Mosaic maternal ancestry in the Great Lakes region of East Africa

The Great Lakes lie within a region of East Africa with very high human genetic diversity, home of many ethno-linguistic groups usually assumed to be the product of a small number of major dispersals. However, our knowledge of these dispersals relies primarily on the inferences of historical, linguistics and oral traditions, with attempts to match up the archaeological evidence where possible. This is an obvious area to which archaeogenetics can contribute, yet Uganda, at the heart of these developments, has not been studied for mitochondrial DNA (mtDNA) variation. Here, we compare mtDNA lineages at this putative genetic crossroads across 409 representatives of the major language groups: Bantu speakers and Eastern and Western Nilotic speakers. We show that Uganda harbours one of the highest mtDNA diversities within and between linguistic groups, with the various groups significantly differentiated from each other. Despite an inferred linguistic origin in South Sudan, the data from the two Nilotic-speaking groups point to a much more complex history, involving not only possible dispersals from Sudan and the Horn but also large-scale assimilation of autochthonous lineages within East Africa and even Uganda itself. The Eastern Nilotic group also carries signals characteristic of West-Central Africa, primarily due to Bantu influence, whereas a much stronger signal in the Western Nilotic group suggests direct West-Central African ancestry. Bantu speakers share lineages with both Nilotic groups, and also harbour East African lineages not found in Western Nilotic speakers, likely due to assimilating indigenous populations since arriving in the region ~3000 years ago

Genetic determinants of risk in pulmonary arterial hypertension: international genome-wide association studies and meta-analysis

Background Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. Methods We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. Findings A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55–2·08], p=5·13×10– ¹⁵) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42–1·71], p=7·65×10– ²⁰) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25–1·48], p=1·69×10– ¹²; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02–8·05]), despite similar baseline disease severity. Interpretation This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. Funding UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR

National trends and survival outcomes of penile squamous cell carcinoma based on human papillomavirus status

Background: There are no series evaluating penile squamous cell carcinoma (pSCC) based on human papillomavirus (HPV) infection. Herein, we present national registry data on clinical and survival outcomes for pSCC based on HPV status. Methods: We performed a retrospective review of 1224 pSCC patients with known HPV staining from the National Cancer Database. Patients with cM1 disease, those who did not receive treatment, or had missing follow-up data were excluded. Logistic regression identified factors associated with locally aggressive disease. Univariable, multivariable, and inverse probability of treatment weighting (IPTW)-Cox proportional hazard modeling were used to assess hazard ratios (HR) associated with overall survival (OS). Results: After exclusion criteria, we identified 825 cases of which 321 (38.9%) were HPV positive. The HPV-positivity rate did not significantly change by year. HPV-positive patients were younger, had lower Charlson-Deyo performance score, and resided in areas with both lower median household income and lower school education completion. HPV-positive tumors presented with lower American Joint Committee on Cancer clinical T-stage (cT), poorer differentiation, lower rates of lymphovascular invasion (LVI), but more node-positive disease (cN+). For those who underwent lymph node surgery, there were no differences in final pathologic stage, upstaging, or presence of extranodal extension. Only tumor differentiation, LVI, and performance score were independent predictors for locally aggressive disease. HPV status was not a predictor of OS (IPTW-HR:0.89, p = 0.13). Conclusions: In the largest series evaluating pSCC based on HPV status, HPV-positive tumors were associated with lower cT stages, less LVI, but more cN + disease. More studies on prognostic factors are needed, and time may still be immature to use HPV information for risk stratification. © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Impacts of Neighborhood Characteristics and Surgical Treatment Disparities on Overall Mortality in Stage I Renal Cell Carcinoma Patients

Racial/ethnic minority groups in the United States have high renal cell carcinoma (RCC) mortality rates. This study assessed surgical treatment disparities across racial/ethnic groups and impacts of neighborhood socioeconomic characteristics on surgical treatments and overall mortality. Stage I RCC patients diagnosed between 2004 and 2016 from National Cancer Database were included (n = 238,141). We assessed differences in associations between race/ethnicity and treatment patterns using logistic regression and between race/ethnicity and overall mortality using Cox regression with and without neighborhood characteristics in the regression models. When compared to non-Hispanic Whites (NHWs), American Indians/Alaska Natives and non-Hispanic Blacks (NHBs) were more likely not to receive surgical care and all racial/ethnic minority groups had significantly increased odds of undergoing radical rather than partial nephrectomy, even after adjusting for neighborhood characteristics. Including surgical treatment and neighborhood factors in the models slightly attenuated the association, but NHBs had a significantly increased risk of overall mortality. NHBs who underwent radical nephrectomy had an increased risk of mortality (HR 1.15, 95% CI: 1.08–1.23), but not for NHBs who underwent partial nephrectomy (HR 0.92, 95% CI: 0.84–1.02). Neighborhood factors were associated with surgical treatment patterns and overall mortality in both NHBs and NHWs. Neighborhood socioeconomic factors may only partly explain RCC disparities. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Genetic variation and immunohistochemical localization of the glucocorticoid receptor in breast cancer cases from the breast cancer care in Chicago cohort

Background: Glucocorticoid, one of the primary mediators of stress, acts via its receptor, the glucocorticoid receptor (GCR/NR3C1), to regulate a myriad of physiological processes. We measured the genetic variation and protein expression of GCR, and the genes that regulate GCR function or response and examined whether these alterations were associated with breast cancer clinicopathological characteristics. Method: We used samples from a multiracial cohort of breast cancer patients to assess the association between breast cancer characteristics and the genetic variants of single nucleotide polymorphisms (SNPs) in GCR/NR3C1, FKBP5, Sgk1, IL-6, ADIPOQ, LEPR, SOD2, CAT, and BCL2. Results: Several SNPs were associated with breast cancer characteristics, but statistical significance was lost after adjustment for multiple comparisons. GCR was detected in all normal breast tissues and was predominantly located in the nuclei of the myoepithelial cell layer, whereas the luminal layer was negative for GCR. GCR expression was significantly decreased in all breast cancer tissue types, compared to nontumor tissue, but was not associated with breast cancer characteristics. We found that high nuclear GCR expression was associated with basal cell marker cytokeratin 5/6 positivity. Conclusion: GCR expression is reduced in breast cancer tissue and correlates with the basal cell marker CK5/6. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Renal cell carcinoma health disparities in stage and mortality among american indians/alaska natives and hispanic americans: Comparison of national cancer database and arizona cancer registry data

Renal cell carcinoma (RCC) is one of the top 10 cancers in the United States. This study assessed RCC health disparities in American Indians/Alaska Natives (AIs/ANs) and Hispanic Americans (HAs) focusing on advanced-stage and mortality. RCC patients’ data were obtained from the National Cancer Database (NCDB) and Arizona Cancer Registry (ACR). Logistic and Cox regression analyses were performed to ascertain the effect of race/ethnicity on stage and mortality, adjusting for neighborhood socioeconomic factors, rural/urban residence pattern, and other factors. In both data sets, AIs/ANs had significantly increased odds of advanced-stage RCC in the unadjusted model, but not in adjusted models. Mexican Americans had higher odds of advanced-stage compared to non-Hispanic Whites in NCDB (OR 1.22, 95% CI: 1.11–1.35) and ACR (OR 2.02, 95% CI: 1.58–2.58), even after adjusting for neighborhood characteristics. AIs/ANs did not show increased mortality risk in NCDB after adjusting for neighborhood characteristics, while the association remained significant in ACR (HR 1.33, 95% CI: 1.03–1.72). The great risk of all-cause and RCC-specific mortality was observed in U.S.-born Mexican Americans in Arizona (HR 3.21, 95% CI: 2.61–3.98 and sub-distribution HR 2.79, 95% CI: 2.05–3.81). RCC disparities in AIs/ANs is partially explained by neighborhood factors, but not in HAs. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Renal Cell Carcinoma Surgical Treatment Disparities in American Indian/Alaska Natives and Hispanic Americans in Arizona

American Indians/Alaska Natives (AI/AN) and Hispanic Americans (HA) have higher kidney cancer incidence and mortality rates compared to non-Hispanic Whites (NHW). Herein, we describe the disparity in renal cell carcinoma (RCC) surgical treatment for AI/AN and HA and the potential association with mortality in Arizona. A total of 5111 stage I RCC cases diagnosed between 2007 and 2016 from the Arizona Cancer Registry were included. Statistical analyses were performed to test the association of race/ethnicity with surgical treatment pattern and overall mortality, adjusting for patients’ demographic, healthcare access, and socioeconomic factors. AI/AN were diagnosed 6 years younger than NHW and were more likely to receive radical rather than partial nephrectomy (OR 1.49 95% CI: 1.07–2.07) compared to NHW. Mexican Americans had increased odds of not undergoing surgical treatment (OR 1.66, 95% CI: 1.08–2.53). Analysis showed that not undergoing surgical treatment and undergoing radical nephrectomy were statistically significantly associated with higher overall mortality (HR 1.82 95% CI: 1.21–2.76 and HR 1.59 95% CI: 1.30–1.95 respectively). Mexican Americans, particularly U.S.-born Mexican Americans, had an increased risk for overall mortality and RCC-specific mortality even after adjusting for neighborhood socioeconomic factors and surgical treatment patterns. Although statistically not significant after adjusting for neighborhood-level socioeconomic factors and surgical treatment patterns, AI/AN had an elevated risk of mortality. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Racial and ethnic disparities in preoperative surgical wait time and renal cell carcinoma tumor characteristics

Racial/ethnic minority groups have a disproportionate burden of kidney cancer. The objective of this study was to assess if race/ethnicity was associated with a longer surgical wait time (SWT) and upstaging in the pre-COVID-19 pandemic time with a special focus on Hispanic Americans (HAs) and American Indian/Alaska Natives (AIs/ANs). Medical records of renal cell carcinoma (RCC) patients who underwent nephrectomy between 2010 and 2020 were retrospectively reviewed (n = 489). Patients with a prior cancer diagnosis were excluded. SWT was defined as the date of diagnostic imaging examination to date of nephrectomy. Out of a total of 363 patients included, 34.2% were HAs and 8.3% were AIs/ANs. While 49.2% of HA patients experienced a longer SWT (≥90 days), 36.1% of Non-Hispanic White (NHW) patients experienced a longer SWT. Longer SWT had no statistically significant impact on tumor characteristics. Patients with public insurance coverage had increased odds of longer SWT (OR 2.89, 95% CI: 1.53–5.45). Public insurance coverage represented 66.1% HA and 70.0% AIs/ANs compared to 56.7% in NHWs. Compared to NHWs, HAs had higher odds for longer SWT in patients with early-stage RCC (OR, 2.38; 95% CI: 1.25–4.53). HAs (OR 2.24, 95% CI: 1.07–4.66) and AIs/ANs (OR 3.79, 95% CI: 1.32–10.88) had greater odds of upstaging compared to NHWs. While a delay in surgical care for early-stage RCC is safe in a general population, it may negatively impact high-risk populations, such as HAs who have a prolonged SWT or choose active surveillance. © 2021 by the authors. Licensee MDPI, Basel, Switzerland.Open access journalThis item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]