 2 in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding calsequestrin 2, CASQ2, when comparing primary tumors of the breast to the tissue of origin, the normal breast. CASQ2 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of CASQ2 in primary tumors of the breast was correlated with recurrence-free survival in patients with normal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. CASQ2 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Differential expression of coding and non-coding RBPMS transcripts in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding RBPMS antisense RNA 1, RBPMS-AS1, when comparing primary tumors of the breast to the tissue of origin, the normal breast. RBPMS-AS1 mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. In a separate dataset, a coding RNA transcribed at the RBPMS locus was differentially expressed in primary tumors of the breast. Analysis of human survival data revealed that primary tumor expression of RBPMS-AS1 was correlated with overall survival in patients with luminal A and HER2+ subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. RBPMS-AS1 may be of relevance to initiation, maintenance or progression of cancers of the female breast.

Differential expression of adrenoceptor alpha 1A in cancers of the breast.

Breast cancer affects women at relatively high frequency (1). We mined published microarray datasets (2, 3) to determine in an unbiased fashion and at the systems level genes most differentially expressed in the primary tumors of patients with breast cancer. We report here significant differential expression of the gene encoding adrenoceptor alpha 1A, ADRA1A, when comparing primary tumors of the breast to the tissue of origin, the normal breast. ADRA1A mRNA was present at significantly lower quantities in tumors of the breast as compared to normal breast tissue. Analysis of human survival data revealed that expression of ADRA1A in primary tumors of the breast was correlated with distant metastasis-free survival in patients with basal-like subtype cancer, demonstrating a relationship between primary tumor expression of a differentially expressed gene and patient survival outcomes influenced by PAM50 molecular subtype. ADRA1A may be of relevance to initiation, maintenance or progression of cancers of the female breast.