The emerging demand for programmable functionalization of existing base nanocarriers necessitates development of an efficient approach for cargo loading that avoids nanoparticle redesign for each individual application. Herein, we demonstrate in vivo a postformulation strategy for lipidic nanocarrier functionalization with the use of a linker peptide, which rapidly and stably integrates cargos into lipidic membranes of nanocarriers after simple mixing through a self-assembling process. We exemplified this strategy by generating a VCAM-1-targeted perfluorocarbon nanoparticle for in vivo targeting in atherosclerosis (ApoE-deficient) and breast cancer (STAT-1-deficient) models. In the atherosclerotic model, a 4.1-fold augmentation in binding to affected aortas was observed for targeted vs. nontargeted nanoparticles (P<0.0298). Likewise, in the breast cancer model, a 4.9-fold increase in the nanoparticle signal from tumor vasculature was observed for targeted vs. nontargeted nanoparticles (P<0.0216). In each case, the nanoparticle was registered with fluorine ((19)F) magnetic resonance spectroscopy of the nanoparticle perfluorocarbon core, yielding a quantitative estimate of the number of tissue-bound nanoparticles. Because other common nanocarriers with lipid coatings (e.g., liposomes, micelles, etc.) can employ this strategy, this peptide linker postformulation approach is applicable to more than half of the available nanosystems currently in clinical trials or clinical uses.

In the light of this confirmatory study, we recommend the systematic analysis of WFS1 gene sequences in patients with parentally inherited diabetes mellitus and deafness (+/- optic atrophy), in particular when diabetogenic mtDNA mutations have been excluded.

Background Professional society guidelines recommend risk-reducing salpingo-oophorectomy (RRSO) for women with pathogenic variants (PVs) in ovarian cancer-risk genes. Personalization of that intervention is based on gene-specific phenotypes; however, the age of ovarian cancer diagnosis in women with PVs in moderate penetrance ovarian cancer-risk genes is not well characterized. Women who had hereditary cancer panel testing from September 2013–May 2019 were included (N = 631,950). Clinical/demographic information was compared for women with a PV in BRIP1, RAD51C, or RAD51D versus in BRCA1 or BRCA2. Results PVs in BRIP1, RAD51C, or RAD51D were identified in 0.5% of all tested women but in 1.6% of women with a history of ovarian cancer (~ 3-fold increase). PVs in BRCA1 or BRCA2 were identified in 2.4% of all tested women but in 6.1% of women with a history of ovarian cancer (~ 2.5-fold increase). The proportion of women with a personal or family history of ovarian cancer was similar among women with a PV in BRIP1, RAD51C, RAD51D, BRCA1, or BRCA2. The median age at ovarian cancer diagnosis was 53 years for BRCA1, 59 years for BRCA2, 65 years for BRIP1, 62 years for RAD51C, and 57 years for RAD51D. Conclusions These data reinforce the importance of identifying PVs in moderate penetrance ovarian cancer-risk genes. The age at ovarian cancer diagnosis was older for women with PVs in BRIP1, RAD51C, or RAD51D, suggesting that it is safe to delay RRSO until age 45–50 in RAD51D PV carriers and possibly until age 50–55 in BRIP and RAD51C PV carriers.

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BACKGROUND: TNBC is among the most aggressive subtypes of invasive breast cancer (BC), and accounts for approximately 10-15% of incidental BC diagnoses. TNBC is associated with early age of onset (median age of diagnosis &lt;50) and disproportionately affects African American women. Breast MRI is currently recommended to screen for BC in women with at least a moderate-to-high lifetime risk of BC (a 2-fold or higher increased risk), and may also be superior to mammogram to screen for TNBC. TNBC has been most closely associated with germline PVs in BRCA1. However, recent studies have suggested that PVs in other genes previously associated with invasive BC may specifically confer high risks of the TNBC subtype. METHODS: Results were analyzed from 627,219 women undergoing clinical multi-gene panel testing at a single US-based commercial laboratory between 5/2013 and 2/2020, including genes associated with hereditary BC and other cancers. Demographic and personal/family history data were collected on a test requisition form. Individuals who had single- or founder-site testing, or prior BRCA1 or BRCA2 testing, were excluded. Multivariable regression analysis was used to examine the association between PVs/suspected PVs and personal history (PHx) of TNBC. Models were adjusted for age, personal/family cancer history, and ancestry. Odds ratios (OR) with 95% confidence intervals (CI) excluding 1.0 were considered significant. RESULTS: In total, 22.4% (140,467/627,219) of women tested reported PHx of BC, of whom 12.8% (17,951/140,467) reported PHx of TNBC. Elevated risks of TNBC were identified in carriers of PVs in 10 genes (see Table). While the highest TNBC risk was associated with PVs in BRCA1 (OR 21.24, 95% CI 19.71-22.88), high risks were also seen for BARD1 (OR 7.05, 95% CI 5.71-8.71), TP53 (OR 5.64, 95% CI 3.08-10.33), PTEN (OR 5.52, 95% CI 2.35-13.00) and PALB2 (OR 5.27, 95% CI 4.55-6.10). Moderate-to-high risks (2-5-fold increased risk) of TNBC were also seen for carriers of PVs in RAD51C, RAD51D, BRCA2, and CDKN2A/P16. By contrast, PVs in NBN, ATM, and CHEK2 were all associated with an apparent decreased risk of TNBC. CONCLUSIONS: PVs in several hereditary cancer genes routinely tested on multi-gene panel tests are associated with high risks (OR&gt;5.0) and moderate-to-high risks (OR 2.0-5.0) of TNBC. These findings can inform practice guidelines about which genes to test when evaluating breast cancer risk and which PV carriers may benefit from intensive breast screening with magnetic resonance imaging (MRI). Odds ratios for TNBC in germline carriers of PV in hereditary cancer risk genesRisk GenePV Positive with TNBCOR95% CIp-valueHigh RiskBRCA1119321.2419.71-22.88&lt;0.001BARD11257.055.71-8.71&lt;0.001TP53125.643.08-10.33&lt;0.001PTEN65.522.35-13.00&lt;0.001PALB22315.274.55-6.10&lt;0.001Moderate-to-High RiskRAD51C864.923.86-6.26&lt;0.001RAD51D454.643.34-6.45&lt;0.001BRCA24884.434.02-4.89&lt;0.001CDKN2A (p16)172.521.52-4.18&lt;0.001Moderate-to-Low RiskBRIP1771.921.51-2.44&lt;0.001Protective EffectNBN140.550.32-0.940.030ATM400.510.37-0.70&lt;0.001CHEK2490.440.33-0.58&lt;0.001HOXB1350.330.14-0.810.015 Citation Format: Michael J Hall, Eric Rosenthal, Susana San Roman, Ryan Bernhisel, John Kidd, Elisha Hughes, Thomas Slavin, Allison Kurian. Triple-negative breast cancer (TNBC) risk with pathogenic variants (PV) in hereditary cancer predisposition genes [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD10-03.