The estimated frequencies of bases at two 5′ to the mutated site for each cancer type.

<p>The bar heights show the estimated frequency for bases A, C, G and T at the −2 position (two 5′ to the mutated site). The error bars show bootstrapped standard errors. (A, B, C, D, E) The intensities of signature 13 (APOBEC signature), signature 1 (the first Pol <i>ϵ</i> signature), signature 8 (the second Pol <i>ϵ</i> signature), signature 10 (ultraviolet signature) and signature 11, respectively, at the −2 position.</p

The mutation signatures for the UCUT data, and the results of down-sampling experiments.

<p>3,072 elements in the full model mutation signatures were shown divided by 6 substitution patterns and strand directions. (A, B) APOBEC and AA signature for the independent model. (C, D) APOBEC and AA signature for the full model. (E, F) APOBEC and AA signature stability (the mean cosine similarity for each down-sampling ratio).</p

The summary of mutation signatures across 30 cancer types [8] obtained using the proposed method.

<p>Here, the substitution patterns and two 5′ and 3′ bases from the mutated sites are taken into account as mutation features. First, mutation signatures were estimated separately in each cancer type, and then similar signatures were merged (see text).</p

The summary of membership of each mutation signature across 30 cancer types obtained using the proposed method.

<p>The summary of membership of each mutation signature across 30 cancer types obtained using the proposed method.</p

An overview of the generative model of somatic mutations proposed in this paper.

<p>Suppose there are three types of mutation sources (mutation signatures) such as ultraviolet, tobacco smoking chemicals and transcription coupled repairs. Each cancer genome has ratios showing which types of mutation sources are contributing to its mutations (membership parameters). The generative model of the pattern of each mutation is: first, one of the mutation signatures is chosen according to the membership parameter. Second, each mutation feature such as substitution patterns and flanking bases is generated by the corresponding multinomial distributions for the selected mutation signature.</p

Examples of visualizations and parameter values for the mutation signatures of the unconstrained (full) model and our independent model, where substitution patterns, two 5′ and 3′ bases and transcription strand direction are considered as mutation features.

<p>(A) The barplots are divided by 6 substitution patterns and transcription strand direction. In each division, 256 bars show joint probabilities of up to two base 5′ and 3′ bases (ApApNpApA, ApApNpApC, ApApNpApG, ApApNpApT, ⋯, TpTpNpTpT). (B, C) An example mutation signature representation and parameter values from our independent model, where mutation features (substitution patterns, two 5′ and 3′ bases and strand direction) are assumed to be independent (<i>L</i> = 6, <i><b>M</b></i> = (6, 4, 4, 4, 4, 2)). In the bottom five rectangles, the width of each box represents the frequencies of bases (A, C, G and T) at the substitution and flanking site. To highlight the most informative flanking sites, the heights of flanking site boxes are scaled by <math><mrow><mn>1</mn><mo>+</mo><mn>0</mn><mo>.</mo><mn>5</mn><mo>×</mo><mo>log</mo><msub><mo>∑</mo><mrow><mi>n</mi><mo>=</mo><mi>A</mi><mo>,</mo><mi>C</mi><mo>,</mo><mi>G</mi><mo>,</mo><mi>T</mi></mrow></msub><msubsup><mi>f</mi><mi>n</mi><mn>2</mn></msubsup></mrow></math>, where <i>f</i>_<i>n</i> is the parameter for each base, which can be interpreted as 1 − 0.5 × Rényi entropy [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005657#pgen.1005657.ref017" target="_blank">17</a>]. This is analogous to the information content scaling used in sequencing logos. In the top rectangle, the height of each box represents the conditional frequencies of mutated bases for each original base (C and T). In the upper right, the height of the + box represents the frequencies of mutations in the coding strand (the plus strand, the sense strand or the untranscribed strand in other words) whose nucleotide sequences directly corresponds to mRNA, whereas the height of − box represents those in the template strand (the minus strand, the antisense strand, the transcribed strand or the noncoding strand in other words) whose sequences are copied during the synthesis of mRNA.</p

Relationships among mutation signature model, topic models, and population structure models.

<p>Relationships among mutation signature model, topic models, and population structure models.</p

Table_1_A complex rearrangement between APC and TP63 associated with familial adenomatous polyposis identified by multimodal genomic analysis: a case report.xlsx

Genetic testing of the APC gene by sequencing analysis and MLPA is available across commercial laboratories for the definitive genetic diagnosis of familial adenomatous polyposis (FAP). However, some genetic alterations are difficult to detect using conventional analyses. Here, we report a case of a complex genomic APC-TP63 rearrangement, which was identified in a patient with FAP by a series of genomic analyses, including multigene panel testing, chromosomal analyses, and long-read sequencing. A woman in her thirties was diagnosed with FAP due to multiple polyps in her colon and underwent total colectomy. Subsequent examination revealed fundic gland polyposis. No family history suggesting FAP was noted except for a first-degree relative with desmoid fibromatosis. The conventional APC gene testing was performed by her former doctor, but no pathogenic variant was detected, except for 2 variants of unknown significance. The patient was referred to our hospital for further genetic analysis. After obtaining informed consent in genetic counseling, we conducted a multigene panel analysis. As insertion of a part of the TP63 sequence was detected within exon16 of APC, further analyses, including chromosomal analysis and long-read sequencing, were performed and a complex translocation between chromosomes 3 and 5 containing several breakpoints in TP63 and APC was identified. No phenotype associated with TP63 pathogenic variants, such as split-hand/foot malformation (SHFM) or ectrodactyly, ectodermal dysplasia, or cleft lip/palate syndrome (EEC) was identified in the patient or her relatives. Multimodal genomic analyses should be considered in cases where no pathogenic germline variants are detected by conventional genetic testing despite an evident medical or family history of hereditary cancer syndromes.</p

DataSheet_1_A complex rearrangement between APC and TP63 associated with familial adenomatous polyposis identified by multimodal genomic analysis: a case report.pdf

Genetic testing of the APC gene by sequencing analysis and MLPA is available across commercial laboratories for the definitive genetic diagnosis of familial adenomatous polyposis (FAP). However, some genetic alterations are difficult to detect using conventional analyses. Here, we report a case of a complex genomic APC-TP63 rearrangement, which was identified in a patient with FAP by a series of genomic analyses, including multigene panel testing, chromosomal analyses, and long-read sequencing. A woman in her thirties was diagnosed with FAP due to multiple polyps in her colon and underwent total colectomy. Subsequent examination revealed fundic gland polyposis. No family history suggesting FAP was noted except for a first-degree relative with desmoid fibromatosis. The conventional APC gene testing was performed by her former doctor, but no pathogenic variant was detected, except for 2 variants of unknown significance. The patient was referred to our hospital for further genetic analysis. After obtaining informed consent in genetic counseling, we conducted a multigene panel analysis. As insertion of a part of the TP63 sequence was detected within exon16 of APC, further analyses, including chromosomal analysis and long-read sequencing, were performed and a complex translocation between chromosomes 3 and 5 containing several breakpoints in TP63 and APC was identified. No phenotype associated with TP63 pathogenic variants, such as split-hand/foot malformation (SHFM) or ectrodactyly, ectodermal dysplasia, or cleft lip/palate syndrome (EEC) was identified in the patient or her relatives. Multimodal genomic analyses should be considered in cases where no pathogenic germline variants are detected by conventional genetic testing despite an evident medical or family history of hereditary cancer syndromes.</p

Patient characteristics of the AMS 3–4 cohort.

Patient characteristics of the AMS 3–4 cohort.</p