Abstract 7897: Novel Rho-GTPase regulatory protein gene family variants are frequent and associate with poor survival in patients (pts) with acute myeloid leukemia (AML)

Cancer Research · 2026-04-03

Abstract Introduction: AML is a molecularly heterogeneous disease that is classified by recurrent cytogenetic abnormalities and gene mutations. Recent studies have shown divergent frequencies of several genetic aberrations depending on genetic ancestry and self-reported race/ethnicity, highlighting the need to broaden sequencing efforts to include more diverse pts. Methods: We performed paired tumor/normal whole exome sequencing (WES) and transcriptome sequencing on 271 ancestry and/or ethnically diverse pts [including 100 African American (AA) and 71 self-identified Hispanic pts; CALGB/Alliance], and a validation cohort of 45 AA pts (University of Pennsylvania). Results: We identified >20 genes to be mutated in 3-8% of pts that were not seen in previous sequencing efforts of predominantly non-Hispanic White/European ancestry (EA) pts. Notably, variants in genes encoding Rho-GTPase regulatory proteins (ARHG family, belonging to the RAS gene superfamily) were identified in 12% of pts, placing these genes in the top 5 of recurrently mutated genes in this pt cohort. This frequency was confirmed in the second cohort of AA pts (n=7/45, 15%). In contrast, analysis of 805 EA adults with WES data (BeatAML 2022) and 877 pediatric AML pts (TARGET) found ARHG gene family variants in 26/805 (3%) and 17/877 (1.9%) of EA AML pts, respectively. With a median age of 41y, ARHG-mutated(m) pts tended to be younger (P=.16) and more often diagnosed with core-binding factor AML (39% vs 19%, P=.02). ARHG mutations frequently co-occurred with NRAS and FLT3 mut (each found in 35% of ARHGm pts). Notably, survival of ARHGm pts was poor, with a median overall survival (OS) of <12 months, thereby mirroring OS of the 2022 European LeukemiaNet (ELN) Adverse risk group. Within the 2022 ELN Favorable risk group in the ancestry diverse cohort, ARHGm pts had shorter OS than ARHGwt pts (P=.02). The clinical outcome was especially poor in young adolescents and adults (AYA, 18-39y) (mut vs wt; 3y disease-free survival, 10% vs 50%, P<.001; 3y OS, 20% vs 55%, P=.008). RNAseq of 17 ARHGm pts showed transcriptomic RAS pathway activation, with 52% displaying a RAS-associated signature, also in the absence of other RAS mutations. Furthermore, bulk transcriptomic analyses of 1250 AML pts identified 120 predicted RAS signature genes, with the upregulated genes being enriched in metallopeptidases, MAP kinase phosphatases, and ARHG genes. Conclusion: We identified mutations in ARHG family genes as frequent yet thus far unrecognized RAS pathway activators in AML associated with poor survival that are not yet included in clinical testing panels. Their lack of recognition is likely due to the heterogeneity of mutationally affected ARHG family genes, enrichment in AYA pts and the high frequency in pts of non-European ancestry, both of which are pt populations that were underrepresented in previous sequencing efforts. Citation Format: Ethan Hamp, Lorenz Oelschläger, Bailee N. Kain, Deedra Nicolet, Krzysztof Mrozek, Katherine E. Miller, Audrey Bollas, Michael C. Walker, Christopher J. Walker, Jill Buss, Andrea Laganson, Andrew J. Carroll, William G. Blum, Bayard L. Powell, Geoffrey L. Uy, Wendy Stock, Marina Y. Konopleva, Richard M. Stone, John C. Byrd, Martin Carroll, Tanmoy Sarkar, Akmaljon Salimov, Benjamin J. Kelly, Electra D. Paskett, Jesse J. Plascak, Shannon McWeeney, Jeffrey W. Tyner, Jeffery Klco, Nathan Salomonis, H. Leighton Grimes, Elaine R. Mardis, Ann-Kathrin Eisfeld. Novel Rho-GTPase regulatory protein gene family variants are frequent and associate with poor survival in patients (pts) with acute myeloid leukemia (AML) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 7897.

Impacts of Neighborhood Persistent Poverty and Socioeconomic Status on Hepatocellular Carcinoma Outcomes: A Large Population‐Based Cohort Study

Cancer Medicine · 2026-03-01

BACKGROUND: Hepatocellular carcinoma (HCC) survival in the United States varies sharply by neighborhood disadvantage. AIM: To determine whether residence in persistently impoverished or low-SES census tracts is independently associated with lower all-cause and HCC-specific survival. METHODS: We identified 51,323 adults with HCC using a population-based retrospective cohort from the Surveillance, Epidemiology, and End Results Research Plus Specialized Database (2006-2020). Two census tract-level socioeconomic exposures were defined: persistent poverty (≥ 20% living below the poverty line for approximately 30 years) and low SES (Yost Index first quintile). Overlap Propensity Score Weighting, combined with marginal structural models, estimated the 1-, 5-, 10-, and 15-year risks of all-cause and HCC-specific mortality. RESULTS: The median follow-up was 16 months, 6058 (11.8%) lived in persistently impoverished tracts, and 9863 (19.5%) lived in low-SES tracts. After weighting, residents of persistently impoverished areas had a 1-year all-cause mortality risk of 46.0% vs. 40.3% (RD, 5.6%; 95% CI, 4.4% to 6.9%; RR, 1.14; 95% CI, 1.11 to 1.17) and an HCC-specific mortality risk of 33.3% vs. 28.6% (RD, 4.8%; 95% CI, 3.2% to 6.3%; RR, 1.17; 95% CI, 1.11 to 1.22). Living in low-SES tracts raised 1-year all-cause mortality risk to 32.5% vs. 30.1% (RD, 4.8%; 95% CI, 3.6% to 6.0%; RR, 1.12; 95% CI, 1.09 to 1.15) and HCC-specific mortality risk to 32.5% vs. 30.1% (RD, 2.5%; 95% CI, 1.4% to 3.5%; RR, 1.08; 95% CI, 1.05 to 1.12). CONCLUSIONS: Both persistent neighborhood poverty and contemporary low SES independently contribute to significant increases in mortality risk after HCC diagnosis.

US Cancer Mortality Rates by Detailed Occupation Among Working-Age Adults, 2020-2023

SSRN Electronic Journal · 2025-01-01

Neighborhood Disinvestment Predicts Shorter Cancer Survival Time among Black Women Diagnosed with Invasive Breast Cancer

Cancer Epidemiology Biomarkers & Prevention · 2025-02-20 · 4 citations

BACKGROUND: Observed neighborhood disinvestment is a chronic social determinant that is understudied in relation to cancer outcomes. This study investigated associations between neighborhood disinvestment, stage at diagnosis, and breast cancer-specific survival (BCSS) time. METHODS: Individual-level data included 844 women, diagnosed 2013 to 2019, from the Women's Circle of Health Follow-up Study, a population-based cohort of breast cancer survivors self-identifying as Black or African American. Neighborhood disinvestment was from a virtual audit of six indicators-garbage, graffiti, dumpsters, building conditions, yard conditions, and abandoned buildings-within 14,671 Google Street View streetscapes estimated at residential addresses using Universal Kriging. We fit accelerated failure time models of BCSS time as functions of neighborhood disinvestment by stage, adjusted for covariates (sociodemographic, lifestyle, and tumor- and treatment-related factors). Participants not experiencing an event at the end of follow-up (August 13, 2023) were right-censored. RESULTS: With a median follow-up time of 89 months, there were 91 breast cancer-specific deaths. Disinvestment and stage statistically interacted (P < 0.01). For stage III and stage II diagnoses, BCSS time decreased by 27% (95% confidence interval, 1%, 48%) and 37% (95% confidence interval, 5%, 58%), respectively, with each SD increase in disinvestment after adjustment for covariates. There was little evidence of associations between disinvestment and survival time among stages I and IV. CONCLUSIONS: The tumor stage-dependent association between greater neighborhood disinvestment and shorter survival time could reflect chronic stress exposures suspected to adversely accumulate over time. IMPACT: Neighborhood disinvestment might be an important, independent marker of social disadvantage impacting breast cancer survival.

Cancer-related health behaviors during the COVID 19 pandemic in geographically diverse samples across the US

BMC Cancer · 2025-01-09 · 1 citations

BACKGROUND: The COVID-19 pandemic involved business closures (e.g., gyms), social distancing policies, and prolonged stressful situations that may have impacted engagement in health behaviors. Our study assessed changes in cancer-related health behaviors during the pandemic, specifically physical activity, fruit/vegetable intake, smoking/tobacco use, and alcohol consumption. METHODS: Eight cancer centers administered mailed/web-based/telephone surveys between June 2020 and March 2021. Surveys assessed demographics, perceptions on social distancing, and self-reported changes of behaviors (less/same/more) associated with cancer prevention or risk, e.g., physical activity, fruit/vegetable intake, tobacco/smoking use, and alcohol consumption. Descriptive analyses and logistic regression models assessed association of variables with behavior change. RESULTS: Most of the 21,911 respondents reported adhering to at least 4(of 5) social distancing measures (72%) and indicated social distancing was very/somewhat important to prevent the spread of COVID-19 (91%). 35% of respondents reported less physical activity, 11% reported less fruit/vegetable intake, 27% reported more smoking/tobacco use (among those who used tobacco/smoking products in past 30 days), and 23% reported more alcohol consumption (among those who reported at least 1 drink in past 30 days) than before the pandemic. Urban residence, younger age, female gender, and worse general health were associated with less physical activity, less fruit/vegetable intake, more smoking/tobacco use, and more alcohol intake. Higher educational attainment was associated with less physical activity and fruit/vegetable intake and more alcohol consumption. Reporting social distancing as important and adhering to more COVID-19 safety practices were associated with less physical activity and more alcohol consumption. CONCLUSION: Our findings suggest that certain demographics and those who adhered to social distancing measures were more likely to self-report unfavorable changes in health behaviors during the pandemic. Future studies should examine if the behaviors returned to baseline following relief from pandemic restrictions, and if these behavior changes are associated with increased cancer incidence and mortality.

Tri-partied analyses define clinical outcomes and molecular features of patients (pts) with acute promyelocytic leukemia (APL)

Blood · 2025-11-03

Abstract Introduction APL is molecularly characterized by t(15;17)/PML::RARA gene fusion as a disease-initiating event and by recurrent gene mutations (mut). Although a highly aggressive disease, its treatment was revolutionized with all-trans retinoic acid (ATRA) and arsenic trioxide (ATO), making APL a curable malignancy. While pt-associated factors [age, socioeconomic status (SES), race/ethnicity, genetic ancestry] and disease-associated features (disease risk, prognostic molecular features) impact outcomes in hematologic diseases, no large-scale analyses have assessed the aforementioned factors in the ATRA/ATO era to identify unmet needs and potentially improve outcomes of APL pts. Methods For nationwide population analyses, we used Flatiron Health real-world database to identify 770 adults diagnosed with APL in 2014-2024 and 2 sets of cancer registries in the Surveillance Epidemiology End Results (SEER) Program of the National Cancer Institute to identify 829 pts in 1995-2019. To assess survival in the setting of clinical trials, we analyzed 249 pts treated on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology (Alliance) protocols with inclusion of ATRA. For Alliance pts, a neighborhood social deprivation index (SDI) was assigned based on pt-reported residence zip code and classified as low (1-25, n=33) or high deprivation (26-100, n=95). Molecular features were analyzed in 224 Flatiron pts who were tested for ≥1 gene with available targeted sequencing data (n=26 genes). To account for potentially unrecognized molecular features of Black pts, we performed integrated genomic profiling (paired tumor/normal whole-exome and transcriptome sequencing) on 23 Black APL pts treated on Alliance protocols. Results In Flatiron database, 14.7% of pts presented with high-risk APL based on defined disease risk stratification [high-risk, white blood cell count (WBC) ≥10x109/L; low-risk, WBC &amp;lt;10 x109/L]. No difference in disease risk was observed by race. Black pts were diagnosed at a younger age (median: Black, 46 years (y) vs White, 54 y; p=0.0013) and there were more White pts diagnosed at age ≥65 y (White 30.1% vs Black 16.3%; p=0.0487). There was no difference in OS by race, ethnicity, SES or disease risk. Negative OS predictors were age ≥65 y at diagnosis [median OS: ≥65 y, 3201 days (d) vs &amp;lt;65 y, NR; p=0.0001) and male sex (median OS: male, 3699 d vs female, NR; p=0.0479). OS of pts receiving ATRA+ATO (3699 d) or intensive chemotherapy+ATRA/ATO (NR) was longer than OS of pts treated with ATRA+other agents (1483 d, p=0.0339). Using SEER data, there was no difference in OS based on self-reported race between Black and White pts before or after 2012. This also held true in race-specific considerations of median household income, Yost index and urban/rural status. As in more recent Flatiron data, the only strong predictor of OS was older age (3y OS rates, 1995-2012: &amp;lt;40y, 79%, 40-59y, 71%, and ≥60y, 44%; 2012-2019: &amp;lt;40y, 92%, 40-59y, 80%, and ≥60y, 56%). OS of Black and White pts did not differ significantly within age groups. We also found no significant difference in OS of Black versus White APL pts treated in the setting of clinical trials. Older age represented a strong negative survival predictor (p&amp;lt;0.001). Pts with SDI &amp;gt;25 (n=95) had a worse OS than pts with SDI &amp;lt;25 (n=33, p=0.03). A comparison of OS of pts treated on clinical trials with OS of pts in population-based analyses found a longer OS for trial pts (3y rates: 84% vs 64%, p&amp;lt;0.001). Molecularly, most prevalent in Flatiron database were mut in FLT3 (FLT3-ITD 40.4%, FLT3 24.5%, FLT3-TKD 17.5%) followed by ETV6 (10.7%), NRAS (7.7%) and TET2 (6.4%). Paired tumor/normal whole exome sequencing of 23 Black pts confirmed FLT3-ITD and/or FLT3-TKD as most frequent mut in 65% of pts. Notably, FLT3-wildtype pts harbored clonal mutations in CALR, MYC and SLIT pathway genes, which hitherto have not been reported in APL. Conclusions We assessed defining features impacting OS of APL pts in the era of ATRA/ATO. In contrast to most cancer types, including AML, we found no survival disparity with respect to race/ethnicity, SES, and disease risk in pts with APL. Older age at diagnosis was a negative OS predictor. A higher frequency of early-onset APL occurred in Black pts. Molecularly, our data reveal the existence of ancestry-associated differences in driver mutations that may represent proliferative signals in addition to the PML::RARA-driven differentiation arrest.

Neighborhood Contexts and Healthcare Utilization in Patients with Breast Cancer Receiving Chemotherapy

Cancer Epidemiology Biomarkers & Prevention · 2025-10-28

BACKGROUND: Racialized economic segregation is linked to higher cancer-specific mortality; however, its impact on healthcare utilization (HCU) remains unclear. This study used the metric Index of Concentration at the Extremes (ICE) and evaluated the association between racial residential segregation (ICErace), racialized economic segregation (ICErace + income), and HCU among patients with breast cancer receiving chemotherapy. METHODS: Patients ≥18 years who received chemotherapy and surgical management for stage I to III breast cancer (2012-2020) were identified in the electronic health record. Census tract-level ICErace and ICErace + income were derived from the 2008 to 2012 American Community Survey. HCU was defined as hospitalizations or emergency room visits during chemotherapy. General estimating equations with robust variance estimated associations between segregation indices and HCU. Mediation analyses examined the effect of ICErace + income on HCU. RESULTS: Among 2,037 women (mean age, 53.7 ± 11.9 years), 10.6% were Black, 84.6% were White, and 4.8% were other. Higher concentrations of White residents were associated with reduced HCU risk [ICErace fifth quintile; risk ratio (RR) = 0.44; 95% confidence interval (CI), 0.32-0.59; reference: first quintile). A significant interaction was observed between ICErace and race (P = 0.009). The relationship between ICErace + income and HCU was nonlinear: HCU risk decreased progressively from the fifth percentile (RR = 0.97; 95% CI, 0.92-0.99) to the 63rd percentile (RR = 0.69; 95% CI, 0.49-0.99). Most of the ICErace + income effect on HCU was direct (OR = 0.88; 95% CI, 0.83-0.93), with minimal mediation by comorbidities (2.0%). CONCLUSIONS: Residence in racially and economically segregated census tracts is associated with greater HCU. IMPACT: These findings highlight structural racism as a determinant of cancer treatment burden, emphasizing the importance of neighborhood context in disparities and care delivery.

Machine Learning-based Chemotoxicity Predictions in Patients with Colorectal Cancer: Integrating Race, Geospatial Social Determinants of Health, and Biological Aging

Research Square · 2025-05-19

Cancer mortality rates by detailed occupation among US working-age adults between 2020 and 2023: a population-based study

The Lancet Oncology · 2025-12-05

Built Environment Change over Time Using Google Street View Assessments of Hispanic Community Health Study/Study of Latinos (HCHS/SOL) Cities

Journal of Urban Health · 2025-06-01 · 4 citations