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.

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.

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.

PURPOSE Breast cancer is the most common form of cancer among women in Latin America. Limited health care access, late-stage diagnosis, and lack of knowledge on the mutation profile of cancer susceptibility genes in low- and middle-income country populations lead to higher mortality rates. To address this health disparity, this study analyzes the breast cancer mutation profile of women from Mexico and Guatemala. Results from this study can be used to improve breast cancer screenings in these countries and for Latin American women living in the United States. METHODS Genomic and clinical data of women with breast tumors were obtained at the Instituto Nacional de Salud Publica in Mexico and Instituto Nacional de Cancerologia in Guatemala. Mutations in known breast cancer susceptibility genes were identified using targeted sequencing and were validated by manual review in the Integrative Genomics Viewer and pathogenicity determined using online databases (ClinVar and Varsome). Finally, variants were compared with corresponding clinical data for population-wide trends. RESULTS The Mexico study identified 14% of cases with pathogenic mutations in a sample of 201 patients and the Guatemala study contained 11% pathogenic mutations in 673 patients. The most frequently mutated genes for both populations were BRCA1, BRCA2, PALB2, and TP53, with BRCA1/2 mutations accounting for 7% to 10% of all variants. Patients with pathogenic mutations were found to have a significantly younger age of onset than patients without mutations, and a family history of breast cancer was pronounced in patients with pathogenic mutations. CONCLUSION The results of this study increase our understanding of the molecular and pathologic characteristics of breast cancer in Latin American women. This list of pathogenic variants and their clinical characteristics should be used to inform cancer screening, diagnosis, and treatment in the United States and abroad.

The immune system has several mechanisms to recognize tumor cells as foreign and eliminate them. Somatically altered genes can create peptides, or neoantigens, that class I HLA (HLA-I) molecules can present to cytotoxic T-cells. As a result, people with suppressed immune systems commonly have a higher rate of cancer. PanCancer data of 9423 tumor exomes from the Cancer Genome Atlas project identified 299 frequently mutated cancer genes, 4 of which (HLA-A, HLA-B, beta-2-microglobulin (B2M), and caspase-8 (CASP8) are associated with the neoantigen presentation system. By mutating genes essential to immune recognition and cytotoxicity, tumors can escape the immune system. Tumors with a high mutation burden (MB) and thus more neoantigens experience even greater pressure to mutate HLA-I genes to escape detection. Therefore, the immune system shapes tumor evolution. Tumors with a higher mutation burden respond more effectively to immune checkpoint inhibitors (ICI) such as anti-PD-L1 and anti-CTLA-4 drugs. However, there are many PD-L1 positive patients who fail to respond. These patients may have immune escape (IE) mutations inhibiting neoantigen presentation to T-cells, and a database of immune escape mutations would help inform cancer treatment and improve response to immunotherapy. From the TCGA Pan-Cancer dataset we identified samples with mutations in HLA-A, HLA-B, HLA-C and mutations or loss of B2M or CASP8. We also identified samples with microsatellite instability (MSI) and mutations in DNA Polymerase E (POLE), both of which are associated with high mutation burden. We predicted individual HLA genotypes using multiple programs and aligned tumor and normal reads to these alleles, and called mutations. We used the Integrative Genome Viewer, to validate the mutations and used multiple programs to identify potential functional effects of missense mutations. Finally, we used chi-squared tests to find associations between genes and phenotypes. There were substantially more mutations in HLA-A and HLA-B genes than in HLA-C. Loss-of-function (LoF) mutations accounted for over 50% of the mutations in HLA-A and 54% in HLA-B, but are significantly suppressed (25%) in HLA-C (X2=21; P=3 × 10-5). Since all HLA-C alleles are ligands for natural killer (NK) cell receptors (KIR) this indicates that NK cell recognition of tumor cells is important. Over 90% of HLA-I missense variants were predicted to be functional (likely to impact the stability, membrane localization, B2M binding, peptide binding of the protein, the signal peptide or T cell recognition). Cervical, head and neck, stomach, colon and lung cancer have the highest level of IE mutations (9-20%). Immune escape mutations were significantly higher in MSI (45%) and POLE mutated (72%) tumors as compared to MSI- and POLE wild type tumors (3.9%, X2=470 P&lt;&lt;0.0001). An increased knowledge of these IE mutations can be useful in identifying tumor or patient subsets that may respond better to ICI therapies. Citation Format: Megan Ren, Mathias Viard, Arman Bashirova, Meredith Yeager, Lisa Mirabello, Mary Carrington, Michael Dean. Immune escape mutations in HLA Class I, B2M and CASP8 genes shape tumor evolution [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2160.