The Erlang distribution approximates the age distribution of incidence of childhood and young adulthood cancers

Background It is widely believed that cancers develop upon acquiring a particular number of (epi) mutations in driver genes, but the law governing the kinetics of this process is not known. We have previously shown that the age distribution of incidence for the 20 most prevalent cancers of old age is best approximated by the Erlang probability distribution. The Erlang distribution describes the probability of several successive random events occurring by the given time according to the Poisson process, which allows an estimate for the number of critical driver events. Methods Here we employ a computational grid search method to find global parameter optima for five probability distributions on the CDC WONDER dataset of the age distribution of childhood and young adulthood cancer incidence. Results We show that the Erlang distribution is the only classical probability distribution we found that can adequately model the age distribution of incidence for all studied childhood and young adulthood cancers, in addition to cancers of old age. Conclusions This suggests that the Poisson process governs driver accumulation at any age and that the Erlang distribution can be used to determine the number of driver events for any cancer type. The Poisson process implies the fundamentally random timing of driver events and their constant average rate. As waiting times for the occurrence of the required number of driver events are counted in decades, and most cells do not live this long, it suggests that driver mutations accumulate silently in the longest-living dividing cells in the body—the stem cells.

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The Poisson process is the universal law of cancer development: driver mutations accumulate randomly, silently, at constant average rate and for many decades, likely in stem cells

10.1101/231027 ◽

2017 ◽

Cited By ~ 1

Author(s):

Aleksey V. Belikov ◽

Alexey D. Vyatkin ◽

Sergey V. Leonov

Keyword(s):

Stem Cells ◽

Probability Distribution ◽

Poisson Process ◽

Old Age ◽

Average Rate ◽

Age Distribution ◽

Cancer Development ◽

Driver Mutations ◽

Erlang Distribution ◽

Universal Law

AbstractBackgroundIt is assumed that cancers develop upon acquiring a particular number of (epi)mutations in driver genes, but the law governing the kinetics of this process is not known. We have recently shown that the age distribution of incidence for 20 most prevalent cancers of old age is best approximated by the Erlang probability distribution. The Erlang distribution describes the probability of several successive random events occurring by the given time according to the Poisson process, which allows to predict the number of critical driver events.ResultsHere we show that the Erlang distribution is the only classical probability distribution that can adequately model the age distribution of incidence for all studied childhood and young adulthood cancers, in addition to cancers of old age.ConclusionsThis validates the Poisson process as the universal law describing cancer development at any age and the Erlang distribution as a useful tool to predict the number of driver events for any cancer type. The Poisson process signifies the fundamentally random timing of driver events and their constant average rate. As waiting times for the occurrence of the required number of driver events are counted in decades, it suggests that driver mutations accumulate silently in the longest-living dividing cells in the body - the stem cells.

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Cancer types with high numbers of driver events are largely preventable

PeerJ ◽

10.7717/peerj.12672 ◽

2022 ◽

Vol 10 ◽

pp. e12672

Author(s):

Aleksey V. Belikov ◽

Sergey V. Leonov

Keyword(s):

Risk Factors ◽

Probability Distribution ◽

Cancer Incidence ◽

Risk Estimation ◽

Age Distribution ◽

Modifiable Risk Factors ◽

Cancer Type ◽

Cancer Types ◽

Extrinsic Risk ◽

Rate Limiting

There is a long-standing debate on whether cancer is predominantly driven by extrinsic risk factors such as smoking, or by intrinsic processes such as errors in DNA replication. We have previously shown that the number of rate-limiting driver events per tumor can be estimated from the age distribution of cancer incidence using the gamma/Erlang probability distribution. Here, we show that this number strongly correlates with the proportion of cancer cases attributable to modifiable risk factors for all cancer types except the ones inducible by infection or ultraviolet radiation. The correlation was confirmed for three countries, three corresponding incidence databases and risk estimation studies, as well as for both sexes: USA, males (r = 0.80, P = 0.002), females (r = 0.81, P = 0.0003); England, males (r = 0.90, P < 0.0001), females (r = 0.67, P = 0.002); Australia, males (r = 0.90, P = 0.0004), females (r = 0.68, P = 0.01). Hence, this study suggests that the more driver events a cancer type requires, the more of its cases are due to preventable anthropogenic risk factors.

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Anthropogenic risk factors as the major cause of cancer driver events

10.1101/486860 ◽

2018 ◽

Author(s):

Aleksey V. Belikov

Keyword(s):

Risk Factors ◽

Probability Distribution ◽

Cancer Incidence ◽

Risk Estimation ◽

Age Distribution ◽

Erlang Distribution ◽

Modifiable Risk Factors ◽

Cancer Driver ◽

Replication Errors ◽

Rate Limiting

AbstractBackgroundI have recently shown that the number of rate-limiting driver events per tumor can be estimated from the age distribution of cancer incidence using the gamma/Erlang probability distribution. It is important to understand how these predictions relate to established risk factors.MethodsThe number of rate-limiting driver events per tumor was estimated using the gamma/Erlang distribution and correlated to the percentage of cancer cases attributable to modifiable risk factors.ResultsThe predicted number of rate-limiting driver events per tumor strongly correlates with the proportion of cancer cases attributable to modifiable risk factors for all cancers except those induced by infection or ultraviolet radiation. The correlation was confirmed for three countries, three corresponding incidence databases and risk estimation studies, as well as for both sexes: USA, males [r=0.80, P=0.002], females [r=0.81, P=0.0003]; England, males [r=0.90, P<0.0001], females [r=0.67, P=0.002]; Australia, males [r=0.90, P=0.0004], females [r=0.68, P=0.01].ConclusionsIt is thus confirmed that predictions based on interpreting the age distribution of cancer incidence as the gamma/Erlang probability distribution have biological meaning, validating the underlying Poisson process as the law governing the development of the majority of cancer types, especially those driven by chemical mutagens. Importantly, this study suggests that the majority of driver events (60-80% in males, 50-70% in females) are induced by anthropogenic carcinogens, and not by cell replication errors or other internal processes.

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Role of Rasayana in Geriatric Care - A Review

Journal of Ayurveda and Integrated Medical Sciences (JAIMS) ◽

10.21760/jaims.v1i1.3636 ◽

2016 ◽

Vol 1 (1) ◽

Author(s):

Yagyik Mishra ◽

Negalur Vijay ◽

Thakor Krunal ◽

Bhat Nagaraj ◽

Shubhasri B.

Keyword(s):

Older People ◽

Old Age ◽

Statistical Data ◽

Geriatric Care ◽

The Body ◽

Psychological Improvement

The growth of any country or society depends on the number of youth dwelling in that country but according to recent statistical data we soon will have older people more than children and more people at extreme old age than ever before. The number of people aged 65 or older is projected to grow from an estimated 524 million in 2010 to nearly 1.5 billion in 2050. Geriatrics (Jarachikitsa) is the branch of medicine dealing exclusively with the problems of aging and the diseases of elderly. The term Rasayana (rejuvination) refers to nourishment or nutrition. Rasayana therapy act essentially on nutrition dynamics and rejuvenate the body on both physical and mental levels. The problems of health due to modernization can be solved by increasing resistance against diseases and psychological improvement by implementing Rasayana therapy. Aging (Jara) is one among the Swabhavika Vyadhis. Jara Chikitsa is one among the Astanga of Ayurveda which is specifically dedicated for geriatric care. As per estimation, India currently has around 75 million persons over 65 years. By proper administration of Rasayana therapy as preventive tool one can delay Jara Janita Vyadhis to occur. This paper highlights the role of Rasayana in geriatric care.

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Links between Inflammation and Postoperative Cancer Recurrence

Journal of Clinical Medicine ◽

10.3390/jcm10020228 ◽

2021 ◽

Vol 10 (2) ◽

pp. 228

Author(s):

Tomonari Kinoshita ◽

Taichiro Goto

Keyword(s):

Clinical Practice ◽

Cancer Cells ◽

Cancer Recurrence ◽

Complete Resection ◽

The Body ◽

Cancer Development ◽

Clinical Settings ◽

Cancer Type ◽

Clinical Indicators ◽

The Status

Despite complete resection, cancer recurrence frequently occurs in clinical practice. This indicates that cancer cells had already metastasized from their organ of origin at the time of resection or had circulated throughout the body via the lymphatic and vascular systems. To obtain this potential for metastasis, cancer cells must undergo essential and intrinsic processes that are supported by the tumor microenvironment. Cancer-associated inflammation may be engaged in cancer development, progression, and metastasis. Despite numerous reports detailing the interplays between cancer and its microenvironment via the inflammatory network, the status of cancer-associated inflammation remains difficult to recognize in clinical settings. In the current paper, we reviewed clinical reports on the relevance between inflammation and cancer recurrence after surgical resection, focusing on inflammatory indicators and cancer recurrence predictors according to cancer type and clinical indicators.

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Genomic immunotherapy (IO) biomarkers detected on comprehensive genomic profiling (CGP) of tissue and circulating tumor DNA (ctDNA).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2541 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2541-2541

Author(s):

Takayuki Yoshino ◽

Hanna Tukachinsky ◽

Jessica Kim Lee ◽

Ethan Sokol ◽

Dean C. Pavlick ◽

...

Keyword(s):

Limit Of Detection ◽

Predictive Biomarkers ◽

Principal Component ◽

Pathogenic Mutation ◽

Circulating Tumor Dna ◽

Driver Mutations ◽

Cancer Type ◽

Liquid Biopsies ◽

Mutational Burden ◽

Relative Prevalence

2541 Background: The dramatic impact of IO on treatment outcomes has heightened interest in predictive biomarkers, including genomic markers such as tumor mutational burden (TMB) and microsatellite instability (MSI). The recent FDA approval of pembrolizumab for previously treated advanced solid tumors with elevated TMB (≥10 mut/Mb on FoundationOne CDx, F1CDx) now requires a better understanding of the prevalence of this and other IO biomarkers detected on CGP, including differences between TMB detected in tissue and mutational burden detected in blood (bTMB). Methods: Tissue and plasma biopsies were profiled with two CGP panels of 324 genes with 0.8 Mb genome coverage (F1CDx and FoundationOne LiquidCDx). Mutational burden was calculated by counting somatic variants (single nucleotide and indels, including synonymous variants, excluding germline and driver mutations) with variant allele frequency (VAF) ≥5% in tissue (TMB) or ≥0.5% in ctDNA (bTMB). MSI score was assessed using 95 repetitive loci and principal component analysis (tissue) or >1,800 repetitive loci (plasma). ctDNA levels were estimated using composite tumor fraction (cTF), a metric based on aneuploidy and VAF. Results: Pan-cancer, TMB ≥10 was detected in 19% of tissue cases (29,238/156,294) and was common in melanoma (53%), small cell (41%), NSCLC (40%), bladder (39%), and endometrial (24%). bTMB ≥10 was detected in 13% of liquid biopsies (806/6,295); prevalence by cancer type was correlated with prevalence of elevated TMB (r = 0.81). Samples with bTMB ≥10 had an elevated cTF (median 13%, IQR 5 - 31%) as compared to samples with bTMB <10 (median 1.8%, IQR 0.6 - 7%, p < 0.001). Among 353 cases with both tissue and liquid CGP results (median 11 months apart), the relative prevalence of TMB ≥10 (12%) and bTMB ≥10 (13%) were similar, with concordant detection in 303 cases (86%). MSI-high (MSI-H) was seen in 2.2% of tissue CGP (3,461/156,294), most often in endometrial (19%), stomach (6.0%), and colorectal (5.3%) cancers, while MSI-H was detected in 0.68% of ctDNA specimens (43/6,295), which were also those with elevated cTF (median 11%, IQR 7 - 23%). Of 3,504 cases with MSI-H signature on tissue or liquid CGP, 1,619 (46%) had a pathogenic mutation detected in MLH1/MSH2/MSH6/PMS2 (15% predicted germline). CD274 amplification was detected in 1,207 cases (0.77%) of tissue CGP and 11 cases (0.17%) in ctDNA. Conclusions: Elevated bTMB is overall less prevalent than elevated tissue TMB, though these biomarkers are detected in similar cancer types. Detection of bTMB ≥10 and MSI-H in liquid biopsy was associated with elevated ctDNA levels, suggesting a limit of detection, and potentially indicating a more aggressive biology in samples positive for these biomarkers. Further investigation is needed to understand the utility of bTMB for identifying high TMB tumors that may benefit from IO.

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ACTIVE LONGEVITY: WAYS TO ACHIEVE IN THE CONTEXT OF THE DEVELOPMENT OF INFORMATIONAL-ENERGETIC MEDICINE

Fitoterapia ◽

10.33617/2522-9680-2021-2-55 ◽

2021 ◽

Vol 2 (2) ◽

pp. 55-61

Author(s):

V. V. Krutov ◽

Keyword(s):

Traditional Medicine ◽

Old Age ◽

The Elderly ◽

The Body ◽

Comprehensive Approach ◽

Allopathic Medicine ◽

Active Aging ◽

Synergistic Approach ◽

Systemic Problems ◽

Information Energy

Keywords: health, Spirit, energy, synergistic approach, gerontology, quality longevity, allopathic medicine, informational-energetic medicine. The article discusses the issue of active aging strategies that differ from those used in traditional medicine. Practice shows that the resources of the latter are insufficient for successfully overcoming the systemic problems of people, growing with aging and maximum in old age. The accumulation of the problematic nature of the physical body in long-lived people requires a special, comprehensive approach to treatment with penetration into the root nature of a person. Based on innovative knowledge, including data from his own research, the author is talking about a synergistic approach that includes, along with the existing practice of treating the elderly, methods of informational- energetic medicine. Medicine, working at the level of the subtle, causal sphere of a person, where the roots of all his diseases lie and are revealed. This way of solving, the author believes, bears the maximum healing effect for the body on all levels of its multidimensionality – substance, information, energy.

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Multi-omic data helps improve prediction of personalised tumor suppressors and oncogenes

10.1101/2022.01.13.476163 ◽

2022 ◽

Author(s):

Malvika Sudhakar ◽

Raghunathan Rengaswamy ◽

Karthik Raman

Keyword(s):

Tumour Progression ◽

Suppressor Gene ◽

Tumour Suppressor Gene ◽

Driver Mutations ◽

Cancer Type ◽

Expression Data ◽

Multiple Cancer ◽

Driver Genes ◽

Cancer Types ◽

Omic Data

The progression of tumorigenesis starts with a few mutational and structural driver events in the cell. Various cohort-based computational tools exist to identify driver genes but require a large number of samples to produce reliable results. Many studies use different methods to identify driver mutations/genes from mutations that have no impact on tumour progression; however, a small fraction of patients show no mutational events in any known driver genes. Current unsupervised methods map somatic and expression data onto a network to identify the perturbation in the network. Our method is the first machine learning model to classify genes as tumour suppressor gene (TSG), oncogene (OG) or neutral, thus assigning the functional impact of the gene in the patient. In this study, we develop a multi-omic approach, PIVOT (Personalised Identification of driVer OGs and TSGs), to train on experimentally or computationally validated mutational and structural driver events. Given the lack of any gold standards for the identification of personalised driver genes, we label the data using four strategies and, based on classification metrics, show gene-based labelling strategies perform best. We build different models using SNV, RNA, and multi-omic features to be used based on the data available. Our models trained on multi-omic data improved predictions compared to mutation and expression data, achieving an accuracy >0.99 for BRCA, LUAD and COAD datasets. We show network and expression-based features contribute the most to PIVOT. Our predictions on BRCA, COAD and LUAD cancer types reveal commonly altered genes such as TP53, and PIK3CA, which are predicted drivers for multiple cancer types. Along with known driver genes, our models also identify new driver genes such as PRKCA, SOX9 and PSMD4. Our multi-omic model labels both CNV and mutations with a more considerable contribution by CNV alterations. While predicting labels for genes mutated in multiple samples, we also label rare driver events occurring in as few as one sample. We also identify genes with dual roles within the same cancer type. Overall, PIVOT labels personalised driver genes as TSGs and OGs and also identifies rare driver genes. PIVOT is available at https://github.com/RamanLab/PIVOT.

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Additive effects of variants of unknown significance in replication repair-associated DNA polymerase genes on mutational burden and prognosis across diverse cancers

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-002336 ◽

2021 ◽

Vol 9 (9) ◽

pp. e002336

Author(s):

Jieer Ying ◽

Lin Yang ◽

Jiani C Yin ◽

Guojie Xia ◽

Minyan Xing ◽

...

Keyword(s):

Hot Spot ◽

The Cancer Genome Atlas ◽

Driver Mutations ◽

Cancer Type ◽

Additive Effects ◽

Variants Of Unknown Significance ◽

Mutational Burden ◽

Pathway Gene ◽

Exonuclease Domain ◽

Unknown Significance

BackgroundDefects in replication repair-associated DNA polymerases often manifest an ultra-high tumor mutational burden (TMB), which is associated with higher probabilities of response to immunotherapies. The functional and clinical implications of different polymerase variants remain unclear.MethodsTargeted next-generation sequencing using a 425-cancer gene panel, which covers all exonic regions of three polymerase genes (POLE, POLD1, and POLH), was conducted in a cohort of 12,266 patients across 16 different tumor types from January 2017 to January 2019. Prognostication of POL variant-positive patients was performed using a cohort of 4679 patients from the The Cancer Genome Atlas (TCGA) datasets.ResultsThe overall prevalence of somatic and germline polymerase variants was 4.2% (95% CI 3.8% to 4.5%) and 0.7% (95% CI 0.5% to 0.8%), respectively, with highest frequencies in endometrial, urinary, prostate, and colorectal cancers (CRCs). While most germline polymerase variants showed no clear functional consequences, we identified a candidate p.T466A affecting the exonuclease domain of POLE, which might be underlying the early onset in a case with childhood CRC. Low frequencies of known hot-spot somatic mutations in POLE were detected and were associated with younger age, the male sex, and microsatellite stability. In both the panel and TCGA cohorts, POLE drivers exhibited high frequencies of alterations in genes in the DNA damage and repair (DDR) pathways, including BRCA2, ATM, MSH6, and ATR. Variants of unknown significance (VUS) of different polymerase domains showed variable penetrance with those in the exonuclease domain of POLE and POLD1 displaying high TMB. VUS in POL genes exhibited an additive effect as carriers of multiple VUS had exponentially increased TMB and prolonged overall survival. Similar to cases with driver mutations, the TMB-high POL VUS samples showed DDR pathway involvement and polymerase hypermutation signatures. Combinatorial analysis of POL and DDR pathway status further supported the potential additive effects of POL VUS and DDR pathway genes and revealed distinct prognostic subclasses that were independent of cancer type and TMB.ConclusionsOur results demonstrate the pathogenicity and additive prognostic value of POL VUS and DDR pathway gene alterations and suggest that genetic testing may be warranted in patients with diverse solid tumors.

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Plexin-B1 mutation drives prostate cancer metastasis

10.1101/2020.07.19.203695 ◽

2020 ◽

Author(s):

Boris Shorning ◽

Neil Trent ◽

David Griffiths ◽

Thomas Worzfeld ◽

Stefan Offermanns ◽

...

Keyword(s):

Prostate Cancer ◽

Cancer Metastasis ◽

Locally Advanced ◽

Tumour Cells ◽

Mouse Genetics ◽

The Body ◽

Cancer Type ◽

Wild Type ◽

Tumour Spread ◽

Mouse Prostate

AbstractProstate cancer mortality is associated with the metastatic spread of tumour cells. A better understanding of the mechanisms which allow a locally advanced tumour to disseminate around the body will identify new therapeutic targets to block this process. One of set of genes implicated in metastasis are plexins, which can promote or suppress tumour progression depending on cancer type and cellular context. We have taken a mouse genetics approach to gain insight into the role of Plexin-B1 in prostate cancer progression in vivo.We show here that genetic deletion of Plexin-B1 in PbCre+Ptenfl/flKrasG12V and PbCre+Ptenfl/flp53fl/fl mouse prostate cancer models significantly decreased metastasis. High levels of prostate epithelial cell-specific expression of wild-type Plexin-B1 in knock-in mice with a PbCre+Ptenfl/flKrasG12V background also significantly decreased metastasis. In contrast, expression of a Plexin-B1 mutant (P1597L; identified from metastatic deposits in prostate cancer patients) in prostate epithelial cells in PbCre+Ptenfl/flKrasG12V and PbCre+Ptenfl/flp53fl/fl mice significantly increased metastasis, in particular metastasis to distant sites. In line with these findings, both deletion and overexpression of wild-type Plexin-B1 reduced invasion of tumour cells into the prostate stroma, while overexpression of mutant Plexin-B1 significantly increased invasion, suggesting that Plexin-B1 has a role in the initial stages of metastasis. Invasion and metastasis also correlated with phosphorylation of myosin light chain, suggesting that Plexin-B1 signals via the Rho/ROCK pathway to promote metastasis.Our results demonstrate that mutant Plexin-B1 promotes metastasis in prostate cancer and represents a new therapeutic target to suppress tumour spread.

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