Citations

AbstractStudies supporting a strong association between tau deposition and neuronal loss, neurodegeneration, and cognitive decline have heightened the allure of tau and tau‐related mechanisms as therapeutic targets. In February 2020, leading tau experts from around the world convened for the first‐ever Tau2020 Global Conference in Washington, DC, co‐organized and cosponsored by the Rainwater Charitable Foundation, the Alzheimer's Association, and CurePSP. Representing academia, industry, government, and the philanthropic sector, presenters and attendees discussed recent advances and current directions in tau research. The meeting provided a unique opportunity to move tau research forward by fostering global partnerships among academia, industry, and other stakeholders and by providing support for new drug discovery programs, groundbreaking research, and emerging tau researchers. The meeting also provided an opportunity for experts to present critical research‐advancing tools and insights that are now rapidly accelerating the pace of tau research.

AbstractMPZL3 is a nuclear‐encoded, mitochondrially localized, immunoglobulin‐like V‐type protein that functions as a key regulator of epithelial cell differentiation, lipid metabolism, ROS production, glycemic control, and energy expenditure. Recently, MPZL3 has surfaced as an important modulator of sebaceous gland function and of hair follicle cycling, an organ transformation process that is also governed by peripheral clock gene activity and PPARγ. Given the phenotype similarities and differences between Mpzl3 and Pparγ knockout mice, we propose that MPZL3 serves as a signaling hub that is regulated by core clock gene products and/or PPARγ to translate signals from these nuclear transcription factors to the mitochondria to modulate circadian and metabolic regulation. Conservation between murine and human MPZL3 suggests that human MPZL3 may have similarly complex functions in health and disease. We summarize current knowledge and discuss future directions to elucidate the full spectrum of MPZL3 functions in mammalian physiology.

AbstractBackgroundRecent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.Methods483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk.ResultsPRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.ConclusionsPopulation-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.

The double Frost suture is a useful supplement to the reconstruction of ipsilateral upper and lower eyelid defects with full-thickness skin grafts. This technique involves silk traction sutures that overlap the upper and lower eyelids to place them on maximal stretch after placement of 2 full-thickness skin grafts. It has the added benefit of protecting the cornea and compressing both grafts under 1 bolster. The authors illustrate this technique in 2 pediatric cases—a congenital melanocytic kissing eyelid nevus and a periocular burn. Each case resulted in large upper and lower anterior lamellar defects, which were reconstructed with supraclavicular and retroauricular free skin grafts. The double Frost sutures counter vertical cicatricial forces during graft healing, obviating the need for staged procedures. Both described cases resulted in excellent graft survival with minimal contracture.

AbstractGene expression profiling can be used for predicting survival in multiple myeloma (MM) and identifying patients who will benefit from particular types of therapy. Some germline single nucleotide polymorphisms (SNPs) act as expression quantitative trait loci (eQTLs) showing strong associations with gene expression levels. We performed an association study to test whether eQTLs of genes reported to be associated with prognosis of MM patients are directly associated with measures of adverse outcome. Using the genotype‐tissue expression portal, we identified a total of 16 candidate genes with at least one eQTL SNP associated with their expression with P < 10−7 either in EBV‐transformed B‐lymphocytes or whole blood. We genotyped the resulting 22 SNPs in 1327 MM cases from the International Multiple Myeloma rESEarch (IMMEnSE) consortium and examined their association with overall survival (OS) and progression‐free survival (PFS), adjusting for age, sex, country of origin and disease stage. Three polymorphisms in two genes (TBRG4‐rs1992292, TBRG4‐rs2287535 and ENTPD1‐rs2153913) showed associations with OS at P < .05, with the former two also associated with PFS. The associations of two polymorphisms in TBRG4 with OS were replicated in 1277 MM cases from the International Lymphoma Epidemiology (InterLymph) Consortium. A meta‐analysis of the data from IMMEnSE and InterLymph (2579 cases) showed that TBRG4‐rs1992292 is associated with OS (hazard ratio = 1.14, 95% confidence interval 1.04‐1.26, P = .007). In conclusion, we found biologically a plausible association between a SNP in TBRG4 and OS of MM patients.

Abstract Background: Benign breast disease (BBD) is a risk factor for breast cancer (BC); however, little is known about the genetic alterations present at the time of BBD diagnosis, and how these relate to risk of incident BC. Methods: A subset of a long-term BBD cohort was selected to examine DNA variation across three BBD groups (42 future estrogen receptor-positive (ER+) BC, 36 future estrogen receptor-negative (ER-) BC and 42 controls cancer-free for at least 16 years post-BBD). DNA extracted from archival formalin fixed, paraffin-embedded (FFPE) tissue blocks was tested and analyzed for presence of DNA alterations using a targeted panel of 93 BC-associated genes. To address artifacts frequently observed in FFPE tissues (e.g., C>T changes), we applied three filtering strategies based on alternative allele frequencies and nucleotide substitution context. Gene-level associations were performed using two burden tests, SKAT-O and logistic regression, and adjusted for clinical and technical covariates including epithelial percentage, histologic impression, patient age and year of BBD biopsy. Results: After filtering, the variant frequency of SNPs in our samples was highly consistent with population allele frequencies reported in 1KG/ExAC (0.986, p <1e-16). Ten genes were found to be associated with later cancer status by four of 12 association methods, with nominal p-values <0.05: MED12, MSH2, BRIP1, PMS1, GATA3, MUC16, FAM175A, EXT2, MLH1 and TGFB1. Additionally, analysis revealed 11 and 19 gene-level associations with p-values <0.05 and OR<1 for all cancer cases and ER- cases, respectively. Comparing between the three case groups, BBD ER+ cases were closer to controls in mutation profile, while BBD ER- cases were distinct. Notably, the variant burden was significantly higher in controls than in either ER+ or ER- cases. CD45 expression was associated with mutational burden (p=0.003).Conclusions: Somatic mutations were more frequent in benign breast tissue from women who did not develop cancer, opening questions of clonal diversity or immune-mediated restraint on future cancer development. CD45 expression was positively associated with mutational burden, most strongly in controls. Further studies in both normal and premalignant tissues are needed to better understand the role of somatic gene mutations and their contribution to future cancer development.

Abstract Background: Women with benign breast disease (BBD) are at increased risk of breast cancer (BC). Classic studies based on film-based mammographic screening and pathology diagnosis of surgical biopsies conducted in the 1980s established a hierarchy of increasing BC risk: non-proliferative (NP) BBD, proliferative BBD without atypia (PDWA) and atypical hyperplasia (AH). Given changes in epidemiological BC risk factors and introduction of percutaneous core needle biopsy (CNB) in mid-1990s, and later, digital mammography, we hypothesized that the patient characteristics and relative frequency of BBD diagnoses have changed over time. Accordingly, we performed a longitudinal analysis of the frequency of patient characteristics and BBD diagnoses in the Mayo BBD cohort. Methods: Utilizing the Mayo Clinic Surgical and Pathology Indices, women ages 18 to 85 who had a BBD biopsy between 1/1/67 and 12/31/13 were identified. Breast pathologists reviewed biopsies masked to diagnoses of incident BC diagnosed in follow-up. Demographic characteristics and BC events were obtained by query of institutional data sources and participant surveys. Trends were evaluated for the following eras: 1: pre-mammogram (1967-1981), 2: pre-CNB (1982-1992), 3: CNB Transition (1993-2001), and 4: CNB (2002-2013). Demographics were formally compared across eras using chi-square tests for categorical variables and analyses of variance (ANOVAs) for continuous variables. Results: From 1967-2013, the cohort includes 19,582 unique women with BBD. The frequency of CNB increased from eras 1-4: 0.04%, 0.6%, 51.3 %, and 88.9%, respectively. Mean age at BBD diagnosis was younger in era 1 (48.0 years) vs eras 2-4 (53.2, 52.0, and 51.8, respectively, p&lt;0.001). The percentage of biopsies diagnosed as PDWA increased from era 1-4 (25.7%, 34.3%, 35.2%, 46.2%, p&lt;0.001), as did the percentage with AH (2.4%, 5.1%, 8.6%, 12.3%, p&lt;0.001). Over eras 1-4, the percentages of women with a strong family history of BC increased (9.9%, 12.7%, 17.1%, and 29.0%, p&lt;0.001) as did mean BMI (24.8, 26.4, 27.4, and 28.6, p&lt;0.001). With a median follow-up of 10.9 years, 1,719 breast cancers have developed, with increasing proportion of noninvasive (DCIS-only) disease across eras 1-4: 15.0%, 21.1%, 21.2%, and 33.2%, p&lt; 0.001. Conclusions: Analysis of this large, single institution BBD cohort for the 46 year period 1967-2013 demonstrates that BC risk factors among BBD patients has changed over time, with subjects demonstrating increasing age, BMI, and family history, and that the percentages of BBD classified as PDWA and AH have increased. Impact on BC risk will be further investigated. Citation Format: Amy Degnim, Karthik Ghosh, Jodi M Carter, Robert A Vierkant, Matthew R Jensen, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Teresa M Allers, Denise L Gehling, Mindy J Kern, Laura M Pacheco-Spann, Celine M Vachon, Derek C Radisky, Daniel W Visscher, Mark E Sherman. Benign breast disease: Temporal trends from 1967 to 2013 [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 PS7-11.

Abstract Background: Women with benign breast disease (BBD) experience an increased risk of breast cancer (BC). Histologic classification of BBD, as non-proliferative disease (NP), proliferative disease without atypia (PDWA) or atypical hyperplasia (AH), stratifies groups of patients into progressively higher categories of BC risk. However, this classification does not comprehensively assess the proliferative state of the epithelium throughout the biopsy. In addition, while AH is considered the most high-risk class of BBD, it is not always a highly proliferative lesion; atypical ductal lesions may reflect focal cytologic and architectural changes. We evaluated the association of an alternative classification of BBD severity and BC risk based on subjective grading of: 1) the maximal degree of epithelial proliferation and 2) multifocality of epithelial proliferation. Methods: Pathologists reviewed biopsies from participants aged 18 to 85 years in the Mayo BBD cohort (2002-2013), masked to BC outcomes, ascertained via questionnaires, tumor registry data and medical record review. Biopsies were classified as NP, PDWA or AH and semi-quantitatively scored for: 1) maximal degree of epithelial proliferation within a focus (DP) (0-3; none to severe) and 2) multifocality of proliferation (MP) (0-3; none to multiple foci). DP and MP scores were also summed to give a DP+MP score (0-6). Associations of DP and MP with BC risk were examined using Cox proportional hazards regression analyses, adjusting for age at BBD biopsy. Women were followed from date of initial biopsy to date of BC, death or last follow-up. Results: Of the 1529 assessable biopsies, 544 (35.6%) were classified as NP, 708 (46.3%) as PDWA and 277 (18.1%) as AH. Both DP and MP scores had significant positive correlation with increasing BBD severity (DP: r=0.51, p&lt; 0.001; MP: r=0.52, p&lt; 0.001). Mean (SD) DP scores were 0.6 (0.6) for NP, 1.6 (0.9) for PDWA, and 1.8 (0.7) for AH (ANOVA p&lt;0.001). Mean (SD) for MP scores were 0.6 (0.6) for NP, 1.4 (0.8) for PDWA, and 1.8 (0.8) for AH (ANOVA p&lt;0.001). Mean (SD) for DP+MP scores were 1.2 (1.2) for NP, 2.9 (1.5) for PDWA, and 3.6 (1.2) for AH (ANOVA p&lt;0.001). With median follow-up of 8.8 years for controls and 5.3 years for cases, 10.6% of the women in the cohort developed BC. Compared to those with DP scores of 0, women with DP scores of 3 had significantly increased BC risk (HR 1.42, 95% CI: 1.16, 1.74, p=0.003). MP was associated with a non-significant increase in BC risk for scores of 3 versus 0 (HR: 1.20, 95% CI: 0.97,1.49, p=0.11). DP+MP scores of 6 conferred the highest BC risk (HR (score 6 vs. 0): 1.62, 95% CI 1.18,2.21, p=0.02). Results did not substantively differ after adjusting for BBD severity as NP, PDWA or AH. Conclusions: In this preliminary analysis within the Mayo BBD cohort, both proliferative degree (DP) and multifocality (MP) scores were correlated with histologic severity of BBD. DP and DP+MP scores were each associated with increased BC risk. We conclude that improved characterization of epithelial proliferation in BBD biopsies may enable refined prediction of individual BC risk. Citation Format: Jodi M Carter, Matthew R Jensen, Robert A Vierkant, Stacey J Winham, Tanya L Hoskin, Marlene Frost, Karthik Ghosh, Derek C Radisky, Amy C Degnim, Mark E Sherman. Epithelial proliferation score as an independent breast cancer risk predictor in benign breast disease [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 PD10-10.