Age-related somatic mutations in the cancer genome

Milholland, Brandon; Auton, Adam; Suh, Yousin; Vijg, Jan

doi:10.18632/oncotarget.5685

Cited by 114 publications

(120 citation statements)

References 20 publications

(24 reference statements)

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“…As in previous reports, the somatic mutation burden increased with patient age (R = 0.39, P = 2.9 × 10 −6 ), except in Burkitt's lymphoma (immunoglobulin hypermutation) and tumours with 'kataegis' events of localized hypermutation at double-stranded breakpoints 14,15 (Extended Data Fig. 1e, f).…”

Section: Mutation Frequencies Across Cancer Typessupporting

confidence: 82%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

1,166

1,156

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The landscape of genomic alterations across childhood cancers a list of authors and affiliations appears at the end of the paper. OPENPan-cancer analyses that examine commonalities and differences among various cancer types have emerged as a powerful way to obtain novel insights into cancer biology. Here we present a comprehensive analysis of genetic alterations in a pan-cancer cohort including 961 tumours from children, adolescents, and young adults, comprising 24 distinct molecular types of cancer. Using a standardized workflow, we identified marked differences in terms of mutation frequency and significantly mutated genes in comparison to previously analysed adult cancers. Genetic alterations in 149 putative cancer driver genes separate the tumours into two classes: small mutation and structural/copy-number variant (correlating with germline variants). Structural variants, hyperdiploidy, and chromothripsis are linked to TP53 mutation status and mutational signatures. Our data suggest that 7-8% of the children in this cohort carry an unambiguous predisposing germline variant and that nearly 50% of paediatric neoplasms harbour a potentially druggable event, which is highly relevant for the design of future clinical trials.Cure rates for childhood cancers have increased to about 80% in recent decades, but cancer is still the leading cause of death by disease in the developed world among children over one year of age 1,2 . Furthermore, many children who survive cancer suffer from long-term sequelae of surgery, cytotoxic chemotherapy, and radiotherapy, including mental disabilities, organ toxicities, and secondary cancers 3 . A crucial step in developing more specific and less damaging therapies is the unravelling of the complete genetic repertoire of paediatric malignancies, which differ from adult malignancies in terms of their histopathological entities and molecular subtypes 4 . Over the past few years, many entityspecific sequencing efforts have been launched, but the few paediatric pan-cancer studies thus far have focused only on mutation frequencies, germline predisposition, and alterations in epigenetic regulators [4][5][6] .We have carried out a broad exploration of cancers in children, adolescents, and young adults, by incorporating small mutations and copy-number or structural variants on somatic and germline levels, and by identifying putative cancer genes and comparing them to those previously reported in adult cancers by The Cancer Genome Atlas (TCGA) 7 . We have also examined mutational signatures and potential drug targets. The compendium of genetic alterations presented here is available to the scientific community at http://www.pedpancan.com.This integrative analysis includes 24 types of cancer and covers all major childhood cancer entities, many of which occur exclusively in children 8 (Fig. 1, Supplementary Table 1). Ninety-five per cent of the patients in this study were diagnosed during childhood or adolescence (aged 18 years or younger) and 5% as young adults (up to 25 years) (Extended Data ...

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Section: Mutation Frequencies Across Cancer Typessupporting

confidence: 82%

The landscape of genomic alterations across childhood cancers

Gröbner¹,

Worst²,

Weischenfeldt³

et al. 2018

Nature

1,166

1,156

View full text Add to dashboard Cite

show abstract

“…A recent study performed on the extensive data set available on The Cancer Genome Atlas (TCGA) portal showed the age-related accumulation of somatic mutations in diverse human tissues [19]. However, it is still an open question whether differences in mutations between the ages are random coincidence or follow distinct patterns.…”

Section: Introductionmentioning

confidence: 99%

Mutational load and mutational patterns in relation to age in head and neck cancer

et al. 2016

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Head and neck squamous cell carcinoma (HNSCC) is a cancer with well-defined tumor causes such as HPV infection, smoking and drinking.Using The Cancer Genome Atlas (TCGA) HNSCC cohort we systematically studied the mutational load as well as patterns related to patient age in HNSCC. To obtain a homogenous set we excluded all patients with HPV infection as well as wild type TP53. We found that the overall mutational load is higher in patients of old age. Through unsupervised hierarchical clustering, we detected distinct mutational clusters in very young as well as very old patients. In the group of old patients, we identified four enriched pathways (“Axon Guidance”, “ECM-Receptor Interaction”, “Focal Adhesion” and “Notch Signaling”) that are only sporadically mutated in the other age groups. Our findings indicate that the four pathways regulate cell motility, tumor invasion and angiogenesis supposedly leading to less aggressive tumors in older age patients. Importantly, we did not see a strict pattern of genes always mutated in older age but rather an accumulation of mutations in the same pathways. Our study provides indications of age-dependent differences in mutational backgrounds of tumors that might be relevant for treatment approaches of HNSCCs patients.

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“…Using data from The Cancer Genome Atlas (TCGA) to systematically study the frequency and spectrum of somatic mutations in thousands of cancer patients and different tumor types as a function of the age of the patient, we found that the number of identified somatic mutations increases exponentially with age. 22 However, since mutations can also arise after neoplastic transformation, during tumor progression, it is difficult to draw definite conclusions other than that mutation frequency increases with age. Others have demonstrated aging-specific signature mutations in human tumors.…”

Section: Current Methods For Mutation Analysismentioning

confidence: 99%

A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden

Vijg

Dong

Zhang

2017

Exp Biol Med (Maywood)

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Somatic mutations cause cancer, possibly other diseases and aging. Yet, very little is known about the frequency of such mutations in vivo, their distribution across the genome, and their possible functional consequences other than cancer. Even in cancer, we do not know the heterogeneity of mutations within a tumor and if seemingly normal cells in its surroundings already have elevated mutation frequencies. Here, we review a new, whole genome amplification system that allows accurate quantification and characterization of single-cell mutational landscapes in human cells and tissues in relation to disease. AbstractPostzygotic mutations in somatic cells lead to genome mosaicism and can be the cause of cancer, possibly other human diseases and aging. Somatic mutations are difficult to detect in bulk tissue samples. Here, we review the available assays for measuring somatic mutations, with a focus on recent single-cell, whole genome sequencing methods.

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Age-related somatic mutations in the cancer genome

Cited by 114 publications

References 20 publications

The landscape of genomic alterations across childhood cancers

The landscape of genomic alterations across childhood cancers

Mutational load and mutational patterns in relation to age in head and neck cancer

A high-fidelity method for genomic sequencing of single somatic cells reveals a very high mutational burden

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