scholarly journals Genetic Predisposition to Sporadic Cancer: How to Handle Major Effects of Minor Genes?

2005 ◽  
Vol 27 (5-6) ◽  
pp. 281-292
Author(s):  
Remond J. A. Fijneman
Keyword(s):  
Cancer Risk ◽  
Allelic Variation ◽  
Human Cancer ◽  
Single Gene ◽  
Molecular Networks ◽  
Snp Analysis ◽  
Gene Effects ◽  
Multiple Tumor ◽  
Sporadic Cancer ◽  
Biological Modules

Predisposition to non-familial, sporadic cancer is strongly influenced by multiple tumor susceptibility genes (TSGs), each with apparently minor effects on the cancer phenotype. Sequence analysis of the human genome has yielded numerous single nucleotide polymorphisms (SNPs), raising the expectation that new low-penetrance TSGs will be identified that can be used to estimate an individuals cancer risk. However, mouse models for human cancer showed that the effects of many low-penetrance TSGs are highly variable due to their involvement in epistatic interactions. Together, these interacting TSGs form large molecular networks, which represent cancer-associated biological modules that influence the tumorigenic process. As a consequence, although allelic variation in one TSG on a permissive genetic Background can have major effects on tumor development, the net effect of allelic variation in multiple interacting TSGs remains hard to predict. Therefore, the predictive value of SNP-analysis to estimate an individuals cancer risk will be restricted to those TSGs that exhibit single-gene effects. New strategies need to be developed to evaluate cancer risk associated with biological modules that are influenced by TSG-networks.

Disparities in pan-cancer patients undergoing germline cancer risk assessment by self-reported race/ethnicity and ancestry.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10508-10508
Author(s):  
Ying L Liu ◽  
Anna Maio ◽  
Yelena Kemel ◽  
Erin E. Salo-Mullen ◽  
Margaret Sheehan ◽  
...  
Keyword(s):  
Cancer Risk ◽  
Cancer Patients ◽  
Cancer Genetics ◽  
Statistical Tests ◽  
Cancer Risk Assessment ◽  
Clinical Genetics ◽  
Multiple Tumor ◽  
Race Ethnicity ◽  
Pan Cancer

10508 Background: Disparities in access to germline testing for cancer patients (pts) have been demonstrated; however, disparities in post-testing care are unknown. We sought to evaluate germline findings and subsequent genetic counseling/care in cancer pts undergoing tumor-germline sequencing to explore differences by self-reported ancestry. Methods: Pan-cancer pts were prospectively consented to tumor-normal sequencing via a custom NGS panel (MSK-IMPACT) from 1/2015-12/2019 inclusive of germline analysis up to 88 genes. Germline analysis was performed as a research non-billable test in 97.5% of cases. Referral to clinical genetics service (CGS) was recommended for all pts with a new positive (likely pathogenic/pathogenic) germline variant (PV). Ancestry was defined using self-reported Federal definitions of race/ethnicity and designations of Ashkenazi Jewish (AJ) ancestry. Pts were categorized into mutually exclusive groups: AJ, White, Non-White (Asian, Black/African American, Hispanic, Other), and unknown. All pts self-identifying as Hispanic were classified as such, regardless of race. Abstracted data on germline findings and downstream CGS follow-up were compared across groups using non-parametric statistical tests. Results: Among the 15,775 pts in this cohort (59.6% White, 15.7% AJ, 20.5% Non-White [6.9% Asian, 6.8% Black, 6.7% Hispanic, 0.1% Other], and 4.2% unknown), 2663 (17%) had a PV. AJ pts had the highest rates of PV (n = 683, 27.6%), and Non-White pts had a lower proportion of PV (n = 433, 13.6%) compared to Whites (n = 1451, 15.5%), p < 0.01, with differences mostly due to increased prevalence of moderate/low penetrance variants in White and AJ pts . These findings were consistent across multiple tumor types. Prior knowledge of the PV (424/2663, 16%) was more common in Non-White (19.9%) and AJ (19.2%) than White pts (13.4%), p < 0.01. Among 2239 pts with new PV, all were referred to CGS, and 1652 (73.8%) pts were seen. Non-White pts had lower rates of completing visits (67.7%) than White (73.7%) and AJ pts (78.8%), p < 0.01, with the lowest rates occurring in Black (63%) and Hispanic (68.1%) pts. All pts without a visit (n = 587) received a close out letter including 139 pts (6.2% of pts with new PV) who had no documentation of receipt of results in the medical record. Higher rates of non-disclosure were observed in Non-White (6.7%) compared to White (5.4%) and AJ (3.4%) pts with new PV, p = 0.032; non-disclosure did not vary by gene penetrance. There was a non-significant trend towards lower rates of cascade testing at CGS in Asian and Black pts with ongoing analysis. Conclusions: Even when traditional barriers to genetic testing were minimized, Non-White pts were less likely to receive recommended cancer genetics follow-up for subsequent cancer risk counseling, with potential implications for oncological care, cancer risk reduction, and at-risk family members.

scholarly journals Variants in the Signaling Protein TSAd are Associated with Susceptibility to Ovarian Cancer in BRCA1/2 Negative High Risk Families

2012 ◽  
Vol 7 ◽  
pp. BMI.S10815 ◽  
Author(s):  
Ludmila Kaplun ◽  
Aviva Levine Fridman ◽  
Wei Chen ◽  
Nancy K. Levin ◽  
Sidra Ahsan ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
High Risk ◽  
Cancer Risk ◽  
Allelic Variation ◽  
High Risk Population ◽  
Ovarian Cancer Risk ◽  
Familial Ovarian Cancer ◽  
Cell Growth And Differentiation ◽  
Brca1 Brca2 ◽  
High Risk Families

A substantial fraction of familial ovarian cancer cases cannot be attributed to specific genetic factors. The discovery of additional susceptibility genes will permit a more accurate assessment of hereditary cancer risk and allow for monitoring of predisposed women in order to intervene at the earliest possible stage. We focused on a population with elevated familial breast and ovarian cancer risk. In this study, we identified a SNP rs926103 whose minor allele is associated with predisposition to ovarian but not breast cancer in a Caucasian high-risk population without BRCA1/ BRCA2 mutations. We have found that the allelic variation of rs926103, which alters amino acid 52 of the encoded protein SH2D2A/TSAd, results in differences in the activity of this protein involved in multiple signal transduction pathways, including regulation of immune response, tumor vascularization, cell growth, and differentiation. Our observation provides a novel candidate genetic biomarker of elevated ovarian cancer risk in members of high-risk families without BRCA1/2 mutations, as well as a potential therapeutic target, TSAd.

scholarly journals Application of biochar to soils may result in plant contamination and human cancer risk due to exposure of polycyclic aromatic hydrocarbons

2018 ◽  
Vol 121 ◽  
pp. 169-177 ◽  
Author(s):  
Jian Wang ◽  
Kang Xia ◽  
Michael Gatheru Waigi ◽  
Yanzheng Gao ◽  
Emmanuel Stephen Odinga ◽  
...  
Keyword(s):  
Polycyclic Aromatic Hydrocarbons ◽  
Cancer Risk ◽  
Aromatic Hydrocarbons ◽  
Human Cancer ◽  
Polycyclic Aromatic ◽  
Plant Contamination

scholarly journals Applications of molecular networks in biomedicine

2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Monica Chagoyen ◽  
Juan A G Ranea ◽  
Florencio Pazos
Keyword(s):  
Single Gene ◽  
Point Of View ◽  
Molecular Networks ◽  
Large Sets ◽  
Software Packages ◽  
Number Of Genes ◽  
Complex Phenomena ◽  
Network Approaches ◽  
Molecular Components ◽  
Standard Software

Abstract Due to the large interdependence between the molecular components of living systems, many phenomena, including those related to pathologies, cannot be explained in terms of a single gene or a small number of genes. Molecular networks, representing different types of relationships between molecular entities, embody these large sets of interdependences in a framework that allow their mining from a systemic point of view to obtain information. These networks, often generated from high-throughput omics datasets, are used to study the complex phenomena of human pathologies from a systemic point of view. Complementing the reductionist approach of molecular biology, based on the detailed study of a small number of genes, systemic approaches to human diseases consider that these are better reflected in large and intricate networks of relationships between genes. These networks, and not the single genes, provide both better markers for diagnosing diseases and targets for treating them. Network approaches are being used to gain insight into the molecular basis of complex diseases and interpret the large datasets associated with them, such as genomic variants. Network formalism is also suitable for integrating large, heterogeneous and multilevel datasets associated with diseases from the molecular level to organismal and epidemiological scales. Many of these approaches are available to nonexpert users through standard software packages.

scholarly journals The emerging role of microRNAs and long noncoding RNAs in drug resistance of hepatocellular carcinoma

2019 ◽  
Vol 18 (1) ◽  
Author(s):  
Ling Wei ◽  
Xingwu Wang ◽  
Liyan Lv ◽  
Jibing Liu ◽  
Huaixin Xing ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Drug Resistance ◽  
Human Cancer ◽  
Noncoding Rnas ◽  
Circular Rna ◽  
Long Noncoding Rnas ◽  
Protein Coding ◽  
Multiple Tumor ◽  
Nucleolar Rnas

Abstract Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the second most lethal human cancer. A portion of patients with advanced HCC can significantly benefit from treatments with sorafenib, adriamycin, 5-fluorouracil and platinum drugs. However, most HCC patients eventually develop drug resistance, resulting in a poor prognosis. The mechanisms involved in HCC drug resistance are complex and inconclusive. Human transcripts without protein-coding potential are known as noncoding RNAs (ncRNAs), including microRNAs (miRNAs), small nucleolar RNAs (snoRNAs), long noncoding RNAs (lncRNAs) and circular RNA (circRNA). Accumulated evidences demonstrate that several deregulated miRNAs and lncRNAs are important regulators in the development of HCC drug resistance which elucidates their potential clinical implications. In this review, we summarized the detailed mechanisms by which miRNAs and lncRNAs affect HCC drug resistance. Multiple tumor-specific miRNAs and lncRNAs may serve as novel therapeutic targets and prognostic biomarkers for HCC.

scholarly journals Omics-wide quantitative B-cell infiltration analyses identify GPR18 for human cancer prognosis with superiority over CD20

2020 ◽  
Vol 3 (1) ◽  
Author(s):  
Yuchen Liu ◽  
Li Wang ◽  
Kwok-Wai Lo ◽  
Vivian Wai Yan Lui
Keyword(s):  
T Cell ◽  
B Cell ◽  
B Lymphocyte ◽  
Human Cancer ◽  
Single Gene ◽  
Cell Activity ◽  
Cancer Prognosis ◽  
Low Grade ◽  
Functional Link ◽  
Human Cancers

AbstractTumor-infiltrating B lymphocyte (TIL-B), and TIL-B-related biomarkers have clinical prognostic values for human cancers. CD20 (encoded by MS4A1) is a widely used TIL-B biomarker. Using TCGA-quantitative multiomics datasets, we first cross-compare prognostic powers of intratumoral CD20 protein, mRNA and TIL-B levels in pan-cancers. Here, we show that MS4A1 and TIL-B are consistently prognostic in 5 cancers (head and neck, lung, cervical, kidney and low-grade glioma), while unexpectedly, CD20 protein levels lack quantitative correlations with MS4A1/TIL-B levels and demonstrate limited prognosticity. Subsequent bioinformatics discovery for TIL-B prognostic gene identifies a single gene, GPR18 with stand-alone prognosticity across 9 cancers (superior over CD20), with further validations in multiple non-TCGA cohorts. GPR18's immune signature denotes major B-cell-T-cell interactions, with its intratumoral expression strongly tied to a “T-cell active”, likely cytolytic, status across human cancers, suggesting its functional link to cytolytic T-cell activity in cancer. GPR18 merits biological and clinical utility assessments over CD20.

scholarly journals Alternative splicing in endothelial cells: novel therapeutic opportunities in cancer angiogenesis

2020 ◽  
Vol 39 (1) ◽  
Author(s):  
Anna Di Matteo ◽  
Elisa Belloni ◽  
Davide Pradella ◽  
Ambra Cappelletto ◽  
Nina Volf ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Human Cancer ◽  
Single Gene ◽  
Predictive Biomarkers ◽  
Protein Isoforms ◽  
Therapeutic Interventions ◽  
Cancer Therapies ◽  
Functional Changes ◽  
Splicing Regulators ◽  
Multiple Protein

AbstractAlternative splicing (AS) is a pervasive molecular process generating multiple protein isoforms, from a single gene. It plays fundamental roles during development, differentiation and maintenance of tissue homeostasis, while aberrant AS is considered a hallmark of multiple diseases, including cancer. Cancer-restricted AS isoforms represent either predictive biomarkers for diagnosis/prognosis or targets for anti-cancer therapies. Here, we discuss the contribution of AS regulation in cancer angiogenesis, a complex process supporting disease development and progression. We consider AS programs acting in a specific and non-redundant manner to influence morphological and functional changes involved in cancer angiogenesis. In particular, we describe relevant AS variants or splicing regulators controlling either secreted or membrane-bound angiogenic factors, which may represent attractive targets for therapeutic interventions in human cancer.

scholarly journals Involvement of APOBEC3B in mutation induction by irradiation

2020 ◽  
Vol 61 (6) ◽  
pp. 819-827
Author(s):  
Yohei Saito ◽  
Hiromasa Miura ◽  
Nozomi Takahashi ◽  
Yoshikazu Kuwahara ◽  
Yumi Yamamoto ◽  
...  
Keyword(s):  
Dna Damage ◽  
Cancer Risk ◽  
Cell Line ◽  
Human Cancer ◽  
Spontaneous Mutation ◽  
Mutation Induction ◽  
Parent Cell ◽  
Induced Mutations ◽  
Parent Cell Line ◽  
Radiation Induced

Abstract To better understand the cancer risk posed by radiation and the development of radiation therapy resistant cancer cells, we investigated the involvement of the cancer risk factor, APOBEC3B, in the generation of radiation-induced mutations. Expression of APOBEC3B in response to irradiation was determined in three human cancer cell lines by real-time quantitative PCR. Using the hypoxanthine-guanine phosphoribosyl transferase (HPRT) mutation assay, mutations in the HPRT gene caused by irradiation were compared between APOBEC3B-deficient human hepatocellular carcinoma (HepG2) cells [APOBEC3B knocked out (KO) using CRISPR-Cas9 genome editing] and the parent cell line. Then, HPRT-mutated cells were individually cultured to perform PCR and DNA sequencing of HPRT exons. X-Irradiation induced APOBEC3B expression in HepG2, human cervical cancer epithelial carcinoma (HeLa) and human oral squamous cell carcinoma (SAS) cells. Forced expression of APOBEC3B increased spontaneous mutations. By contrast, APOBEC3B KO not only decreased the spontaneous mutation rate, but also strongly suppressed the increase in mutation frequency after irradiation in the parent cell line. Although forced expression of APOBEC3B in the nucleus caused DNA damage, higher levels of APOBEC3B tended to reduce APOBEC3B-induced γ-H2AX foci formation (a measure of DNA damage repair). Further, the number of γ-H2AX foci in cells stably expressing APOBEC3B was not much higher than that in controls before and after irradiation, suggesting that a DNA repair pathway may be activated. This study demonstrates that irradiation induces sustained expression of APOBEC3B in HepG2, HeLa and SAS cells, and that APOBEC3B enhances radiation-induced partial deletions.

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