The effects of mutational processes and selection on driver mutations across cancer types

Temko, Daniel; Tomlinson, Ian; Severini, Simone; Schuster-Böeckler, Benjamin; Graham, Trevor A.

doi:10.1101/149096

Cited by 14 publications

(14 citation statements)

References 23 publications

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“…A pilot study was conducted to compare the stability of signatures among different number of minimum SNVs (24, 48, 72 and 96, data not shown), and found that a cut point of 24 is sufficient. This is consistent with recent finding that 20 mutations gave an average classification accuracy of 80% across signatures . Any sample containing at least 24 SNVs was included for downstream assessment in order to enlarge the sample size as much as possible.…”

Section: Methodssupporting

confidence: 86%

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

Wang

Pitt

Zheng

et al. 2019

Intl Journal of Cancer

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Somatic mutation signatures may represent footprints of genetic and environmental exposures that cause different cancer. Few studies have comprehensively examined their association with germline variants, and none in an indigenous African population. SomaticSignatures was employed to extract mutation signatures based on whole‐genome or whole‐exome sequencing data from female patients with breast cancer (TCGA, training set, n = 1,011; Nigerian samples, validation set, n = 170), and to estimate contributions of signatures in each sample. Association between somatic signatures and common single nucleotide polymorphisms (SNPs) or rare deleterious variants were examined using linear regression. Nine stable signatures were inferred, and four signatures (APOBEC C>T, APOBEC C>G, aging and homologous recombination deficiency) were highly similar to known COSMIC signatures and explained the majority (60–85%) of signature contributions. There were significant heritable components associated with APOBEC C>T signature (h2 = 0.575, p = 0.010) and the combined APOBEC signatures (h2 = 0.432, p = 0.042). In TCGA dataset, seven common SNPs within or near GNB5 were significantly associated with an increased proportion (beta = 0.33, 95% CI = 0.21–0.45) of APOBEC signature contribution at genome‐wide significance, while rare germline mutations in MTCL1 was also significantly associated with a higher contribution of this signature (p = 6.1 × 10−6). This is the first study to identify associations between germline variants and mutational patterns in breast cancer across diverse populations and geography. The findings provide evidence to substantiate causal links between germline genetic risk variants and carcinogenesis.

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Section: Methodssupporting

confidence: 86%

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

Wang

Pitt

Zheng

et al. 2019

Intl Journal of Cancer

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“…Of interest, signatures 20 and 26, have been associated with defective MMR (Helleday, Eshtad, & Nik‐Zainal, ; Temko, Tomlinson, Severini, Schuster‐Bockler, & Graham, ; Wellcome Sanger Institute, ), but were not observed in the Lynch‐related sebaceous skin lesions in this study. Only three MMR‐deficient sebaceous lesions were tested in this study and so they may not represent the complete heterogeneity of mutation signatures that are observed in Lynch‐related sebaceous neoplasia.…”

Section: Discussionmentioning

confidence: 56%

Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

Georgeson

Walsh

Clendenning

et al. 2019

Molec Gen & Gen Med

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Background Muir‐Torre syndrome is defined by the development of sebaceous skin lesions in individuals who carry a germline mismatch repair (MMR) gene mutation. Loss of expression of MMR proteins is frequently observed in sebaceous skin lesions, but MMR‐deficiency alone is not diagnostic for carrying a germline MMR gene mutation. Methods Whole exome sequencing was performed on three MMR‐deficient sebaceous lesions from individuals with MSH2 gene mutations (Lynch syndrome) and three MMR‐proficient sebaceous lesions from individuals without Lynch syndrome with the aim of characterizing the tumor mutational signatures, somatic mutation burden, and microsatellite instability status. Thirty predefined somatic mutational signatures were calculated for each lesion. Results Signature 1 was ubiquitous across the six lesions tested. Signatures 6 and 15, associated with defective DNA MMR, were significantly more prevalent in the MMR‐deficient lesions from the MSH2 carriers compared with the MMR‐proficient non‐Lynch sebaceous lesions (mean ± SD =41.0 ± 8.2% vs. 2.3 ± 4.0%, p = 0.0018). Tumor mutation burden was, on average, significantly higher in the MMR‐deficient lesions compared with the MMR‐proficient lesions (23.3 ± 11.4 vs. 1.8 ± 0.8 mutations/Mb, p = 0.03). All four sebaceous lesions observed in sun exposed areas of the body demonstrated signature 7 related to ultraviolet light exposure. Conclusion Tumor mutational signatures 6 and 15 and somatic mutation burden were effective in differentiating Lynch‐related from non‐Lynch sebaceous lesions.

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“…The application of evolutionary theory allows us to infer cell growth dynamics, the number of driver alterations 17,18 and their selective fitness coefficients [19][20][21][22] , as well as the impact of deleterious mutations during cancer progression 23,24 . An evolutionary metric recently used to detect selection in cancer studies is the ratio of nonsynonymous to synonymous mutations, dN/dS 7,8,[25][26][27] .…”

Section: Introductionmentioning

confidence: 99%

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

Zapata

Caravagna

Williams

et al. 2020

Preprint

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Immunoediting is a major force during cancer evolution that selects for clones with low immunogenicity (adaptation), or clones with mechanisms of immune evasion (escape). However, quantifying immunogenicity in the cancer genome and how the tumour-immune coevolutionary dynamics impact patient outcomes remain unexplored. Here we show that the ratio of nonsynonymous to synonymous mutations (dN/dS) in the immunopeptidome quantifies tumor immunogenicity and differentiates between adaptation and escape. We analysed 8,543 primary tumors from TCGA and validated immune dN/dS as a measure of selection associated with immune infiltration in immune-adapted tumours. In a cohort of 308 metastatic patients that received immunotherapy, pre-treatment lesions in non-responders showed increased immune selection (dN/dS<1), whereas responders did not and instead harboured a higher proportion of genetic escape mechanisms. Ultimately, these findings highlight the potential of evolutionary genomic measures to predict clinical response to immunotherapy.

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The effects of mutational processes and selection on driver mutations across cancer types

Cited by 14 publications

References 23 publications

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

Germline variants and somatic mutation signatures of breast cancer across populations of African and European ancestry in the US and Nigeria

Tumor mutational signatures in sebaceous skin lesions from individuals with Lynch syndrome

dN/dSdynamics quantify tumour immunogenicity and predict response to immunotherapy

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