Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies.

PURPOSE: Recruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer. METHODS: We used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala. Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala. RESULTS: We recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001). CONCLUSION: Guatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Germline variants in hereditary breast cancer genes are associated with early age at diagnosis and family history in Guatemalan breast cancer.

PURPOSE: Mutations in hereditary breast cancer genes play an important role in the risk for cancer. METHODS: Cancer susceptibility genes were sequenced in 664 unselected breast cancer cases from Guatemala. Variants were annotated with ClinVar and VarSome. RESULTS: A total of 73 out of 664 subjects (11%) had a pathogenic variant in a high or moderate penetrance gene. The most frequently mutated genes were BRCA1 (37/664, 5.6%) followed by BRCA2 (15/664, 2.3%), PALB2 (5/664, 0.8%), and TP53 (5/664, 0.8%). Pathogenic variants were also detected in the moderate penetrance genes ATM, BARD1, CHEK2, and MSH6. The high ratio of BRCA1/BRCA2 mutations is due to two potential founder mutations: BRCA1 c.212 + 1G > A splice mutation (15 cases) and BRCA1 c.799delT (9 cases). Cases with pathogenic mutations had a significantly earlier age at diagnosis (45 vs 51 years, P < 0.001), are more likely to have had diagnosis before menopause, and a higher percentage had a relative with any cancer (51% vs 37%, P = 0.038) or breast cancer (33% vs 15%, P < 0.001). CONCLUSIONS: Hereditary breast cancer mutations were observed among Guatemalan women, and these women are more likely to have early age at diagnosis and family history of cancer. These data suggest the use of genetic testing in breast cancer patients and those at high risk as part of a strategy to reduce breast cancer mortality in Guatemala.

Changes in Patient Perceptions of the Provider Most Involved in Care During COVID-19 and Corresponding Effects on Patient Trust.

During COVID-19 routine clinical operations were disrupted, including limits on the types of providers allowed to perform in-person care and frequency of times they could enter a patient's room. Whether these changes affected patients' trust in the care they received during hospitalization is unknown. Hospitalized patients on the general medicine service were called after discharge and asked to identify who (attending, resident, etc.) was most involved in their inpatient care, and how much trust they had in the physician caring for them. During the pandemic patients were more likely to report attending physicians (29% to 34%) and nurses (30% to 35%), and less likely to report residents/interns (8.1% to 6.5%) or medical students (1.7% to 1.4%) as most involved in their care (chi-squared test, p = 0.04). Patients reporting their attending physician as most involved in their care were more likely to report trusting their doctor (chi-squared test, p < 0.01). As such, trends in medical education that limit trainees' time in direct patient care may affect the development of clinical and interpersonal skills necessary to establish patient trust.

Preconception, Interconception, and reproductive health screening tools: A systematic review.

OBJECTIVE: To identify and describe the standardized interconception and preconception screening tools for reproductive health needs that are applicable in general outpatient clinical practice. DATA SOURCES AND STUDY SETTING: This systematic review identifies research on pregnancy intention screening and counseling tools, and standardized approaches to preconception and interconception care. We focus on tools designed for clinical settings, but also include research tools with potential for clinical implementation. These tools may include a component of contraceptive counseling, but those focusing solely on contraceptive counseling were excluded. Data were collected from studies done in the United States between January 2000 and March 2022. STUDY DESIGN: We performed a systematic literature search to generate a list of unique tools, assessed the quality of evidence supporting each tool, and described the peer-reviewed clinical applications of each. We used the Mixed Methods Appraisal Tool to appraise the quality of individual studies. DATA COLLECTION/EXTRACTION METHODS: We searched PubMed, Web of Science, and CINAHL databases for standardized preconception and interconception health screening tools published in English from January 2000 through March 2022. We used keywords "preconception care," "interconception care," "family planning," "contraception," "reproductive health services," and "counseling." Utilizing the Preferred Reporting Items for Systematic Reviews guidelines, we screened titles and abstracts to identify studies for full text review. PRINCIPAL FINDINGS: The search resulted in 15,399 studies. After removing 4172 duplicates, we screened 11,227 titles/abstracts and advanced 207 for full-text review. From these, we identified 53 eligible studies representing 22 tools/standardized approaches, of which 10 had evidence from randomized clinical trials. These ranged widely in design, setting, and population of study. CONCLUSIONS: Clinicians have a choice of tools when implementing standard reproductive screening services. A growing body of research can inform the selection of an appropriate tool, and more study is needed to establish effects on long-term patient outcomes.

In silico analysis of histone H3 gene expression during human brain development.

Precise regulation of chromatin structure is essential for proper development of higher eukaryotes, and methylation of histone H3 at lysine-27 (H3K27) by the Polycomb Repressive Complex 2 (PRC2) component EZH2 has emerged as an important and conserved mechanism to ensure silencing of developmentally regulated genes. Recurrent mutations within the histone H3 genes H3F3A and HIST1H3B that convert K27 to methionine (H3K27M) and disrupt the global H3K27 methylation landscape and PRC2-dependent silencing, have recently been identified in pediatric high-grade gliomas including Diffuse Intrinsic Pontine Glioma (DIPG) and Glioblastoma multiforme (GBM; Type IV glioma). These findings have generated renewed interest in the dynamics of histone genes and their expression, which have been difficult to study due to redundancy and high sequence homology within the H3 gene family. In this in silico study, we re-evaluated genomic organization of the human H3 gene family and expression of these genes in the human brain, utilizing public RNA-based sequence datasets for the human genome and brain development. We identified transcriptional activity from at least 17 protein-encoding H3 genes in the developing brain, comprising at least 14 canonical (H3.1)-like and 3 'replication-independent' (H3.3)-like forms, and encoding six distinct H3 isoforms. Transcripts for H3.3 genes including H3F3A show gradual decrease in abundance associated with developmental progression, whereas H3.1 transcripts including HIST1H3B tend to be strongly downregulated at an early prenatal stage and remain essentially silent thereafter. Twelve genes, including members of both H3.1 and H3.3 classes, contain a K27-AAG codon that is mutable to that for M (ATG), whereas the remaining contain the alternative, AAA codon for K at this position. H3F3A is the only H3.3-like gene containing the K27-AAG codon, whereas HIST1H3B is among ten H3.1-like genes containing this codon. This data indicates that, in the early developing human brain, HIST1H3B constitutes the largest proportion of H3.1 transcripts among H3.1 isoforms. We suggest that the apparent overrepresentation of K27M mutations in H3F3A relative to other H3 isoforms may result from its uniqueness among H3.3s for the K27-AAG codon and the functional relationship between H3.3 and PRC2, whereas overrepresentation of K27M mutations in HIST1H3B may be a product of strong relative expression of this gene in the early developing brain.