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Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent.Significance:Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race–group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort.See related commentary by Hamilton et al., p. 2496.This article is highlighted in the In This Issue feature, p. 2483

Supplementary Table from African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

Supplementary Data from African Ancestry–Associated Gene Expression Profiles in Triple-Negative Breast Cancer Underlie Altered Tumor Biology and Clinical Outcome in Women of African Descent

Supplement 2 Figure. NF+BrCa OncoScan CNV Whole Genome Histogram.

IHC Validation

TCGA invasive breast cancer mRNA expression, protein expression, and CNV comparison based on NF1 genetic alterations.

Supplementary Figure 1 from Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1

Supplementary Figure Legend, Tables 1-3 from Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1

Supplementary Table 4 from Mutational Profile of Advanced Primary and Metastatic Radioactive Iodine-Refractory Thyroid Cancers Reveals Distinct Pathogenetic Roles for BRAF, PIK3CA, and AKT1

Background: Inflammatory cells such as tumor infiltrating lymphocytes (comprising T and B cells) are often present in prostate tissue undergoing tumorigenesis but their role in disease progression is unclear. The current study aims to characterize the expression dynamics of CD3, CD4 and CD20 lymphocytes from the pre- to post-malignant prostate environment and the association of these dynamics with aggressive prostate cancer. Methods: The study sample included 72 prostate cancer cases (44 whites and 28 African American) that underwent surgery as their primary treatment and had a benign prostate biopsy at least one year before diagnosis and were followed for biochemical recurrence (BCR). Counts of CD3-, CD4- and CD20-positive lymphocytes were quantified by immunohistochemistry using an automated multi-image processing procedure in pre-malignant benign biopsy (BB), tumor-adjacent benign (TAB) and malignant tumor glandular (MTG) regions of prostatectomy. A cox proportional hazards model was used to estimate the hazard ratio (HR) of time to BCR associated with inflammatory marker count in different regions of the prostate. Clustering was performed to identify similar trends of expression changes of CD3, CD4 and CD20 between the regions - BB, TAG and MTG using Time-series Anytime Density Peaks Clustering (TADPole). Results: The risk of BCR was significantly reduced in men who had an elevated CD20 count in the TAG (HR=0.80, p=0.01) after adjusting for race, age at diagnosis, PSA at the time of benign biopsy and the Gleason grade group. CD3 and CD4 counts in the prostate regions did not show any significant association to BCR. TADPole identified four main different patterns of CD20 expression changes across the BB-TAB-MTG regions namely 1) minimal to no change in expression between the regions (n=45 pairs); 2) high expression in BB/no expression in TAG/higher expression in MTG (n=3 pairs); 3) high expression in BB/higher expression in TAG/no expression in MTG (n=8 pairs); 4) no expression in BB/higher expression in TAG compared to MTG (n=16 pairs). In comparison to the reference group (Cluster 1), Cluster 4 was at 3.5 times higher risk of BCR with an adjusted HR of 3.5 (p=0.0184). Conclusion: Elevated CD20 expression in TAG was associated with less aggressive disease. Furthermore, cases that had CD20 expression highest in their benign prostate adjacent to tumor preceded by absence of CD20 expression in their pre-malignant benign prostate had the most aggressive disease course. Further studies are warranted to understand how CD20 lymphocyte dynamic changes influence prostate tumorigenesis. Citation Format: Sudha M. Sadasivan, Yalei Chen, Nilesh S. Gupta, Ryan Sanii, Kevin R. Bobbitt, Dhananjay A. Chitale, Sean R. Williamson, Andrew G. Rundle, Deliang Tang, Benjamin A. Rybicki. Change in B cell lymphocyte expression from the pre- to post-malignant prostate predicts disease aggressiveness [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 80.

Background: Telomere shortening is linked to aging and may be associated with increased risk for cancer. Most cancer studies have used telomere length in leukocytes rather than in the target tissue of cancer origin. Methods: A case–control study of 524 case–control pairs with a benign prostate biopsy nested within a historical cohort of 10,478 men was conducted to determine whether premalignant prostate telomere length (assessed using a modified qRT-PCR) is associated with prostate cancer risk. Results: Telomere lengths in benign prostate biopsies of cases versus controls were similar (1.46 ± 0.38 vs. 1.45 ± 0.42; P = 0.49). African American (AA) men had significantly shorter telomeres compared with White men (1.51 ± 0.38 vs. 1.63 ± 0.39; P < 0.0001). In race-stratified analyses, increasing telomere length was more strongly associated with prostate cancer risk in White men, wherein those with telomere length in the highest quartile had 1.9-fold greater adjusted risk of prostate cancer compared with men with prostate telomere lengths in the lowest quartile [OR = 1.90; 95% confidence interval (CI) = 1.08–3.36]. Men in the highest telomere length quartile also had a greater risk of aggressive prostate cancer compared with men with telomere lengths in the lowest quartile (OR = 2.78; 95% CI = 1.25–6.19). Conclusions: White men have longer telomeres in benign prostate tissue compared with AA men, and those with the longest telomeres may be at increased risk for prostate cancer, particularly the more aggressive form of the disease. Impact: Race-specific telomere length measures may be an early biomarker of aggressive prostate cancer.

Women of sub-Saharan African descent have disproportionately higher incidence of triple-negative breast cancer (TNBC) and TNBC-specific mortality across all populations. Population studies show racial differences in TNBC biology, including higher prevalence of basal-like and quadruple-negative subtypes in African Americans (AA). However, previous investigations relied on self-reported race (SRR) of primarily U.S. populations. Due to heterogeneous genetic admixture and biological consequences of social determinants, the true association of African ancestry with TNBC biology is unclear. To address this, we conducted RNA sequencing on an international cohort of AAs, as well as West and East Africans with TNBC. Using comprehensive genetic ancestry estimation in this African-enriched cohort, we found expression of 613 genes associated with African ancestry and 2,000+ associated with regional African ancestry. A subset of African-associated genes also showed differences in normal breast tissue. Pathway enrichment and deconvolution of tumor cellular composition revealed that tumor-associated immunologic profiles are distinct in patients of African descent. Significance: Our comprehensive ancestry quantification process revealed that ancestry-associated gene expression profiles in TNBC include population-level distinctions in immunologic landscapes. These differences may explain some differences in race–group clinical outcomes. This study shows the first definitive link between African ancestry and the TNBC immunologic landscape, from an African-enriched international multiethnic cohort. See related commentary by Hamilton et al., p. 2496. This article is highlighted in the In This Issue feature, p. 2483