A genome‐wide analysis of the molecular alterations occurring in the adenomatous and carcinomatous components of the same tumor based on the adenoma–carcinoma sequence

Sugai, Tamotsu; Osakabe, Mitsumasa; Habano, Wataru; Tanaka, Yoshihito; Eizuka, Makoto; Sugimoto, Ryo; Yanagawa, Naoki; Matsumoto, Takayuki; Suzuki, Hiromu

doi:10.1111/pin.13129

Cited by 7 publications

(10 citation statements)

References 32 publications

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“…In isolated adenomatous samples, 36 mRNAs showed differential upregulation, and 71 upregulated and 2 downregulated mRNAs were then set from isolated carcinomatous glands within a tumor. The detailed data and a Venn diagram were previously reported ( Figure 4-B ) ( 24 ).…”

Section: Resultsmentioning

confidence: 99%

“…RT-qPCR was performed using Power SYBR Green PCR Master Mix (Thermo Fisher Scientific) on the CFX96 Touch Real-Time PCR Detection System (Bio-Rad, Hercules, CA, USA). The 2 −Δ Ct method was used to calculate relative gene expression levels based on the Livak and Schmittgen method ( 24 ). The expression levels of each miRNA were compared with that of RNU6B.…”

Section: Methodsmentioning

confidence: 99%

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Genome-Wide Analysis of microRNA and mRNA Expression in Colorectal Intramucosal Neoplasia and Colorectal Cancer With a Microsatellite-Stable Phenotype Based on Adenoma-Carcinoma Sequences

Sugai

Osakabe²,

Niinuma³

et al. 2022

Front. Oncol.

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BackgroundAlthough MicroRNAs (miRNAs) play important roles in various biological processes, the biological functions of miRNAs are achieved through mRNAs. The aim of this study is to identify dysregulated miRNA/mRNA expression patterns in colorectal tumors.MethodsWe examined 42 colorectal tumors [15 adenomas, 8 intramucosal cancers (IMCs), and 19 invasive colorectal cancers (CRCs)] with the microsatellite stable (MSS) phenotype (first cohort). The first cohort was used for genome-wide miRNA and mRNA expression arrays, whereas the second cohort (37 colorectal neoplasias) was used for validation analyses. Finally, we used 15 cases of “adenoma in/with carcinoma” to identify network patterns of miRNAs/mRNAs that were directly associated with neoplastic progression. In addition, simple regression analysis for array-based and RT-PCR analyses was performed to select candidate miRNA–mRNA pairs. Transfection of miRNA mimics was also performed to confirm whether target mRNA expression is affected by specific miRNAs.ResultsSpecific paired miRNA/mRNA networks, including hsa-miR-34a-5p/SLC12A2, hsa-miR-15b-5p/SLC12A2, hsa-miR-195-5p/SLC12A2, hsa-miRNA-502-3p/OLFM4, hsa-miRNA-6807-5p/ZG16, and hsa-miRNA 3064-5p/SH3BGRL3, were identified in samples of adenoma, IMC, and CRC with the MSS phenotype. In adenomatous lesions obtained from the same tumor with a carcinomatous lesion, we identified pairs of miRNA-130a-3p/HSPA8 and miRNA-22-3p/RP53 that were linked to multiple pathways. On the other hand, 2 pairs of miRNA/mRNA (miRNA-660-5p and miRNA-664a-5p/APP) were found in isolated carcinomatous glands. Ectopic expression of miRNA 3064-5p suppressed SH3BGRL3 expression.ConclusionsWe found that networks based on specific pairs of miRNAs/mRNAs contribute to progression from adenomatous and carcinomatous lesions. Our results provide insights into the molecular tumorigenesis of colorectal tumors.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Genome-Wide Analysis of microRNA and mRNA Expression in Colorectal Intramucosal Neoplasia and Colorectal Cancer With a Microsatellite-Stable Phenotype Based on Adenoma-Carcinoma Sequences

Sugai

Osakabe²,

Niinuma³

et al. 2022

Front. Oncol.

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“…It is important for pathologists and gastroenterologists to evaluate the molecular mechanism underlying progression from HGIL to ISL 8 . Although many studies have addressed this mechanism, an effective marker has not been identified.…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have shown that advanced adenomas including HGIL have a high frequency of SCNAs, 8 whereas the number of SCNAs might be higher in metastatic than primary CRC. 20 , 21 Thus, progression from an early‐stage to invasive lesion in CRC seems to involve stepwise accumulation of SCNAs.…”

Section: Discussionmentioning

confidence: 99%

“…Although a combination rather than one of these molecular alteration types contributes to development of colorectal cancer (CRC), SCNAs are attracting attention as a molecular mechanism of tumor progression 5–7 . In fact, a recent study showed that SCNAs accumulate during tumor progression and play a crucial role in neoplastic invasion through the mucosa 8 . Although the total number of changes, rather than their chronological order of appearance, may determine the biological properties of a tumor, SCNAs as well as genetic mutations often occur in a specific sequence 9 …”

Section: Introductionmentioning

confidence: 99%

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Genome‐wide analysis of colorectal cancer based on gene‐based somatic copy number alterations during neoplastic progression within the same tumor

et al. 2022

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Background The objective of this study was to elucidate the association between neoplastic progression and somatic copy number alterations (SCNAs) occurring within the same colorectal cancer (CRC) tumor. Methods We investigated SCNAs to identify the progression from a high‐grade intramucosal lesion (HGIL) to an invasive front lesion (IFL), via an invasive submucosal lesion (ISL), within the same tumor using a crypt isolation method combined with a SNP array. Immunohistochemistry was also performed. Results We identified 51 amplified genes that potentially promote progression from HGIL to ISL and 6 amplified genes involved in the progression from ISL to IFL. Of the 51 genes involved in HGIL to ISL progression, TORC1, MSLN, and STUB1, which are closely associated with CRC, were identified as candidate markers of submucosal invasion. However, no candidate genes were identified among the six genes associated with ISL to IFL progression. In addition, the number of total SCNAs and the number of gains were correlated with cancer progression (from HGIL to IFL). Finally, immunohistochemistry revealed higher expression of TORC1, MSLN, and STUB1 in ISL than in HGIL. Conclusions These results suggest that specific SCNAs are required for acquisition of invasive ability in CRC, and the affected genes are potential markers of invasion.

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Comprehensive Analyses of Somatic Copy Number Alterations and Mutations Based on the Adenoma–Carcinoma Sequence

Sugai,

Osakabe,

Uesugi

et al. 2024

Genes Chromosomes & Cancer

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AimsIdentifying molecular alterations in the adenoma and carcinoma components within the same tumor would greatly contribute to understanding the neoplastic progression of early colorectal cancer.Methods and ResultsWe examined somatic copy number alterations (SCNAs) and mutations involved in the adenoma and carcinoma components obtained from the same tumor in 46 cases of microsatellite‐stable carcinoma in adenoma, using a genome‐wide SNP array and gene mutation panel. In addition, we also performed hierarchical clustering to determine the SCNA frequencies in the tumors, resulting in stratification of the samples into two subgroups according to SCNA frequency. Subgroup 1 was characterized by multiple SCNAs and carcinoma components exclusively, while Subgroup 2 was characterized by a low frequency of SCNAs and both the adenoma and carcinoma components. The numbers of total genes and genes with gains were higher in the carcinoma than adenoma components. The three most frequent gains in both components were located at 1p36.33–1q44, 2p25.3–2q37.3, and 3p26.3–3q29. However, no candidate genes mapped to these regions. APC and KRAS mutations were common in both components, whereas the frequency of TP53 mutations was statistically higher in the carcinoma than adenoma component. However, TP53 mutations were not correlated with SCNA frequency.ConclusionsWe suggest that considerable SCNAs and TP53 mutations are required for progression from adenoma to carcinoma within the same intramucosal neoplastic lesion.

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A genome‐wide analysis of the molecular alterations occurring in the adenomatous and carcinomatous components of the same tumor based on the adenoma–carcinoma sequence

Cited by 7 publications

References 32 publications

Genome-Wide Analysis of microRNA and mRNA Expression in Colorectal Intramucosal Neoplasia and Colorectal Cancer With a Microsatellite-Stable Phenotype Based on Adenoma-Carcinoma Sequences

Genome-Wide Analysis of microRNA and mRNA Expression in Colorectal Intramucosal Neoplasia and Colorectal Cancer With a Microsatellite-Stable Phenotype Based on Adenoma-Carcinoma Sequences

Genome‐wide analysis of colorectal cancer based on gene‐based somatic copy number alterations during neoplastic progression within the same tumor

Comprehensive Analyses of Somatic Copy Number Alterations and Mutations Based on the Adenoma–Carcinoma Sequence

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