Integrins — the principal extracellular matrix (ECM) receptors of the cell — promote cell adhesion, migration, and proliferation, which are key events for cancer growth and metastasis. To date, most integrin-targeted cancer therapeutics have disrupted integrin-ECM interactions, which are viewed as critical for integrin functions. However, such agents have failed to improve cancer patient outcomes. We show that the highly expressed integrin β1 subunit is required for lung adenocarcinoma development in a carcinogen-induced mouse model. Likewise, human lung adenocarcinoma cell lines with integrin β1 deletion failed to form colonies in soft agar and tumors in mice. Mechanistically, we demonstrate that these effects do not require integrin β1–mediated adhesion to ECM but are dependent on integrin β1 cytoplasmic tail-mediated activation of focal adhesion kinase (FAK). These studies support a critical role for integrin β1 in lung tumorigenesis that is mediated through constitutive, ECM binding–independent signaling involving the cytoplasmic tail.

We determined triple-negative breast cancer (TNBC) subtypes, genetic ancestry, and immune features in a cohort of self-reported Black females with TNBC diagnosed at or below age 50. Among 104 tumors, 34.6% were basal-like 1 (BL1), 17.3% basal-like 2 (BL2), 9.6% luminal androgen receptor (LAR), 26.9% mesenchymal (M), and 11.5% unsubtyped (UNS). Subtypes resembled those seen in Europeans or East Asians, with less LAR (9.6% vs. 14.6–24.4%) and more UNS (11.5% vs. 0–7.5%). “High” proportion of West African ancestry was associated with more LAR (14.9% vs. 4.9%) and less M (25.5% vs. 34.2%). M demonstrated reduced immune activity and was marginally associated with worse overall survival in a multivariate model including stage, West African ancestry, BMI, and TILs, meriting future research. Our study is the largest to date of TNBC subtypes in young Black females. These results reinforce TNBC subtypes’ application across populations and potential use as a prognostic biomarker.

Breast cancer (BC) risks imparted by CHEK2 c.1100delC (“1100delC”) germline pathogenic/likely pathogenic variant (GPV) are 20–30%, compared to CHEK2 c.470T>C (“I157T”) GPV with <20%, leading to different breast screening recommendations through MRI. We compared cancer risk management (CRM) across these two GPVs. Study participants were adult females with an 1100delC or I157T GPV drawn from the Inherited Cancer Registry (ICARE) across the United States. Cancer history, clinical characteristics, and CRM were compared using chi-squared tests, t-tests, and logistic regression. Of 150 CHEK2 carriers, 40.7% had BC, with a mean age of 50. Comparing 1100delC and I157T GPVs, there were no differences in rates of (1) breast MRI among those with (65.2% versus 55.6% of 23 and 9; p = 0.612) and without (44.0% versus 44.8% of 50 and 29; p = 0.943) BC; (2) risk-reducing mastectomy among those with (50% versus 38.9% of 46 and 15; p = 0.501) and without (13.8% versus 6.5% of 58 and 31; p = 0.296) BC; and (3) risk-reducing salpingo-oophorectomy among those with (24.2% versus 22.2% of 45 and 18; p = 0.852) and without (17.5% versus 16.7% of 57 and 30; p = 0.918) BC. The results suggest over-screening with breast MRI among CHEK2 I157T GPV carriers and possible overuse of risk-reducing surgeries among CHEK2 carriers.

SET domain-containing protein 2 ( SETD2 ) is commonly mutated in renal cell carcinoma. SETD2 methylates histone H3 as well as a growing list of non-histone proteins. To explore SETD2-dependent regulation of the kidney cancer proteome, we performed a systems-wide analysis of protein lysine-methylation and expression in wild type (WT) and SETD2- knock out (KO) kidney cells. We observed decreased lysine methylation of the translation elongation factor eEF1A1. EEF1AKMT2 and EEF1AKMT3 are known to methylate eEF1A1, and we show here that their expression is dependent on SET-domain function of SETD2 . Globally, we observe differential expression of hundreds of proteins in WT versus SETD2- KO cells, including increased expression of many involved in protein translation. Finally, we observe decreased progression free survival and loss of EEF1AKMT2 gene expression in SETD2- mutated tumors. Overall, these data suggest that SETD2- mutated ccRCC, via loss of enzymetic function of the SET domain, displays dysregulation of protein translation as a potentially important component of the transformed phenotype.

Introduction: Genetic testing for hereditary cancer syndromes, particularly BRCA1 and BRCA2 ( BRCA ) germline pathogenic or likely pathogenic variants (GPVs), is critical in informing surgical decisions for women with breast cancer. Young Black women are historically underrepresented in genetic testing and research, making it essential to understand how testing timing influences treatment choices. We evaluated how the timing of BRCA testing affected surgical management among young Black women with breast cancer. Methods: Participants were drawn from a population-based cohort of Black women diagnosed with invasive breast cancer at age 50 or younger, recruited via Florida and Tennessee cancer registries. Data were collected through structured questionnaires, electronic health records, and lab reports, including information on genetic testing, BRCA status, and treatment. Participants were categorized by timing of BRCA testing (pre-surgical vs post-surgical) and GPV status. Chi-squared tests assessed associations between testing timing, BRCA status, and surgical treatment. Results: Among 633 participants, people with a BRCA GPV who were tested before surgery (n = 29) were significantly more likely to undergo bilateral mastectomy (82.8%) than those tested after surgery (40%). Timing of testing and BRCA status were both strongly associated with surgery received ( P < 0.0001). Conclusion: BRCA testing at diagnosis and prior to surgery is significantly associated with surgical management in young Black women with breast cancer. These findings highlight the importance of timely genetic testing, especially in populations with historically lower testing rates.

Background: Black women are more likely to develop and die from early‐onset breast cancer. Hereditary breast cancer (HBC) is strongly associated with early age of onset. Accordingly, HBC characteristics in young Black women were evaluated. Methods: Black women diagnosed with invasive breast cancer at age 50 years or younger between 2005 and 2018 were recruited through the state cancer registries in Florida and Tennessee. Participants were asked to complete a questionnaire, sign medical records releases, and donate a saliva sample for free genetic testing to identify HBC germline pathogenic or likely pathogenic variant (GPV). Women with sporadic versus hereditary breast cancer were compared, based on age distribution, clinical characteristics, and family cancer history. Results: Among 686 participants with confirmed genetic testing, 15.3% had GPVs in breast and/or ovarian cancer predisposition genes, including BRCA1 (7.7%), BRCA2 (4.5%), PALB2 (0.9%), and ATM (0.7%), with 1.5% in other genes. Compared to the sporadic group, triple‐negative breast cancers were overrepresented among BRCA1 carriers (23.6% vs. 75.5%; p < .001), and family history of breast cancer was significantly more frequent among BRCA1 , BRCA2 , and PALB2 carriers (all p < .05). The majority of breast cancers occurred by age 40 years in BRCA1 carriers (52.8%), compared to other genes, where age was more evenly distributed. Conclusion: Among unselected young Black women with breast cancer, our findings demonstrate that the highest frequency of HBC GPVs are in BRCA1 , BRCA2, and PALB2, with identification of distinct histopathologic and demographic characteristics across HBC genes, underscoring the critical need for genetic testing in all populations.