scholarly journals The impact of rare germline variants on human somatic mutation processes

2021 ◽  
Author(s):  
Mischan Vali-Pour ◽  
Ben Lehner ◽  
Fran Supek
Keyword(s):  
Somatic Mutation ◽  
Human Cancer ◽  
European Ancestry ◽  
Novel Genes ◽  
Data Set ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Germline Variation ◽  
The Impact ◽  
Mutational Processes

Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We performed a comprehensive gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a FDR of 1%. We associated rare inherited deleterious variants in novel genes such as MSH3, EXO1, SETD2, and MTOR with two different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, and WRN with deficiency in homologous recombination repair. In addition, we identified associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the novel genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the newly-identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

scholarly journals Mutational signatures of DNA mismatch repair deficiency in C. elegans and human cancers

2017 ◽  
Author(s):  
B Meier ◽  
NV Volkova ◽  
Y Hong ◽  
P Schofield ◽  
PJ Campbell ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Dna Mismatch Repair ◽  
Mutational Signatures ◽  
Dna Mismatch ◽  
C Elegans ◽  
Replication Errors ◽  
Human Cancers ◽  
Repair Deficiency ◽  
Mmr Deficiency ◽  
Mutational Processes

ABSTRACTThroughout their lifetime cells are subject to extrinsic and intrinsic mutational processes leaving behind characteristic signatures in the genome. DNA mismatch repair (MMR) deficiency leads to hypermutation and is found in different cancer types. While it is possible to associate mutational signatures extracted from human cancers with possible mutational processes the exact causation is often unknown. Here we use C. elegans genome sequencing of pms-2 and mlh-1 knockouts to reveal the mutational patterns linked to C. elegans MMR deficiency and their dependency on endogenous replication errors and errors caused by deletion of the polymerase ε subunit pole-4. Signature extraction from 215 human colorectal and 289 gastric adenocarcinomas revealed three MMR-associated signatures, one of which closely resembles the C. elegans MMR spectrum and strongly discriminates microsatellite stable and unstable tumors (AUC=98%). A characteristic difference between human and C. elegans MMR deficiency is the lack of elevated levels of NCG>NTG mutations in C. elegans, likely caused by the absence of cytosine (CpG) methylation in worms. The other two human MMR signatures may reflect the interaction between MMR deficiency and other mutagenic processes, but their exact cause remains unknown. In summary, combining information from genetically defined models and cancer samples allows for better aligning mutational signatures to causal mutagenic processes.

scholarly journals Mismatch repair deficiency is not sufficient to increase tumor immunogenicity

2021 ◽  
Author(s):  
Peter M K Westcott ◽  
Francesc Muyas ◽  
Olivia Smith ◽  
Haley Hauck ◽  
Nathan J Sacks ◽  
...  
Keyword(s):  
Mismatch Repair ◽  
Human Cancer ◽  
Tumor Cell Line ◽  
Immune Checkpoint Blockade ◽  
Mismatch Repair Deficiency ◽  
Dna Mismatch ◽  
T Cell Infiltration ◽  
Repair Deficiency ◽  
Tumor Mutational Burden

AbstractDNA mismatch repair deficiency (MMRd) in human cancer is associated with high tumor mutational burden (TMB), frameshift mutation-derived neoantigens, increased T cell infiltration, and remarkable responsiveness to immune checkpoint blockade (ICB) therapy. Nevertheless, about half of MMRd tumors do not respond to ICB for unclear reasons. While tumor cell line transplant models of MMRd have reinforced the importance of TMB in immune response, critical questions remain regarding the role of immunosurveillance in the evolution of MMRd tumors induced in vivo. Here, we developed autochthonous mouse models of lung and colon cancer with highly efficient ablation of MMR genes via in vivo CRISPR/Cas9 targeting. Surprisingly, MMRd in these models did not result in increased immunogenicity or response to ICB. Mechanistically, we showed this lack of immunogenicity to be driven by profound intratumoral heterogeneity (ITH). Studies in animals depleted of T cells further demonstrated that immunosurveillance in MMRd tumors has no impact on TMB but shapes the clonal architecture of neoantigens by exacerbating ITH. These results provide important context for understanding immune evasion in cancers with high TMB and have major implications for therapies aimed at increasing TMB.

scholarly journals Process-specific somatic mutation distributions vary with three-dimensional genome structure

2018 ◽  
Author(s):  
Kadir C. Akdemir ◽  
Victoria T. Le ◽  
Sarah Killcoyne ◽  
Devin A. King ◽  
Ya-Ping Li ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
X Chromosome ◽  
Genome Organization ◽  
Somatic Mutations ◽  
Light Exposure ◽  
Human Cancer ◽  
Three Dimensional ◽  
Cancer Evolution ◽  
Cancer Types ◽  
Mutational Processes

AbstractSomatic mutations arise during the life history of a cell. Mutations occurring in cancer driver genes may ultimately lead to the development of clinically detectable disease. Nascent cancer lineages continue to acquire somatic mutations throughout the neoplastic process and during cancer evolution (Martincorena and Campbell, 2015). Extrinsic and endogenous mutagenic factors contribute to the accumulation of these somatic mutations (Zhang and Pellman, 2015). Understanding the underlying factors generating somatic mutations is crucial for developing potential preventive, therapeutic and clinical decisions. Earlier studies have revealed that DNA replication timing (Stamatoyannopoulos et al., 2009) and chromatin modifications (Schuster-Böckler and Lehner, 2012) are associated with variations in mutational density. What is unclear from these early studies, however, is whether all extrinsic and exogenous factors that drive somatic mutational processes share a similar relationship with chromatin state and structure. In order to understand the interplay between spatial genome organization and specific individual mutational processes, we report here a study of 3000 tumor-normal pair whole genome datasets from more than 40 different human cancer types. Our analyses revealed that different mutational processes lead to distinct somatic mutation distributions between chromatin folding domains. APOBEC- or MSI-related mutations are enriched in transcriptionally-active domains while mutations occurring due to tobacco-smoke, ultraviolet (UV) light exposure or a signature of unknown aetiology (signature 17) enrich predominantly in transcriptionally-inactive domains. Active mutational processes dictate the mutation distributions in cancer genomes, and we show that mutational distributions shift during cancer evolution upon mutational processes switch. Moreover, a dramatic instance of extreme chromatin structure in humans, that of the unique folding pattern of the inactive X-chromosome leads to distinct somatic mutation distribution on X chromosome in females compared to males in various cancer types. Overall, the interplay between three-dimensional genome organization and active mutational processes has a substantial influence on the large-scale mutation rate variations observed in human cancer.

scholarly journals Mutational Signatures Driven by Epigenetic Determinants Enable the Stratification of Patients with Gastric Cancer for Therapeutic Intervention

Cancers ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 490
Author(s):  
Jaqueline Ramalho Buttura ◽  
Monize Nakamoto Provisor Santos ◽  
Renan Valieris ◽  
Rodrigo Duarte Drummond ◽  
Alexandre Defelicibus ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Treatment Effectiveness ◽  
De Novo ◽  
Area Under The Curve ◽  
Promoter Hypermethylation ◽  
Mutational Signatures ◽  
Dna Mismatch ◽  
Repair Deficiency ◽  
Molecular Aspects ◽  
The Impact

DNA mismatch repair deficiency (dMMR) is associated with the microsatellite instability (MSI) phenotype and leads to increased mutation load, which in turn may impact anti-tumor immune responses and treatment effectiveness. Various mutational signatures directly linked to dMMR have been described for primary cancers. To investigate which mutational signatures are associated with prognosis in gastric cancer, we performed a de novo extraction of mutational signatures in a cohort of 787 patients. We detected three dMMR-related signatures, one of which clearly discriminates tumors with MLH1 gene silencing caused by promoter hypermethylation (area under the curve = 98%). We then demonstrated that samples with the highest exposure of this signature share features related to better prognosis, encompassing clinical and molecular aspects and altered immune infiltrate composition. Overall, the assessment of the prognostic value and of the impact of modifications in MMR-related genes on shaping specific dMMR mutational signatures provides evidence that classification based on mutational signature exposure enables prognosis stratification.

Age at Exposure to Parental Suicide and the Subsequent Risk of Suicide in Young People

Crisis ◽  
2018 ◽  
Vol 39 (1) ◽  
pp. 27-36 ◽  
Author(s):  
Kuan-Ying Lee ◽  
Chung-Yi Li ◽  
Kun-Chia Chang ◽  
Tsung-Hsueh Lu ◽  
Ying-Yeh Chen
Keyword(s):  
Young People ◽  
Proportional Hazards ◽  
Proportional Hazards Model ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Birth Registry ◽  
Data Set ◽  
Parental Suicide ◽  
The Impact ◽  
Age At Exposure

Abstract. Background: We investigated the age at exposure to parental suicide and the risk of subsequent suicide completion in young people. The impact of parental and offspring sex was also examined. Method: Using a cohort study design, we linked Taiwan's Birth Registry (1978–1997) with Taiwan's Death Registry (1985–2009) and identified 40,249 children who had experienced maternal suicide (n = 14,431), paternal suicide (n = 26,887), or the suicide of both parents (n = 281). Each exposed child was matched to 10 children of the same sex and birth year whose parents were still alive. This yielded a total of 398,081 children for our non-exposed cohort. A Cox proportional hazards model was used to compare the suicide risk of the exposed and non-exposed groups. Results: Compared with the non-exposed group, offspring who were exposed to parental suicide were 3.91 times (95% confidence interval [CI] = 3.10–4.92 more likely to die by suicide after adjusting for baseline characteristics. The risk of suicide seemed to be lower in older male offspring (HR = 3.94, 95% CI = 2.57–6.06), but higher in older female offspring (HR = 5.30, 95% CI = 3.05–9.22). Stratified analyses based on parental sex revealed similar patterns as the combined analysis. Limitations: As only register-­based data were used, we were not able to explore the impact of variables not contained in the data set, such as the role of mental illness. Conclusion: Our findings suggest a prominent elevation in the risk of suicide among offspring who lost their parents to suicide. The risk elevation differed according to the sex of the afflicted offspring as well as to their age at exposure.

State Medical Boards' Perceptions of a Minimum Data Set and Current Practices for Collecting Physician Information

2013 ◽  
Vol 99 (4) ◽  
pp. 40-45 ◽  
Author(s):  
Aaron Young ◽  
Philip Davignon ◽  
Margaret B. Hansen ◽  
Mark A. Eggen
Keyword(s):  
Media Coverage ◽  
The United States ◽  
Minimum Data Set ◽  
Direct Patient Care ◽  
Physician Workforce ◽  
Data Set ◽  
Minimum Data ◽  
State Medical Boards ◽  
The Impact ◽  
Current Practices

ABSTRACT Recent media coverage has focused on the supply of physicians in the United States, especially with the impact of a growing physician shortage and the Affordable Care Act. State medical boards and other entities maintain data on physician licensure and discipline, as well as some biographical data describing their physician populations. However, there are gaps of workforce information in these sources. The Federation of State Medical Boards' (FSMB) Census of Licensed Physicians and the AMA Masterfile, for example, offer valuable information, but they provide a limited picture of the physician workforce. Furthermore, they are unable to shed light on some of the nuances in physician availability, such as how much time physicians spend providing direct patient care. In response to these gaps, policymakers and regulators have in recent years discussed the creation of a physician minimum data set (MDS), which would be gathered periodically and would provide key physician workforce information. While proponents of an MDS believe it would provide benefits to a variety of stakeholders, an effort has not been attempted to determine whether state medical boards think it is important to collect physician workforce data and if they currently collect workforce information from licensed physicians. To learn more, the FSMB sent surveys to the executive directors at state medical boards to determine their perceptions of collecting workforce data and current practices regarding their collection of such data. The purpose of this article is to convey results from this effort. Survey findings indicate that the vast majority of boards view physician workforce information as valuable in the determination of health care needs within their state, and that various boards are already collecting some data elements. Analysis of the data confirms the potential benefits of a physician minimum data set (MDS) and why state medical boards are in a unique position to collect MDS information from physicians.

The Impact of Green Labels on U.S. Hotel Net Operating Income: Operating Statements Analyses

2019 ◽  
Vol 11 (1) ◽  
pp. 156-173
Author(s):  
Spenser Robinson ◽  
A.J. Singh
Keyword(s):  
Environmental Design ◽  
Green Buildings ◽  
Small Sample ◽  
Sample Survey ◽  
Data Set ◽  
Operating Income ◽  
Energy Star ◽  
The Impact ◽  
Industry Professionals

This paper shows Leadership in Energy and Environmental Design (LEED) certified hospitality properties exhibit increased expenses and earn lower net operating income (NOI) than non-certified buildings. ENERGY STAR certified properties demonstrate lower overall expenses than non-certified buildings with statistically neutral NOI effects. Using a custom sample of all green buildings and their competitive data set as of 2013 provided by Smith Travel Research (STR), the paper documents potential reasons for this result including increased operational expenses, potential confusion with certified and registered LEED projects in the data, and qualitative input. The qualitative input comes from a small sample survey of five industry professionals. The paper provides one of the only analyses on operating efficiencies with LEED and ENERGY STAR hospitality properties.

Sign in / Sign up

Export Citation Format

Share Document