Citations

Background. Lynch syndrome is the most common genetic predisposition for hereditary cancer. Carriers of pathogenic changes in mismatch repair (MMR) genes have an increased risk of developing colorectal (CRC), endometrial, ovarian, urinary tract, prostate, and other cancers, depending on which gene is malfunctioning. In Lynch syndrome, differences in cancer incidence (penetrance) according to the gene involved have led to the stratification of cancer surveillance. By contrast, any differences in penetrance determined by the type of pathogenic variant remain unknown. Objective. To determine cumulative incidences of cancer in carriers of truncating and missense or aberrant splicing pathogenic variants of the MLH1 and MSH2 genes. Methods. Carriers of pathogenic variants of MLH1 (path_MLH1) and MSH2 (path_MSH2) genes filed in the Prospective Lynch Syndrome Database (PLSD) were categorized as truncating or missense/aberrant splicing according to the InSiGHT criteria for pathogenicity. Results. Among 5199 carriers, 1045 had missense or aberrant splicing variants, and 3930 had truncating variants. Prospective observation years for the two groups were 8205 and 34,141 years, respectively, after which there were no significant differences in incidences for cancer overall or for colorectal cancer or endometrial cancers separately. Conclusion. Truncating and missense or aberrant splicing pathogenic variants were associated with similar average cumulative incidences of cancer in carriers of path MLH1 and path_MSH2.

Abstract BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Nutrient excess and physical inactivity are primary drivers of numerous age‐related chronic diseases. A growing body of evidence has implicated cellular senescence, a process in which cells lose the ability to divide and concurrently damage neighboring cells by the factors they secrete, as an underlying mechanism of aging and its associated conditions. However, the impact of lifestyle choices on the age‐associated accumulation of senescent cells remains poorly understood. Thus, we examined the effects of a fast food diet (FFD) and a voluntary exercise intervention on multiple parameters of healthspan and cellular senescence using a transgenic mouse model that expresses green fluorescent protein (GFP) in p16 Ink4a ‐positive senescent cells. As expected, 12‐month old male mice that had received the FFD diet for 5 months demonstrated significantly greater gains in body weight and fat mass compared to mice fed a standard chow diet. Moreover, mice fed the FFD exhibited hyperinsulinemia, impaired glucose tolerance, reduced exercise capacity, and diastolic dysfunction. Impressively, providing an exercise wheel (26.9 ± 6.9 km/wk) in parallel with the FFD nullified the deleterious effects of the FFD on body weight and composition, whole‐body metabolism, physical performance and cardiac function. Strikingly, our data further suggest that exercise markedly lowers the number of cells in visceral fat depots that express GFP and stain positively for senescent‐associated β‐galactosidase; markers of senescence, that are highly abundant in sedentary mice fed the FFD. Correspondingly, FFD‐induced expression of senescence‐associated inflammatory factors was also diminished by the exercise intervention. Collectively, our data suggest that lifestyle choices may affect the abundance of senescence cells with advancing age, and exercise may partly mediate its salutary effects on multiple organ systems by preventing their accumulation and/or mediating their removal.

Abstract Lineage-ambiguous leukemias are high-risk malignancies of poorly understood genetic basis. Here, we describe a distinct subgroup of acute leukemia with expression of myeloid, T lymphoid, and stem cell markers driven by aberrant allele-specific deregulation of BCL11B, a master transcription factor responsible for thymic T-lineage commitment and specification. Mechanistically, this deregulation was driven by chromosomal rearrangements that juxtapose BCL11B to superenhancers active in hematopoietic progenitors, or focal amplifications that generate a superenhancer from a noncoding element distal to BCL11B. Chromatin conformation analyses demonstrated long-range interactions of rearranged enhancers with the expressed BCL11B allele and association of BCL11B with activated hematopoietic progenitor cell cis-regulatory elements, suggesting BCL11B is aberrantly co-opted into a gene regulatory network that drives transformation by maintaining a progenitor state. These data support a role for ectopic BCL11B expression in primitive hematopoietic cells mediated by enhancer hijacking as an oncogenic driver of human lineage-ambiguous leukemia. Significance: Lineage-ambiguous leukemias pose significant diagnostic and therapeutic challenges due to a poorly understood molecular and cellular basis. We identify oncogenic deregulation of BCL11B driven by diverse structural alterations, including de novo superenhancer generation, as the driving feature of a subset of lineage-ambiguous leukemias that transcend current diagnostic boundaries. This article is highlighted in the In This Issue feature, p. 2659

e20016 Background: An elevated serum LDH level is an adverse prognostic factor in NDMM. However, this category includes quantitative serum LDH levels that range from just over the upper limit of normal (ULN) to levels that may be 2 or more-fold higher than the ULN. This binary classification of serum LDH level of “normal versus elevated” fails to discriminate between the different disease biology that exists among NDMM patients with elevated serum LDH levels. Thus, we attempted to further stratify NDMM patients by the level of their serum LDH and determine its impact on OS. Methods: The cohort included patients diagnosed with NDMM from the Mayo Clinic, Rochester from 2003 - 2017 who were treated with novel agent induction therapy and had serum LDH levels measured at the time of diagnosis. The serum LDH levels were stratified into three levels: Normal (LDH < 222 U/L), Elevated (LDH 223-444 U/L), and Very Elevated (LDH >444 U/L or >2x upper limit of normal). Survival analysis was performed using the Kaplan-Meier survival analysis and compared via the log-rank method. Results: The cohort consists of 1,196 NDMM patients with a median age of 65 (22 – 95). R-ISS classification and cytogenetic risk were available for 968 and 970 patients respectively. The median serum LDH level was (162 U/L (3- 1260)) and an elevated LDH was present in 199 patients (17%). The median OS for patients with normal (N = 997; 83%), elevated (N = 170; 13%) and very elevated (N = 29; 3%) LDH levels were 76 months, 57 months and 23 months respectively (P < 0.001). The impact of these different levels of LDH on OS by R-ISS stage and cytogenetic risk is shown in the Table. Conclusions: A very small subset of NDMM patients has very elevated LDH levels that confer an exceptionally poor OS irrespective of R-ISS stage and cytogenetic risk. Future studies elucidating their disease biology responsible for such poor OS outcomes are warranted.[Table: see text]

4136 Background: The genomic alterations which characterize PDAC holds great promise for novel therapeutic interventions. Constitutive signaling via mutated KRAS is considered the signature pathognomonic alteration in PDAC, less than 10% of patients (pts) have tumors which are KRAS wild type (WT). We retrospectively reviewed our institutional genomic database to characterize PDAC pts with KRAS WT tumors. Methods: We reviewed electronic medical records of PDAC pts who underwent comprehensive genomic profiling (CPG) utilizing Foundation One CDx (50.6%) or TEMPUS (49.4%) between 2015-2020. Demographic and disease characteristics were compared between cohorts using Wilcoxon rank-sum test or chi-square tests. Left truncation at the time of CGP was used to account for the time of entry into the study cohort. Kaplan-Meier method was used for survival curve estimation, and log-rank test was used for between-group comparison. Cox regression was used to adjust for confounders. Results: We identified 235 patients: median age at diagnosis was 65 years and 52% were male. Clinical stages at diagnosis were localized (resectable/borderline resectable), locally advanced, or metastatic in 105 (44.7%), 61 (26.0%), and 69 (29.4%) patients, respectively. KRAS status was mutated in 212 (90%) patients: the most common alterations being G12D (48%), G12V (28%) and G12R (14%). KRAS WT status was noted in 23 (9.8%) pts, actionable genomic alterations in this subgroup are summarized in the table. Baseline demographic and treatment characteristics were similar between patients with KRAS mutated and WT tumors. Of the 23 patients with KRAS WT tumors, 16 (69.6%) completed all planned curative intent therapy compared to 121 (57.3%) of the 212 KRAS mutated pts (p=0.26). Median Overall Survival of patients with KRAS mutated tumors was 18.6 months compared to 44.1 months for WT pts (p=0.03). Adjusting for stage, WT vs. mutated status was associated with a 62% decreased hazard of death (HR 0.38 [0.18-0.83]; p=0.016). Conclusions: Patients with KRAS WT PDAC appear to have a distinct biology compared to those with KRAS mutations, meriting exploration in larger data sets. Further, comprehensive whole genome or transcriptomic characterization of KRAS WT tumors is necessary to identify putative driver alterations as well as actionable therapeutic targets.[Table: see text]

Abstract Background: Use of menopausal hormone therapy (MHT) is associated with increased risk for breast cancer. However, the relevant mechanisms and its interaction with genetic variants are not fully understood. Methods: We conducted a genome-wide interaction analysis between MHT use and genetic variants for breast cancer risk in 27,585 cases and 34,785 controls from 26 observational studies. All women were post-menopausal and of European ancestry. Multivariable logistic regression models were used to test for multiplicative interactions between genetic variants and current MHT use. We considered interaction p-values<5x10-8 as genome-wide significant, and p-values<1x10-5 as suggestive. Linkage disequilibrium (LD)-based clumping was performed to identify independent candidate variants.Results: None of the 9.7 million genetic variants tested for interactions with MHT use reached genome-wide significance. Only 213 variants, representing 18 independent loci, had p-values<1x105. The strongest evidence was found for rs4674019 (p-value=2.27x10-7), which showed genome-wide significant interaction (p-value=3.8x10-8) with current MHT use when analysis was restricted to population-based studies only. Limiting the analyses to combined estrogen-progesterone MHT use only or to estrogen receptor (ER) positive cases did not identify any genome-wide significant evidence of interactions. Conclusions: In this large genome-wide SNP-MHT interaction study of breast cancer, we found no strong support for common genetic variants modifying the effect of MHT on breast cancer risk. These results suggest that common genetic variation has limited impact on the observed MHT–breast cancer risk association.

Abstract Background Reductions in the use of broad-spectrum antibiotics is a cornerstone of antimicrobial stewardship. We aim to demonstrate use of the Desirability of Outcome Ranking Approach for the Management of Antimicrobial Therapy (DOOR MAT) to evaluate the treatment of Escherichia coli and Klebsiella pneumoniae bloodstream infections in patients from the Veterans Health Administration (VHA) across a decade. Methods Using electronic records, we determined empiric and definitive antibiotic treatments, clinical characteristics, and 30-day mortality of patients with monomicrobial E. coli and K. pneumoniae bloodstream infections hospitalized in VHA medical centers from 2009 to 2018. Focusing on patients treated with parenteral β-lactams and with available antibiotic susceptibility testing results, we applied a range of DOOR MAT scores that reflect the desirability of antibiotic choices according to spectrum and activity against individual isolates. We report trends in resistance and desirability of empiric and definitive antibiotic treatments. Results During the 10-year period analyzed, resistance to expanded-spectrum cephalosporins and fluoroquinolones increased in E. coli but not in K. pneumoniae, while resistance to carbapenems and piperacillin-tazobactam remained unchanged. In 6451 cases analyzed, we observed improvements in DOOR MAT scores consistent with deescalation. Improvement in desirability of definitive treatment compared with empiric treatment occurred in 26% of cases, increasing from 16% in 2009 to 34% in 2018. Reductions in overtreatment were sustained and without negative impact on survival. Conclusions DOOR MAT provides a framework to assess antibiotic treatment of E. coli and K. pneumoniae bloodstream infections and can be a useful metric in antimicrobial stewardship.

Abstract Background Across complex traits, common variants explain only a modest amount of variance, with SNP-heritability consistently below heritability estimates from close relatives. Here, we examined the contribution of rare variant to tobacco use risk in up to 26,000 individuals of European ancestry in the Trans-Omics for Precision Medicine (TOPMed) program with whole genome sequence (WGS;~30X coverage).Method We grouped about 35 million genetic variants by their minor allele frequencies (MAF) and linkage disequilibrium (LD) and estimated SNP-heritability for age of smoking initiation (N = 14,747), cigarettes smoked per day (N = 15,425), smoking cessation (N = 17,871) and initiation (N = 26,340) using linear mixed model. Rare variant population structure is detected and adjusted for by permutation procedure. We estimated an upper bound for narrow-sense heritability for tobacco use using available pedigrees consisting of close relatives in TOPMed.Results Rare variants with MAF 0.1–0.01%, mostly from non-protein altering region, accounted for 26% of variation in age of initiation and 15% for cessation. Follow-up analysis indicated that about one-third of these rare variants contribtion is potentially confounded with rare variants structure even after adjusting for principal components. After further conservative adjustment of population structure, we estimated SNP-based heritability to be 0.21 (SE = 0.08) for age of initiation, 0.15 (0.06) for cigarettes per day, 0.21 (0.09) for cessation, and 0.24 (0.07) for initiation, 1.8–4.5 times higher than previous SNP-based estimates. Our pedigree-based upper-bound for SNP-based heritability ranged from 0.18–0.35.Conclusion The substantial contribution of rare variants for several smoking phenotypes sheds light on the missing heritability and genetic etiology of tobacco use. It also informs fine-mapping strategies since the majority of the rare variant contribution was located in non-coding regulatory regions.