Genetic and Cellular Architecture of Breast Cancer Risk in Multi-Ancestry Studies of 159,297 Cases and 212,102 Controls.

Breast cancer genome-wide association studies (GWAS) have identified over 200 independent genome-wide significant susceptibility markers. However, most studies have focused on one or two ancestral groups. We examined breast cancer genetic architecture using GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR) and Hispanic/Latina (H/L) samples, totaling 159,297 cases and 212,102 controls, comprising the largest multi-ancestry study of breast cancer to date.

Genomic and Immune Landscape of Pancreatic Ductal Adenocarcinoma Associated with Germline Pathogenic Variants in ATM.

Background: Germline pathogenic variants (PVs) in ATM increase the risk of pancreatic ductal adenocarcinoma (PDAC) but the underlying tumor biology of PDAC associated with germline PVs in ATM have not been adequately explored.

Experimental Design: Whole-genome (WGS), whole-exome (WES), and RNA-sequencing were performed on PDAC tumors from 25 germline ATM PVs carriers diagnosed at Mayo Clinic between 2007 and 2017. Somatic and copy number alterations, mutational signatures, transcriptomic subtypes, and the immune landscape were evaluated.

Analysis of , and related Fanconi anemia identifies scope to expand disease phenotypic features and predict breast cancer risk in heterozygotes.

Recessive Fanconi anemia (FA) phenotype is used in classification of , and variants with respect to dominant hereditary breast-ovarian cancer syndrome. We assessed its utility by examining the spectrum of phenotypes observed in individuals biallelic for , or pathogenic variants, and exploring the relationship between cancer presentation and allele severity score based on variant molecular features. A data collection instrument comprising 158 Human Phenotype Ontology (HPO) terms was used to document clinical features for individuals with FA from published and/or prospectively collected (total n=172, 43 previously unpublished) phenotypic data.

Analysis of more than 400,000 women provides case-control evidence for BRCA1 and BRCA2 variant classification.

Clinical genetic testing identifies variants causal for hereditary cancer, information that is used for risk assessment and clinical management. Unfortunately, some variants identified are of uncertain clinical significance (VUS), complicating patient management. Case-control data is one evidence type used to classify VUS.

Risk of lymphoid malignancy associated with cancer predisposition genes.

We investigated the prevalence of rare inherited pathogenic variants (PV) in 19 cancer predisposition genes regularly included on multi-gene panel testing based on NCCN guidelines and their association with the risk of lymphoid malignancies (LM) overall and by common lymphoma subtypes and multiple myeloma. The study population included newly diagnosed LM cases (N = 6990) and unrelated controls (N = 42,632), excluding individuals with a history of hematologic malignancy. Whole exome sequencing was performed on DNA from whole blood.

Functional evaluation and clinical classification of BRCA2 variants.

Germline BRCA2 loss-of function variants, which can be identified through clinical genetic testing, predispose to several cancers. However, variants of uncertain significance limit the clinical utility of test results. Thus, there is a need for functional characterization and clinical classification of all BRCA2 variants to facilitate the clinical management of individuals with these variants.

Polygenic score distribution differences across European ancestry populations: implications for breast cancer risk prediction.

Background: The 313-variant polygenic risk score (PRS) provides a promising tool for clinical breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed.

Methods: We explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer diagnosis, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 223,316 females without breast cancer diagnosis from the UK Biobank.

Real-World Evidence on Prescribing Patterns and Clinical Outcomes of Metastatic Breast Cancer Patients Treated with PARP Inhibitors: The Mayo Clinic Experience.

Purpose: This study evaluates real-world outcomes, toxicities, and prescribing patterns of PARP inhibitors (PARPis) for the treatment of metastatic breast cancer (MBC).

Patients And Methods: Electronic health records of 62 MBC patients treated with olaparib (n = 48) or talazoparib (n = 14) at Mayo Clinic System between 2017 and 2022 were analyzed. Time-to-treatment-failure (TTF) was assessed utilizing the Kaplan-Meier method.

Pathogenic Variants in Cancer Susceptibility Genes Predispose to Ductal Carcinoma In Situ of the Breast.

Purpose: To determine the relationship between germline pathogenic variants (PV) in cancer predisposition genes and the risk of ductal carcinoma in situ (DCIS).

Experimental Design: Germline PV frequencies in breast cancer predisposition genes (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, PALB2, RAD51C, and RAD51D) were compared between DCIS cases and unaffected controls and between DCIS and invasive ductal breast cancer (IDC) cases from a clinical testing cohort (n = 9,887), a population-based cohort (n = 3,876), and the UK Biobank (n = 2,421). The risk of contralateral breast cancer (CBC) for DCIS cases with PV was estimated in the population-based cohort.

Utility of Targeted Sequencing Compared to FISH for Detection of Chronic Lymphocytic Leukemia Copy Number Alterations.

Chronic lymphocytic leukemia (CLL) is characterized by multiple copy number alterations (CNAs) and somatic mutations that are central to disease prognosis, risk stratification, and mechanisms of therapy resistance. Fluorescence in situ hybridization (FISH) panels are widely used in clinical applications as the gold standard for screening prognostic chromosomal abnormalities in CLL. DNA sequencing is an alternative approach to identifying CNAs but is not an established method for clinical CNA screening.

Functional analysis and clinical classification of 462 germline BRCA2 missense variants affecting the DNA binding domain.

Variants of uncertain significance (VUSs) in BRCA2 are a common result of hereditary cancer genetic testing. While more than 4,000 unique VUSs, comprised of missense or intronic variants, have been identified in BRCA2, the few missense variants now classified clinically as pathogenic or likely pathogenic are predominantly located in the region encoding the C-terminal DNA binding domain (DBD). We report on functional evaluation of the influence of 462 BRCA2 missense variants affecting the DBD on DNA repair activity of BRCA2 using a homology-directed DNA double-strand break repair assay.

Differences in polygenic score distributions in European ancestry populations: implications for breast cancer risk prediction.

The 313-variant polygenic risk score (PRS) provides a promising tool for breast cancer risk prediction. However, evaluation of the PRS across different European populations which could influence risk estimation has not been performed. Here, we explored the distribution of PRS across European populations using genotype data from 94,072 females without breast cancer, of European-ancestry from 21 countries participating in the Breast Cancer Association Consortium (BCAC) and 225,105 female participants from the UK Biobank.

Tumor mutational load is prognostic for progression to therapy among high-count monoclonal B-cell lymphocytosis.

High-count monoclonal B-cell lymphocytosis (HCMBL) is a precursor condition to chronic lymphocytic leukemia (CLL). We have shown that among individuals with HCMBL, the CLL-International Prognostic Index (CLL-IPI) is prognostic for time-to-first therapy (TTFT). Little is known about the prognostic impact of somatically mutated genes among individuals with HCMBL.

Saturation genome editing-based functional evaluation and clinical classification of BRCA2 single nucleotide variants.

Unlabelled: Germline BRCA2 loss-of function (LOF) variants identified by clinical genetic testing predispose to breast, ovarian, prostate and pancreatic cancer. However, variants of uncertain significance (VUS) (n>4000) limit the clinical use of testing results. Thus, there is an urgent need for functional characterization and clinical classification of all variants.

ENIGMA CHEK2gether Project: A Comprehensive Study Identifies Functionally Impaired CHEK2 Germline Missense Variants Associated with Increased Breast Cancer Risk.

Purpose: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, hampering the clinical utility of germline genetic testing (GGT).

Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.

Unlabelled: Pathogenic protein-truncating variants of RAD51C, which plays an integral role in promoting DNA damage repair, increase the risk of breast and ovarian cancer. A large number of RAD51C missense variants of uncertain significance (VUS) have been identified, but the effects of the majority of these variants on RAD51C function and cancer predisposition have not been established. Here, analysis of 173 missense variants by a homology-directed repair (HDR) assay in reconstituted RAD51C-/- cells identified 30 nonfunctional (deleterious) variants, including 18 in a hotspot within the ATP-binding region.