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The following shows an example of how to run Mutalisk using the sample data.

1. Genome assembly

2. Input file

 The input file format of this tool is VCF file.
 You can select multiple files (max 300).

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3. Mutational signatures

3-1. MLE method

 COSMIC

3-2. Cancer type
3-3. Select the mutational signatures.
Signature1     

Signature 1 is the result of an endogenous mutational process initiated by spontaneous deamination of 5-methylcytosine.
Signature2     

Signature 2 has been attributed to activity of the AID/APOBEC family of cytidine deaminases. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family.
Signature3     

Signature 3 is associated with failure of DNA double-strand break-repair by homologous recombination.

Signature4     

Signature 4 is associated with smoking and its profile is similar to the mutational pattern observed in experimental systems exposed to tobacco carcinogens (e.g., benzo[a]pyrene). Signature 4 is likely due to tobacco mutagens.
Signature5     

The aetiology of Signature 5 is unknown.
Signature6     

Signature 6 is associated with defective DNA mismatch repair and is found in microsatellite unstable tumours.

Signature7     

Based on its prevalence in ultraviolet exposed areas and the similarity of the mutational pattern to that observed in experimental systems exposed to ultraviolet light Signature 7 is likely due to ultraviolet light exposure.
Signature8     

The aetiology of Signature 8 remains unknown.
Signature9     

Signature 9 is characterized by a pattern of mutations that has been attributed to polymerase η, which is implicated with the activity of AID during somatic hypermutation.

Signature10   

It has been proposed that the mutational process underlying this signature is altered activity of the error-prone polymerase POLE. The presence of large numbers of Signature 10 mutations is associated with recurrent POLE somatic mutations, viz., Pro286Arg and Val411Leu.
Signature11   

Signature 11 exhibits a mutational pattern resembling that of alkylating agents. Patient histories have revealed an association between treatments with the alkylating agent temozolomide and Signature 11 mutations.
Signature12   

The aetiology of Signature 12 remains unknown.

Signature13   

Signature 13 has been attributed to activity of the AID/APOBEC family of cytidine deaminases converting cytosine to uracil. On the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems, a role for APOBEC1, APOBEC3A and/or APOBEC3B in human cancer appears more likely than for other members of the family. Signature 13 causes predominantly C>G mutations. This may be due to generation of abasic sites after removal of uracil by base excision repair and replication over these abasic sites by REV1.
Signature14   

The aetiology of Signature 14 remains unknown.
Signature15   

Signature 15 is associated with defective DNA mismatch repair.

Signature16   

The aetiology of Signature 16 remains unknown.
Signature17   

The aetiology of Signature 17 remains unknown.
Signature18   

The aetiology of Signature 18 remains unknown.

Signature19   

The aetiology of Signature 19 remains unknown.
Signature20   

Signature 20 is believed to be associated with defective DNA mismatch repair.
Signature21   

The aetiology of Signature 21 remains unknown.

Signature22   

Signature 22 has been found in cancer samples with known exposures to aristolochic acid. Additionally, the pattern of mutations exhibited by the signature is consistent with the one previous observed in experimental systems exposed to aristolochic acid.
Signature23   

The aetiology of Signature 23 remains unknown.
Signature24   

Signature 24 has been found in cancer samples with known exposures to aflatoxin. Additionally, the pattern of mutations exhibited by the signature is consistent with that previous observed in experimental systems exposed to aflatoxin.

Signature25   

The aetiology of Signature 25 remains unknown.
Signature26   

Signature 26 is believed to be associated with defective DNA mismatch repair.
Signature27   

The aetiology of Signature 27 remains unknown.

Signature28   

The aetiology of Signature 28 remains unknown.
Signature29   

Signature 29 has been found in cancer samples from individuals with a tobacco chewing habit.
Signature30   

The aetiology of Signature 30 remains unknown.
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Reference to the mutational signatures:
※ Signatures of Mutational Processes in Human Cancer

 PCAWG - SigProfiler (provisional)

3-2. Cancer type
3-3. Select the mutational signatures.
 Full screening  Random sampling
SBS1       

An endogenous mutational process initiated by spontaneous or enzymatic deamination of 5-methylcytosine to thymine which generates G:T mismatches in double stranded DNA. Failure to detect and remove these mismatches prior to DNA replication results in fixation of the T substitution for C.
SBS2       

Attributed to activity of the AID/APOBEC family of cytidine deaminases on the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems. APOBEC3A is probably responsible for most mutations in human cancer, although APOBEC3B may also contribute (these differ in the sequence context two bases 5’ to the mutated cytosine, see 1,536 mutation classification signature extraction). Signature SBS2 mutations may be generated directly by DNA replication across uracil or by error prone polymerases replicating across abasic sites generated by base excision repair removal of uracil.
SBS3       

Defective homologous recombination-based DNA damage repair which manifests predominantly as small indels and genome rearrangements due to abnormal double strand break repair but also in the form of this base substitution signature.
SBS4       

Associated with tobacco smoking. Its profile is similar to the mutational spectrum observed in experimental systems exposed to tobacco carcinogens such as benzo[a]pyrene. Signature 4 is, therefore, likely due to direct DNA damage by tobacco smoke mutagens.

SBS5       

Unknown. Signature SBS5 mutational burden is enriched in bladder cancer samples with ERCC5 mutations. The rate of signature SBS5 can be elevated due to tobacco smoking in many cancer types.
SBS6       

Signature SBS6 is associated with defective DNA mismatch repair and is found in microsatellite unstable tumours.
SBS7a     

Signatures SBS7a/b/c/d are found in cancers of the skin from sun exposed areas, therefore, these are likely to be due to exposure to ultraviolet light. Signature SBS 7a may possibly be the consequence of just one of the two major known UV photoproducts, cyclobutane pyrimidine dimers or 6-4 photoproducts, although there is no evidence for this hypothesis and it is unclear which of these photoproducts may be responsible.
SBS7b     

Signatures SBS7a/b/c/d are found in cancers of the skin from sun exposed areas, therefore, these are likely to be due to exposure to ultraviolet light. Signature SBS7b may possibly be the consequence of just one of the two major known UV photoproducts, cyclobutane pyrimidine dimers or 6-4 photoproducts, although there is no evidence for this hypothesis and it is unclear which of these photoproducts may be responsible.

SBS7c     

Signatures SBS7a/b/c/d are found in cancers of the skin from sun exposed areas, therefore, these are likely to be due to exposure to ultraviolet light. Signature SBS7c is possibly the consequence of translesion DNA synthesis by enzymes with propensity to insert T, rather than A, opposite ultraviolet induced thymidine and cytidine photodimers. The preponderance of T>A rather than T>C mutations may reflect the heavier burden of thymidine compared to cytidine dimers induced by UV light.
SBS7d     

Signatures SBS7a/b/c/d are found in cancers of the skin from sun exposed areas, therefore, these are likely to be due to exposure to ultraviolet light. Signature SBS7d is possibly the consequence of translesion DNA synthesis by error-prone polymerases with greater propensity to insert G, rather than A, opposite UV light induced thymidine and cytidine photodimers.
SBS8       

Unknown.
SBS9       

Attributed to mutations induced during replication by polymerase η across lesions induced by activation induced cytidine deaminase as part of somatic hypermutation.

SBS10a   

Polymerase epsilon exonuclease domain mutations.
SBS10b   

Polymerase epsilon exonuclease domain mutations.
SBS11     

Signature SBS11 exhibits a mutational pattern resembling that of alkylating agents. Patient histories indicate an association between previous treatment with the alkylating agent temozolomide and Signature SBS11 mutations.
SBS12     

Unknown.

SBS13     

Attributed to activity of the AID/APOBEC family of cytidine deaminases on the basis of similarities in the sequence context of cytosine mutations caused by APOBEC enzymes in experimental systems. APOBEC3A is probably responsible for most mutations in human cancer, although APOBEC3B may also contribute (these differ in the sequence context two bases 5’ to the mutated cytosine, see 1536 mutation classification signature extraction). Signature SBS13 mutations are likely generated by error prone polymerases (such as REV1) replicating across abasic sites generated by base excision repair removal of uracil.
SBS14     

Defective DNA mismatch repair.
SBS15     

Defective DNA mismatch repair.
SBS16     

Unknown.

SBS17a   

Unknown.
SBS17b   

Unknown.
SBS18     

Possibly damage by reactive oxygen species.
SBS19     

Unknown.

SBS20     

Unknown.
SBS21     

DNA mismatch repair deficiency.
SBS22     

Aristolochic acid exposure. Found in cancer samples with known exposures to aristolochic acid and the pattern of mutations exhibited by the signature is consistent with that observed in experimental systems of aristolochic acid exposure.
SBS23     

Unknown.

SBS24     

Aflatoxin exposure. Signature SBS24 has been found in cancer samples with known exposures to aflatoxin and the pattern of mutations exhibited by the signature is consistent with that observed in experimental systems exposed to aflatoxin.
SBS25     

Unknown. However, some Hodgkin’s cell line samples in which the signature has been found were from patients exposed to chemotherapy.
SBS26     

Defective DNA mismatch repair.
SBS27     

Possible sequencing artefact.

SBS28     

Unknown.
SBS29     

Signature SBS29 has been found in cancer samples from individuals with a tobacco chewing habit.
SBS30     

Signature SBS30 is due to deficiency in base excision repair and, more specifically, to inactivating mutations in NTHL1.
SBS31     

Prior chemotherapy treatment with platinum drugs.

SBS32     

Prior treatment with azathioprine to induce immunosuppression.
SBS33     

Unknown.
SBS34     

Unknown.
SBS35     

Prior chemotherapy treatment with platinum drugs.

SBS36     

Defective base excision repair, including DNA damage due to reactive oxygen species, due to biallelic germline or somatic MUTYH mutations.
SBS37     

Unknown.
SBS38     

Unknown. Found only in ultraviolet light associated melanomas suggesting a potential indirect damage from UV-light.
SBS39     

Unknown.

SBS40     

Unknown.
SBS41     

Unknown.
SBS42     

Occupational exposure to haloalkanes.
SBS43     

Unknown. Possible sequencing artefact.

SBS44     

Defective DNA mismatch repair.
SBS45     

Likely artefact due to 8-oxo-guanine introduced during sequencing.
SBS46     

Likely sequencing artefact.
SBS47     

Likely sequencing artefact.

SBS48     

Likely sequencing artefact.
SBS49     

Possible sequencing artefact.
SBS50     

Likely sequencing artefact.
SBS51     

Possible sequencing artefact.

SBS52     

Possible sequencing artefact.
SBS53     

Likely sequencing artefact.
SBS54     

Potential sequencing artefact. Potential contamination with germline variants.
SBS55     

Potential sequencing artefact.

SBS56     

Potential sequencing artefact.
SBS57     

Potential sequencing artefact.
SBS58     

Potential sequencing artefact.
SBS59     

Potential sequencing artefact.

SBS60      

Known sequencing artefact.
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 Custom signatures

3-2. Select the mutational signatures.
Please upload your own signature file for the decomposition of mutational signatures. A tab-delimited sample signature file is available below:
For additional information on the formatting of the signature file, please refer to the Tutorials page.
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4. Genomic & epigenomic annotation

Localized hypermutation (kataegis)
Transcriptional strand bias
GC content
[ ENCODE dataset reference cell ]
DNA replication timing
DNaseI hypersensitivity
Histone modification
(NA) : Not Available
Reference to the genomic/epigenomic data:
※ The ENCODE Project & UCSC genome browser

National Cancer Center. 323 Ilsan-ro, Ilsandong-gu, Goyang-si Gyeonggi-do, 10408, Republic of Korea