Secondary somatic glioblastoma arising from a mature ovarian cystic teratoma in a patient with underlying Li-Fraumeni syndrome.

•First report of a secondary somatic glioblastoma arising from MCT-MT in a patient with underlying Li-Fraumeni syndrome.•The rarity of glioblastoma arising from MCT-MT warrants investigation for underlying genetic predisposition.•Glioblastomas arising from MCT-MT appear to exhibit wild type IDH gene status.•Advanced-stage glioblastoma arising from MCT-MT exhibits aggressive behavior and requires adjuvant therapy.•Optimal adjuvant therapy regimen for glioblastoma arising from MCT-MT remains unknown.

Coverage of Fertility Preservation and Treatment Among Surgical Trainees in the United States of America.

INTRODUCTION: Surgery trainees spend their prime fertility years in training, which leads to delays in childbearing, accompanying infertility challenges, and high-risk pregnancies. Literature report of institutional support for fertility preservation (egg/sperm freezing) and treatment is lacking. The cost is particularly prohibitive while receiving a resident physician salary. This study aimed to assess availability of fertility resources and institutional coverage of fertility services to US General Surgery Residents (GSR) and Breast Fellows. METHODS: We composed and distributed a 26-question survey to GS residency and fellowship program directors nationwide to survey residents and fellows. Summary and descriptive statistics were tabulated, and categorical variables were analyzed using Pearson's chi square test. RESULTS: A total of 234 US surgical trainees (male n = 75, female n = 155, unreported n = 4) completed the survey. Total of 12 % of trainees reported having been counseled on family planning/fertility treatment during training, and only 5.1% were counseled on fertility preservation. Perceived lack of support from program (p = 0.027) and counseling of fertility preservation (p = 0.009) were significantly associated with female gender. A minority (12.5%) reported having insurance coverage for fertility preservation and 26% had coverage of fertility treatment. In addition, 2.6% respondents pursued fertility preservation while in training and 33% reported they would pursue fertility preservation if it was covered by insurance. CONCLUSIONS: Fertility preservation is rarely discussed in US General Surgery residency programs. The large majority of GSR lacks awareness of insurance coverage of fertility preservation and treatment. Strong efforts are necessary to improve fertility education for GSR and insurance coverage to meet trainee's needs.

Targeted cancer treatment and fertility: effect of immunotherapy and small molecule inhibitors on female reproduction.

Targeted cancer therapy is rapidly evolving the landscape of personalized health care. Novel approaches to selectively impeding tumour growth carry significant potential to improve survival outcomes, particularly for reproductive-aged patients harbouring treatment refractory disease. Current agents fall within two classes: immunotherapy and small molecule inhibitors. These are collectively divided into the following subclasses: monoclonal antibodies; immunomodulators; adoptive cell therapy; treatment vaccines; kinase inhibitors; proteasome inhibitors; metalloproteinase and heat shock protein inhibitors; and promoters of apoptosis. The short- and long-term effects of these treatments on the female reproductive system are not well understood. As a result, clinicians are rendered unable to appropriately counsel women on downstream effects to their fertility. Data-driven consensus recommendations are desperately needed. This review aims to characterize the effect of targeted cancer therapy on the female hypothalamic-pituitary-ovary axis, direct ovarian function and conception.

The Microbiome and Gynecologic Cancer: Current Evidence and Future Opportunities.

PURPOSE OF REVIEW: We review the emerging evidence regarding the relationship between the microbiota of the gastrointestinal and female reproductive tracts and gynecologic cancer. RECENT FINDINGS: The microbiome has essential roles in maintaining health. In recent years, the microbiota of the gastrointestinal and female reproductive tracts have been linked to many diseases, including gynecologic cancer. Alterations to the bacterial populations in a microbiota, or dysbiosis, have been shown to favor a pro-carcinogenic state through altered immune responses, dysregulated hormone metabolism, and modulation of the cell cycle. Pre-clinical and clinical studies have emerged, demonstrating that specific bacteria or microbial communities may be associated with increased risk for uterine, ovarian, and cervical cancers. Notably, numerous studies have linked a non-Lactobacillus-dominant vaginal microbiota, composed of anaerobic bacteria, with HPV infection, persistence, and development of invasive cervical cancer. Similarly, next-generation high-throughput sequencing techniques have enabled the characterization of unique microbiotas in patients with malignant and benign gynecologic conditions, shedding light on new associations between bacterial species and gynecologic cancers. Harnessing the power of the microbiome for early diagnosis, therapeutic intervention and modulation creates tremendous potential to optimize gynecologic cancer outcomes in the future.

Linkage of Alzheimer disease families with Puerto Rican ancestry identifies a chromosome 9 locus.

The genetic admixture of Caribbean Hispanics provides an opportunity to discover novel genetic factors in Alzheimer disease (AD). We sought to identify genetic variants for AD through a family-based design using the Puerto Rican (PR) Alzheimer Disease Initiative (PRADI). Whole-genome sequencing (WGS) and parametric linkage analysis were performed for 100 individuals from 23 multiplex PRADI families. Variants were prioritized by minor allele frequency (<0.01), functional potential [combined annotation dependent depletion score (CADD) >10], and co-segregation with AD. Variants were further ranked using an independent PR case-control WGS dataset (PR10/66). A genome-wide significant linkage peak was found in 9p21 with a heterogeneity logarithm of the odds score (HLOD) >5.1, which overlaps with an AD linkage region from two published independent studies. The region harbors C9orf72, but no expanded repeats were observed in the families. Seven variants prioritized by the PRADI families also displayed evidence for association in the PR10/66 (p < 0.05), including a missense variant in UNC13B. Our study demonstrated the importance of family-based design and WGS in genetic study of AD.

Increased APOE ε4 expression is associated with the difference in Alzheimer's disease risk from diverse ancestral backgrounds.

INTRODUCTION: Apolipoprotein E (APOE) ε4 confers less risk for Alzheimer's disease (AD) in carriers with African local genomic ancestry (ALA) than APOE ε4 carriers with European local ancestry (ELA). Cell type specific transcriptional variation between the two local ancestries (LAs) could contribute to this disease risk differences. METHODS: Single-nucleus RNA sequencing was performed on frozen frontal cortex of homozygous APOE ε4/ε4 AD patients: seven with ELA, four with ALA. RESULTS: A total of 60,908 nuclei were sequenced. Within the LA region (chr19:44-46Mb), APOE was the gene most differentially expressed, with ELA carriers having significantly more expression (overall P < 1.8E-317 ) in 24 of 32 cell clusters. The transcriptome of one astrocyte cluster, with high APOE ε4 expression and specific to ELA, is suggestive of A1 reactive astrocytes. DISCUSSION: AD patients with ELA expressed significantly greater levels of APOE than ALA APOE ε4 carriers. These differences in APOE expression could contribute to the reduced risk for AD seen in African APOE ε4 carriers.

Novel Variants in LRRK2 and GBA Identified in Latino Parkinson Disease Cohort Enriched for Caribbean Origin.

Background: The Latino population is greatly understudied in biomedical research, including genetics. Very little information is available on presence of known variants originally identified in non-Hispanic white patients or novel variants in the Latino population. The Latino population is admixed, with contributions of European, African, and Amerindian ancestries. Therefore, the ancestry surrounding a gene (local ancestry, LA) can be any of the three contributing ancestries and thus can determine the presence or risk effect of variants detected. Methods: We sequenced the major exons and exons of reported Latino-specific variants in GBA and LRRK2 and performed genome-wide genotyping for LA assessments in 79 Latino Parkinson disease (PD) patients, of which ~80% identified as Caribbean Latino. Results: We observed five carriers of LRRK2 p.G2019S, one GBA p.T408M, and three GBA p.N409S on European as well as three GBA p.L13R on African LA backgrounds. Previous Latino variant GBA p.K237E was not observed in this dataset. A novel highly conserved and predicted damaging variant LRRK2 p.D734N was identified in two unrelated individuals with African LA. Additionally, we identified rare, functional variants LRRK2 p.P1480L and GBA p.S310G in one individual each heterozygous for European/Amerindian LA. Discussion: Additional functional analysis will be needed to determine the pathogenicity of the novel variants in PD. However, the identification of novel disease variants in the Latino cohort potentially contributing to PD supports to importance of inclusion of Latinos in genetics research to provide insight in PD genetics in Latinos specifically as well as other populations with the same ancestral contributions.

Thrombocytosis as a Biomarker in Type II, Non-Endometrioid Endometrial Cancer.

Thrombocytosis (platelets ≥ 400K) is a common hematologic finding in gynecologic malignancies and associated with worse outcomes. Limited data exist on the prognostic capability of thrombocytosis in women with high-grade endometrial cancer (EC). Our objective was to describe the associations between elevated platelets at diagnosis, clinicopathologic features, and survival outcomes among women with high-grade, non-endometrioid EC. A review of the institutional cancer registry was performed to identify these women treated between 2005 and 2017. Sociodemographic, clinical, and outcomes data were collected. Analyses were performed using chi-square tests, Cox proportional hazards models, and the Kaplan-Meier method. A total of 271 women were included in the analysis. A total of 19.3% of women had thrombocytosis at diagnosis. Thrombocytosis was associated with reduced median overall survival (OS) compared with those not displaying thrombocytosis (29.4 months vs. 60 months, p < 0.01). This finding was most pronounced in uterine serous carcinoma (16.4 months with thrombocytosis vs. 34.4 months without, p < 0.01). While non-White women had shorter median OS for the whole cohort in the setting of thrombocytosis (29.4 months vs. 39.6 months, p < 0.01), among those with uterine serous carcinoma (USC), this finding was reversed, with decreased median OS in White women (22.1 vs. 16.4 months, p = 0.01). Thrombocytosis is concluded to have negative associations with OS and patient race.

Dual Fulvestrant-Trametinib Therapy in Recurrent Low-Grade Serous Ovarian Cancer.

Low-grade serous ovarian carcinoma (LGSOC) is known to exhibit chemoresistance. Effective treatment options for recurrent disease are few and often limited to hormone antagonism. Combination of endocrine therapies with MEK-inhibitors displays synergism in preclinical ovarian cancer models, however. This brief communication presents the use of combination anti-estrogenic and MEK-inhibitor therapies, fulvestrant and trametinib, as treatment in a heavily pretreated patient with estrogen receptor-positive, recurrent LGSOC. The dual-therapy regimen was well tolerated and appeared to confer 9 months of progression-free survival. Further investigation is warranted to explore this effect.

Use of local genetic ancestry to assess TOMM40-523' and risk for Alzheimer disease.

OBJECTIVE: Here, we re-examine TOMM40-523' as a race/ethnicity-specific risk modifier for late-onset Alzheimer disease (LOAD) with adjustment for local genomic ancestry (LGA) in Apolipoprotein E (APOE) ε4 haplotypes. METHODS: The TOMM40-523' size was determined by fragment analysis and whole genome sequencing in homozygous APOE ε3 and APOE ε4 haplotypes of African (AF) or European (EUR) ancestry. The risk for LOAD was assessed within groups by allele size. RESULTS: The TOMM40-523' length did not modify risk for LOAD in APOE ε4 haplotypes with EUR or AF LGA. Increasing length of TOMM40-523' was associated with a significantly reduced risk for LOAD in EUR APOE ε3 haplotypes. CONCLUSIONS: Adjustment for LGA confirms that TOMM40-523' cannot explain the strong differential risk for LOAD between APOE ε4 with EUR and AF LGA. Our study does confirm previous reports that increasing allele length of the TOMM40-523' repeat is associated with decreased risk for LOAD in carriers of homozygous APOE ε3 alleles and demonstrates that this effect is occurring in those individuals with the EUR LGA APOE ε3 allele haplotype.

Endometrial cancer among a cohort of urban Haitian immigrants.

BACKGROUND: Black women are known to have a higher risk of aggressive endometrial cancers. Little data exist about the role of nativity as a determinant of survival outcomes in women with this disease. AIM: Our objective was to evaluate a population of Haitian immigrants with endometrial cancer in an urban setting using the Florida Cancer Data System (FCDS). METHODS: A search of FCDS identified 107 women born in Haiti and who received treatment for invasive endometrial cancer in Miami-Dade County between 1989 and 2013. Clinicopathologic data were extracted to describe the cohort and assess associations with overall survival. Statistical analyses were performed using Cox proportional hazards models, the log-rank test, and the Kaplan-Meier method, with significance set at P ≤ 0.05. RESULTS: Median age at diagnosis was 65 years. 63.9% of the patients had a type II, high-grade, histology, and 52.6% presented with extrauterine metastatic disease. Nearly three quarters had health insurance. Within the entire cohort, only presence of extrauterine disease was associated with worse overall survival [Hazard ratio (HR) = 2.70, 95% confidence interval (CI): 1.31-5.57, P = 0.007]. However, after stratification by histologic grade, both age (HR = 0.88, 95%CI: 0.81-0.96, P = 0.002) and extrauterine disease (HR = 2.49, 95%CI: 1.01-6.21, P = 0.049) were independently associated with worse survival, but only in women with type II malignancies. CONCLUSION: Urban Haitian women with endometrial cancer have a high burden of aggressive histologies. Additional investigation to explain the etiology of these findings is needed.

The Puerto Rico Alzheimer Disease Initiative (PRADI): A Multisource Ascertainment Approach.

INTRODUCTION: Puerto Ricans, the second largest Latino group in the continental US, are underrepresented in genomic studies of Alzheimer disease (AD). To increase representation of this group in genomic studies of AD, we developed a multisource ascertainment approach to enroll AD patients, and their family members living in Puerto Rico (PR) as part of the Alzheimer's Disease Sequencing Project (ADSP), an international effort to advance broader personalized/precision medicine initiatives for AD across all populations. METHODS: The Puerto Rico Alzheimer Disease Initiative (PRADI) multisource ascertainment approach was developed to recruit and enroll Puerto Rican adults aged 50 years and older for a genetic research study of AD, including individuals with cognitive decline (AD, mild cognitive impairment), their similarly, aged family members, and cognitively healthy unrelated individuals age 50 and up. Emphasizing identification and relationship building with key stakeholders, we conducted ascertainment across the island. In addition to reporting on PRADI ascertainment, we detail admixture analysis for our cohort by region, group differences in age of onset, cognitive level by region, and ascertainment source. RESULTS: We report on 674 individuals who met standard eligibility criteria [282 AD-affected participants (42% of the sample), 115 individuals with mild cognitive impairment (MCI) (17% of the sample), and 277 cognitively healthy individuals (41% of the sample)]. There are 43 possible multiplex families (10 families with 4 or more AD-affected members and 3 families with 3 AD-affected members). Most individuals in our cohort were ascertained from the Metro, Bayamón, and Caguas health regions. Across health regions, we found differences in ancestral backgrounds, and select clinical traits. DISCUSSION: The multisource ascertainment approach used in the PRADI study highlights the importance of enlisting a broad range of community resources and providers. Preliminary results provide important information about our cohort that will be useful as we move forward with ascertainment. We expect that results from the PRADI study will lead to a better understanding of genetic risk for AD among this population.

BAP1 Loss Is Associated with DNA Methylomic Repatterning in Highly Aggressive Class 2 Uveal Melanomas.

PURPOSE: The strong association between BAP1 mutations and metastasizing Class 2 uveal melanoma (UM) suggests that epigenetic alterations may play a significant role in tumor progression. Thus, we characterized the impact of BAP1 loss on the DNA methylome in UM.Experimental Design: Global DNA methylation was analyzed in 47 Class 1 and 45 Class 2 primary UMs and in UM cells engineered to inducibly deplete BAP1. RNA-Seq was analyzed in 80 UM samples and engineered UM cells. RESULTS: Hypermethylation on chromosome 3 correlated with downregulated gene expression at several loci, including 3p21, where BAP1 is located. Gene set analysis of hypermethylated and downregulated genes identified axon guidance and melanogenesis as deregulated pathways, with several of these genes located on chromosome 3. A novel hypermethylated site within the BAP1 locus was found in all Class 2 tumors, suggesting that BAP1 itself is epigenetically regulated. Highly differentially methylated probes were orthogonally validated using bisulfite sequencing, and they successfully distinguished Class 1 and Class 2 tumors in 100% of cases. In functional validation experiments, BAP1 knockdown in UM cells induced methylomic repatterning similar to UM tumors, enriched for genes involved in axon guidance, melanogenesis, and development. CONCLUSIONS: This study, coupled with previous work, suggests that the initial event in the divergence of Class 2 UM from Class 1 UM is loss of one copy of chromosome 3, followed by mutation of BAP1 on the remaining copy of chromosome 3, leading to the methylomic repatterning profile characteristic of Class 2 UMs.

Ancestral origin of ApoE ε4 Alzheimer disease risk in Puerto Rican and African American populations.

The ApoE ε4 allele is the most significant genetic risk factor for late-onset Alzheimer disease. The risk conferred by ε4, however, differs across populations, with populations of African ancestry showing lower ε4 risk compared to those of European or Asian ancestry. The cause of this heterogeneity in risk effect is currently unknown; it may be due to environmental or cultural factors correlated with ancestry, or it may be due to genetic variation local to the ApoE region that differs among populations. Exploring these hypotheses may lead to novel, population-specific therapeutics and risk predictions. To test these hypotheses, we analyzed ApoE genotypes and genome-wide array data in individuals from African American and Puerto Rican populations. A total of 1,766 African American and 220 Puerto Rican individuals with late-onset Alzheimer disease, and 3,730 African American and 169 Puerto Rican cognitively healthy individuals (> 65 years) participated in the study. We first assessed average ancestry across the genome ("global" ancestry) and then tested it for interaction with ApoE genotypes. Next, we assessed the ancestral background of ApoE alleles ("local" ancestry) and tested if ancestry local to ApoE influenced Alzheimer disease risk while controlling for global ancestry. Measures of global ancestry showed no interaction with ApoE risk (Puerto Rican: p-value = 0.49; African American: p-value = 0.65). Conversely, ancestry local to the ApoE region showed an interaction with the ApoE ε4 allele in both populations (Puerto Rican: p-value = 0.019; African American: p-value = 0.005). ApoE ε4 alleles on an African background conferred a lower risk than those with a European ancestral background, regardless of population (Puerto Rican: OR = 1.26 on African background, OR = 4.49 on European; African American: OR = 2.34 on African background, OR = 3.05 on European background). Factors contributing to the lower risk effect in the ApoE gene ε4 allele are likely due to ancestry-specific genetic factors near ApoE rather than non-genetic ethnic, cultural, and environmental factors.