Mutational signatures: Difference between revisions
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| ⚫ | '''Mutational signatures in cancer''' <!-- The current Wikipedia article focuses on general concepts of mutational signatures modelling and the proposed underlying mutational mechanisms leading to these signatures, and therefore, limited information on cancer types will be included --> (or "scars") are characteristic combinations of mutation types arising from specific [[mutagenesis]] processes such as DNA replication infidelity, exogenous and endogenous genotoxic exposures, defective DNA repair pathways and DNA enzymatic editing.<ref name="Forbes2017">{{cite journal | vauthors = Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, Cole CG, Ward S, Dawson E, Ponting L, Stefancsik R, Harsha B, Kok CY, Jia M, Jubb H, Sondka Z, Thompson S, De T, Campbell PJ | display-authors = 6 | title = COSMIC: somatic cancer genetics at high-resolution | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D777-D783 | date = January 2017 | pmid = 27899578 | pmc = 5210583 | doi = 10.1093/nar/gkw1121 }}</ref> |
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| ⚫ | '''Mutational signatures in cancer''' <!-- The current Wikipedia article focuses on general concepts of mutational signatures modelling and the proposed underlying mutational mechanisms leading to these signatures, and therefore, limited information on cancer types will be included --> (or "scars") are characteristic combinations of mutation types arising from specific [[mutagenesis]] processes such as DNA replication infidelity, exogenous and endogenous genotoxic exposures, defective DNA repair pathways and DNA enzymatic editing.<ref name="Forbes2017">{{cite journal | vauthors = Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, Cole CG, Ward S, Dawson E, Ponting L, Stefancsik R, Harsha B, Kok CY, Jia M, Jubb H, Sondka Z, Thompson S, De T, Campbell PJ | display-authors = 6 | title = COSMIC: somatic cancer genetics at high-resolution | journal = Nucleic Acids Research | volume = 45 | issue = D1 | pages = D777-D783 | date = January 2017 | pmid = 27899578 | pmc = 5210583 | doi = 10.1093/nar/gkw1121 }}</ref> |
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Such signatures provide insight into the biological mechanisms involved in [[carcinogenesis]]. Advances in the fields of [[oncogenomics]] have enabled the development of molecularly [[targeted therapy]] mainly addressing gain of function oncogenic mechanisms (e.g. EGFR inhibitors in colorectal cancer<ref name="Seow2016">{{cite journal | vauthors = Seow, H, Yip, WK, and Fifis, T | title = Advances in Targeted and Immunobased Therapies for Colorectal Cancer in the Genomic Era | journal = OncoTargets and Therapy | issue = 9 | date = March 2016 | doi = 10.2147/OTT.S95101 }}</ref>), but more recently, mutational signatures profiling has proven successful in guiding the use of targeted therapies (e.g. immunotherapy in mismatch repair deficient of diverse cancer types,<ref name="pmid=28235882">{{cite journal | vauthors = Chuk, MK, Chang, JT, Theoret, MR, Sampene, E, He, K, Weis, SL, Helms, WS, Jin, R, Li, H, Yu, J, Zhao, H, Zhao, L, Paciga, M, Schmiel, D, Rawat, R, Keegan, P, and Pazdur, R | title = FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. | journal = Clinical Cancer Research | volume = 23 | issue = 19 | pages = 5666–5670 | date = October 2017| pmid = "28235882" | doi = 10.1158/1078-0432.CCR-16-0663 }}</ref> platinum and PARP1 inhibitor for [[synthetic lethality]] in homologous recombination deficient breast cancer <ref name="ONeil2017">{{cite journal | vauthors = O'Neil, NJ, Bailey, ML, and Hieter, P | title = Synthetic Lethality and Cancer | journal = Nature Publishing Group | volume = 18 | issue = 10| pages = 613–23 | date = June 26, 2017 | doi = 10.1038/nrg.2017.47 }}</ref> ). |
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==General concepts== |
==General concepts== |
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[[File:Identification mutational signatures.jpg |thumb|right |700px |'''Conceptual workflow of somatic mutational signatures identification.''' Diverse mutagenesis processes shape the somatic landscape of tumors. Deciphering the underlying patterns of cancer mutations allows to uncover relationships between these recurrent patterns of mutations and infer possible causal mutational processes.]] |
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| ⚫ | ===Mechanisms – overview=== <!-- The mutational signature classification of this Wikipedia article segregates the genotoxins under a separate section for simplification, but [[mutagenesis]] mechanisms overlap between genotoxins-induced signatures and DNA repair mechanisms (e.g. Signature 4 and nucleotide excision repair) --> |
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| ⚫ | The biological [[mutagenesis]] mechanisms underlying mutational signatures (e.g. COSMIC Signatures 1 to 30) include, but are not limited to:{{efn|name=classification_signature_mechanisms|As DNA replication, maintenance and repair is not a linear process, some signatures are caused by overlapping mutagenesis mechanisms.}}<ref name="Alexandrov2013" /> |
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===Genomic data=== |
===Genomic data=== |
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====Types of mutations: base substitutions==== |
====Types of mutations: base substitutions==== |
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| ⚫ | There are six classes of base substitution: C>A, C>G, C>T, T>A, T>C, T>G. Of note, C>A and G>T substitutions are considered equivalent and are both counted as part of the "C>A" class because it is not possible to differentiate on which DNA strand (forward or reverse) the substitution initially occurred. Taking the information from the 5' and 3' adjacent bases (also called flanking base pairs or trinucleotide context) lead to 96 possible mutation types (e.g. A[C>A]A, A[C>A]T, etc.). The mutation catalog of a tumor is created by categorizing each single nucleotide variant (SNV) (synonyms: [[base-pair substitution]] or substitution [[point mutation]]) in one of the 96 mutation types and counting the total number of substitutions for each of these 96 mutation types (see figure). |
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| ⚫ | [[File:Figure 1. MutationTypes.tif |thumb | |
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| ⚫ | [[File:Figure 1. MutationTypes.tif |thumb |left |baseline |450px | The 96 mutation types concept from Alexandrov et al.<ref name="Alexandrov2013" /> Considering the 5' flanking base (A, C, G, T), the 6 substitution classes (C>A, C>G, C>T, T>A, T>C, T>G) and 3' flanking base (A, C, G, T) leads to a 96 mutation types classification (4 x 6 x 4 = 96). The 16 possible mutation types of the substitution class C>A are shown as an example.]] |
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| ⚫ | There are six classes of base substitution: C>A, C>G, C>T, T>A, T>C, T>G. Of note, C>A and G>T substitutions are considered equivalent and are both counted as part of the "C>A" class because it is not possible to differentiate on which DNA strand (forward or reverse) the substitution initially occurred. Taking the information from the 5' and 3' adjacent bases (also called flanking base pairs or trinucleotide context) lead to 96 possible mutation types (e.g. A[C>A]A, A[C>A]T, etc.). The mutation catalog of a tumor is created by categorizing each single nucleotide variant (SNV) (synonyms: [[base-pair substitution]] or substitution [[point mutation]]) in one of the 96 mutation types and counting the total number of substitutions for each of these 96 mutation types ( |
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====Tumor mutation catalog==== |
====Tumor mutation catalog==== |
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[[Homologous recombination]] deficiency leads to Signature 3 substitution pattern, but also to increase burden of structural variants. In the absence of [[homologous recombination]], [[non-homologous end joining]] leads to large structural variants such as [[chromosomal translocations]], [[chromosomal inversions]] and [[copy number variants]]. |
[[Homologous recombination]] deficiency leads to Signature 3 substitution pattern, but also to increase burden of structural variants. In the absence of [[homologous recombination]], [[non-homologous end joining]] leads to large structural variants such as [[chromosomal translocations]], [[chromosomal inversions]] and [[copy number variants]]. |
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| ⚫ | ===Mechanisms – overview=== <!-- The mutational signature classification of this Wikipedia article segregates the genotoxins under a separate section for simplification, but [[mutagenesis]] mechanisms overlap between genotoxins-induced signatures and DNA repair mechanisms (e.g. Signature 4 and nucleotide excision repair) --> |
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| ⚫ | The biological [[mutagenesis]] mechanisms underlying mutational signatures (e.g. COSMIC Signatures 1 to 30) include, but are not limited to:{{efn|name=classification_signature_mechanisms|As DNA replication, maintenance and repair is not a linear process, some signatures are caused by overlapping mutagenesis mechanisms.}}<ref name="Alexandrov2013" /> |
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==Mutational signatures== |
==Mutational signatures== |
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Signature 11 was identified in tumors previously exposed to temozolomide, an alkylating agent.<ref name="Alexandrov2015" /> This signature is enriched for C>T substitutions on guanine bases due to transcription-coupled [[nucleotide excision repair]]. A strong transcriptional strand-bias is present in this signature. |
Signature 11 was identified in tumors previously exposed to temozolomide, an alkylating agent.<ref name="Alexandrov2015" /> This signature is enriched for C>T substitutions on guanine bases due to transcription-coupled [[nucleotide excision repair]]. A strong transcriptional strand-bias is present in this signature. |
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====Tobacco==== |
====Tobacco==== |
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Revision as of 02:02, 2 March 2018
Mutational signatures in cancer (or "scars") are characteristic combinations of mutation types arising from specific mutagenesis processes such as DNA replication infidelity, exogenous and endogenous genotoxic exposures, defective DNA repair pathways and DNA enzymatic editing.[1]
Such signatures provide insight into the biological mechanisms involved in carcinogenesis. Advances in the fields of oncogenomics have enabled the development of molecularly targeted therapy mainly addressing gain of function oncogenic mechanisms (e.g. EGFR inhibitors in colorectal cancer[2]), but more recently, mutational signatures profiling has proven successful in guiding the use of targeted therapies (e.g. immunotherapy in mismatch repair deficient of diverse cancer types,[3] platinum and PARP1 inhibitor for synthetic lethality in homologous recombination deficient breast cancer [4] ).
General concepts
Mechanisms – overview
The biological mutagenesis mechanisms underlying mutational signatures (e.g. COSMIC Signatures 1 to 30) include, but are not limited to:[a][5]
- DNA replication infidelity
- DNA proofreading (e.g. Signature 10 and POLE)
- Genotoxins
- Endogenous (e.g. 5-methylcytosine deamination and Signature 1)
- Exogenous/carcinogens
- Ultraviolet radiation (Signature 7)
- Alkylating agents (Signature 11)
- Tobacco (Signature 4)
- DNA repair deficiency
- Homologous recombination deficiency (e.g. Signature 3)
- Mismatch repair deficiency (Signatures 6, 15, 20, 26)
- Enzymatic DNA editing
- APOBEC cytidine deaminases (Signatures 2 and 13)
Genomic data
Cancer mutational signatures analyses requires genomic data from cancer genome sequencing with paired-normal DNA sequencing in order to create the tumor mutation catalog (mutation types and counts) of a specific tumor. A team from the Cancer Genome Project created an algorithm to extract mutational signatures from single nucleotide variant (SNV) and indels profiling from cancer whole genome sequencing (tumor and normal DNA) data.[5]
Different types of mutations (e.g. single nucleotide variants, indels, structural variants) can be used individually or in combination to model mutational signatures in cancer.
Types of mutations: base substitutions
There are six classes of base substitution: C>A, C>G, C>T, T>A, T>C, T>G. Of note, C>A and G>T substitutions are considered equivalent and are both counted as part of the "C>A" class because it is not possible to differentiate on which DNA strand (forward or reverse) the substitution initially occurred. Taking the information from the 5' and 3' adjacent bases (also called flanking base pairs or trinucleotide context) lead to 96 possible mutation types (e.g. A[C>A]A, A[C>A]T, etc.). The mutation catalog of a tumor is created by categorizing each single nucleotide variant (SNV) (synonyms: base-pair substitution or substitution point mutation) in one of the 96 mutation types and counting the total number of substitutions for each of these 96 mutation types (see figure).
Tumor mutation catalog
Once the mutation catalog (e.g. counts for each of the 96 mutation types) of a tumor is obtained, there are two approaches to decipher the contributions of different mutational signatures to tumor genomic landscape:
- The mutation catalog of the tumor is compared to a reference mutation catalogue, or mutational signatures reference dataset, such as the 30 Signatures of Mutational Processes in Human Cancer [5] from the Catalogue of Somatic Mutation In Cancer (COSMIC) database.[1]
- De novo mutational signatures modelling can be accomplished using statistical methods such as non-negative matrix factorization to identify potential novel mutational processes.[6]
Identifying the contributions of diverse mutational signatures to carcinogenesis provides insight into tumor biology and can offer opportunities for targeted therapy.
Types of mutations: indels
Signature 3, seen in homologous recombination (HR) deficient tumour, is associated with increased burden of large indels (up to 50 nucleotides) with overlapping microhomology at the breakpoints.[5] In such tumors, DNA double-strand breaks are repaired by the imprecise repair mechanisms of non-homologous end joining (NHEJ) instead of high fidelity HR repair.
Signature 6, seen in tumors with microsatellite instability, also features enrichment of 1bp indels in nucleotide repeat regions.
Types of mutations: structural variants
Homologous recombination deficiency leads to Signature 3 substitution pattern, but also to increase burden of structural variants. In the absence of homologous recombination, non-homologous end joining leads to large structural variants such as chromosomal translocations, chromosomal inversions and copy number variants.
Mutational signatures
A brief description of selected mutational processes and their associated mutational signatures in cancer will be included in the sections below. Some signatures are ubiquitous across diverse cancer types (e.g. Signature 1) while some others tend to associate with specific cancers (e.g. Signature 9 and lymphoid malignancies).[5]
Some mutational signatures feature strong transcriptional-bias with substitutions preferentially affecting one of the DNA strands, either the transcribed or untranscribed strand (Signatures 5, 7, 8, 10, 12, 16).[5]
Signature 1 features a predominance of C>T transitions in the Np[C>T]G trinucleotide contexts and correlates with the age of patient at time of cancer diagnosis. The underlying proposed biological mechanism is the spontaneous deamination of 5-methylcytosine.[5]
Signature 5 has a predominance of T>C substitutions in the ApTpN trinucleotide context with transcriptional strand bias.[7]
Homologous recombination deficiency
Signature 3 displays high mutation counts of multiple mutation classes and is associated with germline and somatic BRCA1 and BRCA2 mutations in several cancer types (e.g. breast, pancreatic, ovarian, prostate). This signature results from DNA double-strand break repair deficiency (or homologous recombination deficiency. Signature 3 is associated with high burden of indels with microhomology at breakpoints.[7]
APOBEC enzymes
Signature 2 and Signature 13 are enriched for C>T and C>G substitutions and are thought to arise from cytidine deaminase activity of the AID/APOBEC enzymes family.[7]
A germline deletion polymorphism involving APOBEC3A and APOBEC3B is associated with high burden of Signature 2 and Signature 13 mutations.[8] This polymorphism is considered to be of moderate penetrance (two-fold to four-fold background risk) for breast cancer risk.[9] The exact roles and mechanisms underlying APOBEC-mediated genome editing are not yet fully delineated, but AID/APOBEC complex is thought to be involved in host immune response to viral infections and lipid metabolism.[10]
Both Signature 2 and Signature 13 are feature cytosine to uracil substitutions due to cytidine deaminases. Signature 2 has a higher proportion of C[T>C]N substitutions and Signature 13 a higher proportion of T[C>G]N substitutions. APOBEC3A and APOBEC3B-mediated mutagenesis preferentially involve the lagging DNA strand during replication.[11]
Mismatch repair deficiency
Four COSMIC mutational signatures have been associated with DNA mismatch repair deficiency and found in tumors with microsatellite instability: Signature 6, 15, 20 and 26.[7]
DNA proofreading
Signature 10 has a transcriptional bias and is enriched for C>A substitutions in the TpCpT context as well as T>G substitutions in the TpTpTp context.[7] Signature 10 is associated with altered function of POLE polymerase, which result in deficient proofreading activity. Both germline and somatic POLE exonuclease domain mutations are associated with Signature 10.[12]
Base excision repair
Somatic enrichment for tranversion mutations (G:C>T:A) has been associated with base excision repair (BER) deficiency and linked to defective MUTYH, a DNA glycosylase, in colorectal cancer.[13] Direct DNA oxidative damage leads to the creation of 8-Oxoguanine, which if remains un-repaired, will lead to incorporation of Adenine instead of Cytosine during DNA replication. MUTYH glycosylase excise the mismatched Adenine from 8-oxoGuanine:Adenine base pairing, therefore enabling DNA repair mechanisms involving OGG1 (Oxoguanine glycosylase) and NUDT1 (Nudix hydrolase 1, also known as MTH1, MutT homolog 1) to remove the damaged 8-Oxoguanine.[14]
Exposures to exogenous genotoxins
Selected exogenous genotoxins/carcinogens and their mutagen-induced DNA damage and repair mechanisms have been linked to specific molecular signatures.
Ultraviolet radiation
Signature 7 has a predominance CC>TT dinucleotide mutations at the pyrimidine-pyrimidine photodimers repaired via transcription-coupled nucleotide excision repair. It has a strong transcriptional bias with C>T substitutions enriched on the untranscribed DNA strand.[7] Ultraviolet radiation exposure is the proposed underlying mutagenic mechanism of this signature.
Alkylating agents
Signature 11 was identified in tumors previously exposed to temozolomide, an alkylating agent.[7] This signature is enriched for C>T substitutions on guanine bases due to transcription-coupled nucleotide excision repair. A strong transcriptional strand-bias is present in this signature.
Tobacco
Both Signature 4 (tobacco smoking, lung cancers) and Signature 29 (tobacco chewing, gingivo-buccal oral squamous cell carcinoma) display transcriptional strand-bias and enrichment for C>A substitutions, but their respective composition and patterns (proportion of each mutation types) differ slightly.[7]
The proposed underlying mechanism of Signature 4 is the removal of DNA adducts (tobacco [[benzo[a]pyrene]] covalently bounded to guanine) by the transcription-coupled nucleotide excision repair (NER) machinery.[15]
Immunoglobulin gene hypermutation
Signature 9 has been identified in chronic lymphocytic leukemia and malignant B-cell lymphoma and feature enrichment for T>G transversion events. It is thought to result from error-prone polymerase n (POLH gene)-associated mutagenesis.[5]
Recently, polymerase n error-prone synthesis signature has been linked to non-hematological cancers such as skin cancers, and was hypothesized to contribute to YCG motif mutagenesis and could partly explain the increase TC dinucleotides substitutions.[16]
Note list
- ^ As DNA replication, maintenance and repair is not a linear process, some signatures are caused by overlapping mutagenesis mechanisms.
References
- ^ a b Forbes SA, Beare D, Boutselakis H, Bamford S, Bindal N, Tate J, et al. (January 2017). "COSMIC: somatic cancer genetics at high-resolution". Nucleic Acids Research. 45 (D1): D777–D783. doi:10.1093/nar/gkw1121. PMC 5210583. PMID 27899578.
- ^ Seow, H, Yip, WK, and Fifis, T (March 2016). "Advances in Targeted and Immunobased Therapies for Colorectal Cancer in the Genomic Era". OncoTargets and Therapy (9). doi:10.2147/OTT.S95101.
{{cite journal}}: Vancouver style error: name in name 5 (help)CS1 maint: unflagged free DOI (link) - ^ Chuk, MK, Chang, JT, Theoret, MR, Sampene, E, He, K, Weis, SL, Helms, WS, Jin, R, Li, H, Yu, J, Zhao, H, Zhao, L, Paciga, M, Schmiel, D, Rawat, R, Keegan, P, and Pazdur, R (October 2017). "FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma". Clinical Cancer Research. 23 (19): 5666–5670. doi:10.1158/1078-0432.CCR-16-0663. PMID "28235882" "28235882".
{{cite journal}}: Check|pmid=value (help); Vancouver style error: name in name 33 (help) - ^ O'Neil, NJ, Bailey, ML, and Hieter, P (June 26, 2017). "Synthetic Lethality and Cancer". Nature Publishing Group. 18 (10): 613–23. doi:10.1038/nrg.2017.47.
{{cite journal}}: Vancouver style error: name in name 5 (help) - ^ a b c d e f g h i j Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SA, Behjati S, Biankin AV, et al. (August 2013). "Signatures of mutational processes in human cancer". Nature. 500 (7463): 415–21. doi:10.1038/nature12477. PMC 3776390. PMID 23945592.
- ^ a b Zhao EY, Shen Y, Pleasance E, Kasaian K, Leelakumari S, Jones M, et al. (December 2017). "Homologous Recombination Deficiency and Platinum-Based Therapy Outcomes in Advanced Breast Cancer". Clinical Cancer Research. 23 (24): 7521–7530. doi:10.1158/1078-0432.CCR-17-1941. PMID 29246904.
- ^ a b c d e f g h Alexandrov LB, Jones PH, Wedge DC, Sale JE, Campbell PJ, Nik-Zainal S, Stratton MR (December 2015). "Clock-like mutational processes in human somatic cells". Nature Genetics. 47 (12): 1402–7. doi:10.1038/ng.3441. PMC 4783858. PMID 26551669.
- ^ Middlebrooks CD, Banday AR, Matsuda K, Udquim KI, Onabajo OO, Paquin A, et al. (November 2016). "Association of germline variants in the APOBEC3 region with cancer risk and enrichment with APOBEC-signature mutations in tumors". Nature Genetics. 48 (11): 1330–1338. doi:10.1038/ng.3670. PMID 27643540.
- ^ Nik-Zainal S, Wedge DC, Alexandrov LB, Petljak M, Butler AP, Bolli N, et al. (May 2014). "Association of a germline copy number polymorphism of APOBEC3A and APOBEC3B with burden of putative APOBEC-dependent mutations in breast cancer". Nature Genetics. 46 (5): 487–91. doi:10.1038/ng.2955. PMC 4137149. PMID 24728294.
- ^ Yang B, Li X, Lei L, Chen J (September 2017). "APOBEC: From mutator to editor". Journal of Genetics and Genomics = Yi Chuan Xue Bao. 44 (9): 423–437. doi:10.1016/j.jgg.2017.04.009. PMID 28964683.
- ^ Hoopes JI, Cortez LM, Mertz TM, Malc EP, Mieczkowski PA, Roberts SA (February 2016). "APOBEC3A and APOBEC3B Preferentially Deaminate the Lagging Strand Template during DNA Replication". Cell Reports. 14 (6): 1273–1282. doi:10.1016/j.celrep.2016.01.021. PMC 4758883. PMID 26832400.
- ^ Rayner E, van Gool IC, Palles C, Kearsey SE, Bosse T, Tomlinson I, Church DN (February 2016). "A panoply of errors: polymerase proofreading domain mutations in cancer". Nature Reviews. Cancer. 16 (2): 71–81. doi:10.1038/nrc.2015.12. PMID 26822575.
- ^ a b Viel, A, Bruselles, A, Meccia, E, Fornasarig, M, Quaia, M, Canzonieri, V, Policicchio, E, Urso, ED, Agostini, M, Genuardi, M, Lucci-Cordisco, E, Venesio, T, Martayan, A, Diodoro, MG, Sanchez-Mete, L, Stigliano, V, Mazzei, F, Grasso, F, Giuliani, A, Baiocchi, M, Maestro, R, Giannini, G, Tartaglia, M, Alexandrov, LB, Bignami, M (April 2017). "A Specific Mutational Signature Associated with DNA 8-Oxoguanine Persistence in MUTYH-defective Colorectal Cancer". EBioMedicine. 20: 39–49. doi:10.1016/j.ebiom.2017.04.022. PMID 28551381.
- ^ David, SS, O'Shea, VL, Kundu, S (2007). "Base-excision repair of oxidative DNA damage". Nature. 447 (7147): 941–950. doi:10.1038/nature05978. PMID 17581577.
- ^ Alexandrov LB, Ju YS, Haase K, Van Loo P, Martincorena I, Nik-Zainal S, Totoki Y, Fujimoto A, Nakagawa H, Shibata T, Campbell PJ, Vineis P, Phillips DH, Stratton MR (November 2016). "Mutational signatures associated with tobacco smoking in human cancer". Science (New York, N.Y.). 354 (6312): 618–622. doi:10.1126/science.aag0299. PMID 27811275.
- ^ Rogozin IB, Goncearenco A, Lada AG, De S, Yurchenkod V, Nudelman G, Panchenko AR, Cooper DN, Pavlov YI (February 2018). "DNA polymerase η mutational signatures are found in a variety of different types of cancer". Cell Cycle: 1–8. doi:10.1080/15384101.2017.1404208. PMID 29139326.