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Promsorn J, Chadbunchachai P, Somsap K, Paonariang K, Sa-ngaimwibool P, Apivatanasiri C, Lahoud RM, Harisinghani M. Imaging features associated with survival outcomes among colorectal cancer patients with and without KRAS mutation. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2021. [DOI: 10.1186/s43055-020-00393-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Abstract
Background
Mutations in Kirsten rat sarcoma proto-oncogene (KRAS) have been shown to be associated with advanced-stage colorectal cancer (CRC), negative disease outcomes, and poor response to treatment. The purpose of this study was to investigate which CT features are biomarkers for KRAS gene mutation and impact the survival outcomes of colorectal cancer patients.
Results
Of the 113 CRC patients included in the study, 46 had KRAS mutations (40.71%) and 67 had no mutations (59.29%). Regional lymph node necrosis was the only imaging feature significantly associated with KRAS mutation (P = 0.011). Higher T staging and liver, lung, and distant metastasis were prognostic factors for CRC (P = 0.014, P < 0.001, P = 0.022, P < 0.001, respectively). There were no significant differences in overall survival between patients with KRAS mutations and those without (P = 0.159). However, in patients with no KRAS mutation, those with CRC on the left side had a significantly higher rate of survival than those with CRC on the right (P = 0.005).
Conclusion
Regional lymph node necrosis may be an imaging biomarker of CRC with KRAS mutation, possibly indicating poor prognosis.
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Sugai T, Osakabe M, Habano W, Tanaka Y, Eizuka M, Sugimoto R, Yanagawa N, Matsumoto T, Suzuki H. 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. Pathol Int 2021; 71:582-593. [PMID: 34263942 PMCID: PMC8518074 DOI: 10.1111/pin.13129] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2021] [Accepted: 05/19/2021] [Indexed: 12/24/2022]
Abstract
Identification of molecular alterations occurring in the adenomatous and carcinomatous components within the same tumor would greatly enhance understanding of the neoplastic progression of colorectal cancer. We examined somatic copy number alterations (SCNAs) and mRNA expression at the corresponding loci involved in the adenoma–carcinoma sequence in the isolated adenomatous and cancer glands of the same tumor in 15 cases of microsatellite‐stable “carcinoma in adenoma,” using genome‐wide SNP and global gene expression arrays. Multiple copy‐neutral loss of heterozygosity events were detected at 4q13.2, 15q15.1, and 14q24.3 in the adenomatous component and at 4q13.2, 15q15.1, and 14q24.3 in the carcinomatous component. There were significant differences in the copy number (CN) gain frequencies at 20q11.21–q13.33, 8q13.3, 8p23.1, and 8q21.2–q22.2 between the adenomatous and carcinomatous components. Finally, we found a high frequency of five genotypes involving CN gain with upregulated expression of the corresponding gene (RPS21, MIR3654, RSP20, SNORD54, or ASPH) in the carcinomatous component, whereas none of these genotypes were detected in the adenomatous component. This finding is interesting in that CN gain with upregulated gene expression may enhance gene function and play a crucial role in the progression of an adenoma into a carcinomatous lesion.
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Affiliation(s)
- Tamotsu Sugai
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Mitsumasa Osakabe
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Wataru Habano
- Department of Pharmacodynamics and Molecular Genetics, School of Pharmacy, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Yoshihito Tanaka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Makoto Eizuka
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Ryo Sugimoto
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Naoki Yanagawa
- Department of Molecular Diagnostic Pathology, School of Medicine, Iwate Medical University, Shiwagun'yahabachou, Japan
| | - Takayuki Matsumoto
- Division of Gastroenterology, Department of Internal Medicine, Shiwagun'yahabachou, Japan
| | - Hiromu Suzuki
- Department of Molecular Biology, School of Medicine, Sapporo Medical University, Cyuuouku, Sapporo, Japan
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Kuno T, Tsukui Y, Takano S, Maekawa S, Yamaguchi T, Yoshida T, Kobayashi S, Iwamoto F, Ishida Y, Kawakami S, Tanaka K, Fukasawa Y, Muraoka M, Fukasawa M, Shindo H, Inoue T, Nakayama Y, Mochizuki K, Sato T, Enomoto N. Genetic alterations related to endoscopic treatment of colorectal tumors. JGH OPEN 2019; 4:75-82. [PMID: 32055701 PMCID: PMC7008167 DOI: 10.1002/jgh3.12220] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/07/2019] [Revised: 05/20/2019] [Accepted: 05/25/2019] [Indexed: 12/24/2022]
Abstract
Background and Aim Genetic indicators of endoscopic resection for colorectal carcinoma remain inconclusive. This study analyzed genetic changes in early colorectal tumors that could inform decisions for endoscopic procedures. Methods A total of 83 colorectal tumors from 81 patients, including adenoma (n = 7), Tis–T1a (n = 22), T1b (n = 14), and advanced carcinoma (n = 40), were analyzed. Tis tumors (n = 16) and some T1 carcinomas (n = 11) were analyzed as mixed adenomas and carcinomas. Lesions were laser‐capture microdissected for DNA extraction, and targeted sequencing of 50 cancer‐related genes was performed. Genetic data were then correlated with clinical records, including magnifying endoscopic findings. Results Numbers of gene alteration rates in TP53 and SMAD4 increased with tumor progression from adenoma to carcinoma. Frequencies of mutant variants in TP53 (P = 0.004) and rates of copy number loss in SMAD4 (P = 0.006) increased in carcinoma components of mixed tumors compared to adenoma components. Moreover, adenoma components of T1b carcinomas had higher TP53 mutation rates than Tis or T1a carcinomas (P = 0.011) and pure adenomas (P = 0.026). Gene alterations in TP53 (P = 0.0055) and SMAD4 (P = 0.0055) increased in cases with irregular surface patterns of magnifying endoscopic findings. Conclusions Numbers of copy number variations and TP53 and SMAD4 alterations were related to colorectal tumor progression. TP53 alteration rates in adenoma components were high in T1b carcinomas, warranting complete treatment with en bloc resection. Magnifying endoscopic findings might reflect the genetic status of colorectal tumors.
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Affiliation(s)
- Toru Kuno
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yuya Tsukui
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan.,Department of Gastroenterology Koyo Hospital Hokuto Japan
| | - Shinichi Takano
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Shinya Maekawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Tatsuya Yamaguchi
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Takashi Yoshida
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Shoji Kobayashi
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Fumihiko Iwamoto
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yasuaki Ishida
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Satoshi Kawakami
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Keisuke Tanaka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yoshimitsu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Masaru Muraoka
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Mitsuharu Fukasawa
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Hiroko Shindo
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Taisuke Inoue
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Yasuhiro Nakayama
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Kunio Mochizuki
- Department of Pathology, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Tadashi Sato
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
| | - Nobuyuki Enomoto
- First Department of Internal Medicine, Faculty of Medicine University of Yamanashi Chuo Japan
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Kanazawa T, Watanabe T, Nagawa H. Does Early Polypoid Colorectal Cancer with Depression Have a Pathway Other than Adenoma-Carcinoma Sequence? TUMORI JOURNAL 2018; 89:408-11. [PMID: 14606645 DOI: 10.1177/030089160308900412] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In the carcinogenesis of colorectal cancer, the concept of adenoma-carcinoma sequence is widely accepted. In this pathway, polypoid adenoma develops into early polypoid cancer and then progresses to advanced cancer. Alternatively, some groups insist that in the de novo pathway in which early cancers develop without preexisting adenoma, flat or depressed early cancers develop into advanced cancer. According to these two different concepts of carcinogenesis, early polypoid cancers may include two distinct types of lesions, early polypoid cancers without central depression via the adenoma-carcinoma sequence and early polypoid cancers with central depression via de novo carcinogenesis. We analyzed 45 submucosal cancer specimens histologically diagnosed as polypoid by clinicopathological features and K-ras mutation in early polypoid cancers with and without depression to clarify whether there was a difference between the two groups. No significant difference in clinicopathological features was found between the two groups. Also, a high incidence of K-ras mutation was observed in both groups. This suggests that early polypoid cancers with depression have a similar genetic background to polypoid cancers without depression, which follows the adenoma-carcinoma sequence. It is possible that whether or not the tumor has a depression does not indicate the distinct pathway of colorectal carcinogenesis.
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Affiliation(s)
- Takamitsu Kanazawa
- Department of Surgical Oncology, Graduate School of Medical Sciences, Faculty of Medicine, University of Tokyo, Bunkyo-ku, Tokyo, Japan.
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5
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Development and endoscopic appearance of colorectal tumors are characterized by the expression profiles of miRNAs. Med Mol Morphol 2018; 51:82-88. [DOI: 10.1007/s00795-018-0186-y] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2018] [Accepted: 03/06/2018] [Indexed: 12/17/2022]
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Analysis of molecular alterations in laterally spreading tumors of the colorectum. J Gastroenterol 2017; 52:715-723. [PMID: 27704264 DOI: 10.1007/s00535-016-1269-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/10/2015] [Accepted: 09/19/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Colorectal laterally spreading tumors (LSTs) are classified into LST-Gs and LST-NGs, according to macroscopic findings. In the present study, we determined the genetic and epigenetic alterations within colorectal LSTs and protruding adenomas. METHODS A crypt isolation method was used to isolate DNA from tumors and normal glands of 73 macroscopically verified colorectal LSTs (histologically defined adenomas; 38 LST-Gs and 35 LST-NGs) and 36 protruding adenomas. The DNA was processed using polymerase chain reaction (PCR) microsatellite assays, single-strand conformation polymorphism (SSCP) assays, and pyrosequencing to detect chromosomal allelic imbalance (AI), mutations in APC, KRAS, and TP53, and the methylation of MLH1, MGMT, CDKN2A, HPP1, RASSF2A, SFRP1, DKK1, ZFP64, and SALL4 genes. In addition, methylation status was examined using the following set of markers: MIN1, MINT2, MINT31, MLH1, and CDKN2A (with classification of negative/low and high). Microsatellite instability (MSI) was also examined. RESULTS 5q AI and methylation of the SFRP1 and SALL4 genes were common molecular events in both LST-Gs and LST-NGs. Neither MSI nor mutations in BRAF ware observed in the LSTs. TP53 mutations were rarely found in LSTs. The frequencies of KRAS and APC mutations and the methylation levels of ZFP64, RASSF2A, and HPP1 genes were significantly higher in LST-Gs than in LST-NGs. Protruding adenomas showed alterations common to LST-Gs. Negative/low methylation status was common among the three types of tumors. CONCLUSION Combined genetic and epigenetic data suggested that the molecular mechanisms of tumorigenesis were different between LST-Gs and LST-NGs.
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Kashida H. Non-polypoid colorectal neoplasms are no longer unique to Japan, but do not mix up flat and depressed lesions. Dig Endosc 2015; 27:300-2. [PMID: 25754006 DOI: 10.1111/den.12455] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Affiliation(s)
- Hiroshi Kashida
- Department of Gastroenterology and Hepatology, Kinki University Faculty of Medicine, Osaka, Japan
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Nakagawa Y, Akao Y, Taniguchi K, Kamatani A, Tahara T, Kamano T, Nakano N, Komura N, Ikuno H, Ohmori T, Jodai Y, Miyata M, Nagasaka M, Shibata T, Ohmiya N, Hirata I. Relationship between expression of onco-related miRNAs and the endoscopic appearance of colorectal tumors. Int J Mol Sci 2015; 16:1526-1543. [PMID: 25584614 PMCID: PMC4307318 DOI: 10.3390/ijms16011526] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Accepted: 12/25/2014] [Indexed: 01/08/2023] Open
Abstract
Accumulating data indicates that certain microRNAs (miRNAs or miRs) are differently expressed in samples of tumors and paired non-tumorous samples taken from the same patients with colorectal tumors. We examined the expression of onco-related miRNAs in 131 sporadic exophytic adenomas or early cancers and in 52 sporadic flat elevated adenomas or early cancers to clarify the relationship between the expression of the miRNAs and the endoscopic morphological appearance of the colorectal tumors. The expression levels of miR-143, -145, and -34a were significantly reduced in most of the exophytic tumors compared with those in the flat elevated ones. In type 2 cancers, the miRNA expression profile was very similar to that of the exophytic tumors. The expression levels of miR-7 and -21 were significantly up-regulated in some flat elevated adenomas compared with those in exophytic adenomas. In contrast, in most of the miR-143 and -145 down-regulated cases of the adenoma-carcinoma sequence and in some of the de novo types of carcinoma, the up-regulation of oncogenic miR-7 and/or -21 contributed to the triggering mechanism leading to the carcinogenetic process. These findings indicated that the expression of onco-related miRNA was associated with the morphological appearance of colorectal tumors.
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Affiliation(s)
- Yoshihito Nakagawa
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Yukihiro Akao
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
| | - Kohei Taniguchi
- The United Graduate School of Drug Discovery and Medical Information Sciences, Gifu University, Gifu 501-1193, Japan.
| | - Akemi Kamatani
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Tomomitsu Tahara
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Toshiaki Kamano
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Naoko Nakano
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Naruomi Komura
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Hirokazu Ikuno
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Takafumi Ohmori
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Yasutaka Jodai
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Masahiro Miyata
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Mistuo Nagasaka
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Tomoyuki Shibata
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Naoki Ohmiya
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
| | - Ichiro Hirata
- Department of Gastroenterology, School of Medicine, Fujita Health University, Kutsukake-cho, Aichi 470-1192, Japan.
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Konda K, Konishi K, Yamochi T, Ito YM, Nozawa H, Tojo M, Shinmura K, Kogo M, Katagiri A, Kubota Y, Muramoto T, Yano Y, Kobayashi Y, Kihara T, Tagawa T, Makino R, Takimoto M, Imawari M, Yoshida H. Distinct molecular features of different macroscopic subtypes of colorectal neoplasms. PLoS One 2014; 9:e103822. [PMID: 25093594 PMCID: PMC4122357 DOI: 10.1371/journal.pone.0103822] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2014] [Accepted: 07/01/2014] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Colorectal adenoma develops into cancer with the accumulation of genetic and epigenetic changes. We studied the underlying molecular and clinicopathological features to better understand the heterogeneity of colorectal neoplasms (CRNs). METHODS We evaluated both genetic (mutations of KRAS, BRAF, TP53, and PIK3CA, and microsatellite instability [MSI]) and epigenetic (methylation status of nine genes or sequences, including the CpG island methylator phenotype [CIMP] markers) alterations in 158 CRNs including 56 polypoid neoplasms (PNs), 25 granular type laterally spreading tumors (LST-Gs), 48 non-granular type LSTs (LST-NGs), 19 depressed neoplasms (DNs) and 10 small flat-elevated neoplasms (S-FNs) on the basis of macroscopic appearance. RESULTS S-FNs showed few molecular changes except SFRP1 methylation. Significant differences in the frequency of KRAS mutations were observed among subtypes (68% for LST-Gs, 36% for PNs, 16% for DNs and 6% for LST-NGs) (P<0.001). By contrast, the frequency of TP53 mutation was higher in DNs than PNs or LST-Gs (32% vs. 5% or 0%, respectively) (P<0.007). We also observed significant differences in the frequency of CIMP between LST-Gs and LST-NGs or PNs (32% vs. 6% or 5%, respectively) (P<0.005). Moreover, the methylation level of LINE-1 was significantly lower in DNs or LST-Gs than in PNs (58.3% or 60.5% vs. 63.2%, P<0.05). PIK3CA mutations were detected only in LSTs. Finally, multivariate analyses showed that macroscopic morphologies were significantly associated with an increased risk of molecular changes (PN or LST-G for KRAS mutation, odds ratio [OR] 9.11; LST-NG or DN for TP53 mutation, OR 5.30; LST-G for PIK3CA mutation, OR 26.53; LST-G or DN for LINE-1 hypomethylation, OR 3.41). CONCLUSION We demonstrated that CRNs could be classified into five macroscopic subtypes according to clinicopathological and molecular differences, suggesting that different mechanisms are involved in the pathogenesis of colorectal tumorigenesis.
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Affiliation(s)
- Kenichi Konda
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kazuo Konishi
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
- * E-mail:
| | - Toshiko Yamochi
- Department of Pathology, Showa University School of Medicine, Tokyo, Japan
| | - Yoichi M. Ito
- Department of Biostatistics, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Hisako Nozawa
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Masayuki Tojo
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Kensuke Shinmura
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Mari Kogo
- Department of Hospital Pharmaceutics, Showa University School of Pharmacy, Tokyo, Japan
| | - Atsushi Katagiri
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yutaro Kubota
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Takashi Muramoto
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yuichiro Yano
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Yoshiya Kobayashi
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Toshihiro Kihara
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Teppei Tagawa
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Reiko Makino
- Clinical Collaborating laboratory, Showa University School of Medicine, Tokyo, Japan
| | - Masafumi Takimoto
- Department of Pathology, Showa University School of Medicine, Tokyo, Japan
| | - Michio Imawari
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
| | - Hitoshi Yoshida
- Division of Gastroenterology, Department of Medicine, Showa University School of Medicine, Tokyo, Japan
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Scarpa M, Castagliuolo I, Castoro C, Pozza A, Scarpa M, Kotsafti A, Angriman I. Inflammatory colonic carcinogenesis: A review on pathogenesis and immunosurveillance mechanisms in ulcerative colitis. World J Gastroenterol 2014; 20:6774-6785. [PMID: 24944468 PMCID: PMC4051917 DOI: 10.3748/wjg.v20.i22.6774] [Citation(s) in RCA: 74] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Accepted: 02/27/2014] [Indexed: 02/06/2023] Open
Abstract
Ulcerative colitis (UC) is characterized by repeated flare-ups of inflammation that can lead to oncogenic insults to the colonic epithelial. UC-associated carcinogenesis presents a different sequence of tumorigenic events compared to those that contribute to the development of sporadic colorectal cancer. In fact, in UC, the early events are represented by oxidative DNA damage and DNA methylation that can produce an inhibition of oncosuppressor genes, mutation of p53, aneuploidy, and microsatellite instability. Hypermethylation of tumor suppressor and DNA mismatch repair gene promoter regions is an epigenetic mechanism of gene silencing that contribute to tumorigenesis and may represent the first step in inflammatory carcinogenesis. Moreover, p53 is frequently mutated in the early stages of UC-associated cancer. Aneuploidy is an independent risk factor for forthcoming carcinogenesis in UC. Epithelial cell-T-cell cross-talk mediated by CD80 is a key factor in controlling the progression from low to high grade dysplasia in UC-associated carcinogenesis.
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MESH Headings
- Cell Transformation, Neoplastic/genetics
- Cell Transformation, Neoplastic/immunology
- Cell Transformation, Neoplastic/metabolism
- Cell Transformation, Neoplastic/pathology
- Colitis, Ulcerative/complications
- Colitis, Ulcerative/genetics
- Colitis, Ulcerative/immunology
- Colitis, Ulcerative/metabolism
- Colitis, Ulcerative/pathology
- Colonic Neoplasms/etiology
- Colonic Neoplasms/genetics
- Colonic Neoplasms/immunology
- Colonic Neoplasms/metabolism
- Colonic Neoplasms/pathology
- DNA Damage
- DNA Methylation
- Disease Progression
- Epigenesis, Genetic
- Gene Expression Regulation, Neoplastic
- Humans
- Inflammation Mediators/metabolism
- Neoplasm Grading
- Oncogenes
- Oxidative Stress
- Risk Factors
- T-Lymphocytes/immunology
- T-Lymphocytes/metabolism
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11
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Tracking the molecular features of nonpolypoid colorectal neoplasms: a systematic review and meta-analysis. Am J Gastroenterol 2013; 108:1042-56. [PMID: 23649184 DOI: 10.1038/ajg.2013.126] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2012] [Accepted: 03/16/2013] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Nonpolypoid colorectal neoplasms (NP-CRNs) are proposed as a major contributor to the occurrence of interval cancers, but their underlying biology remains controversial. We conducted a systematic review and meta-analysis to clarify the major biological events in NP-CRNs. METHODS We systematically searched for studies examining molecular characteristics of NP-CRNs. We performed random effect meta-analyses. We measured the heterogeneity among studies using I(2) and possible publication bias using funnel plots. RESULTS Fifty-three studies on KRAS, APC, or BRAF mutations, microsatellite instability (MSI), CpG island methylator phenotype (CIMP), or DNA promoter hypermethylation were included. We observed less KRAS mutations (summary odds ratio (OR) 0.30, confidence interval (CI)=0.19-0.46, I(2)=77.4%, CI=70.1-82.9) and APC mutations (summary OR 0.42, CI=0.24-0.72, I(2)=22.6%, CI=0.0-66.7) in NP-CRNs vs. protruded CRNs, whereas BRAF mutations were more frequent (summary OR 2.20, CI=1.01-4.81, I(2)=0%, CI=0-70.8), albeit all with large heterogeneity. Less KRAS mutations were especially found in NP-CRNs subtypes: depressed CRNs (summary OR 0.12, CI=0.05-0.29, I(2)=0%, CI=0-67.6), non-granular lateral spreading tumors (LSTs-NG) (summary OR 0.61, CI=0.37-1.0, I(2)=0%, CI=0-74.6), and early nonpolypoid carcinomas (summary OR 0.11, CI=0.06-0.19, I(2)=0%, CI=0-58.3). MSI frequency was similar in NP-CRNs and protruded CRNs (summary OR 0.99, CI=0.21-4.71, I(2)=70.3%, CI=38.4-85.7). Data for promoter hypermethylation and CIMP were inconsistent, precluding meaningful conclusions. CONCLUSIONS This meta-analysis provides indications that NP-CRNs are molecularly different from protruded CRNs. In particular, some subtypes of NP-CRNs, the depressed and LST-NG, are featured by less KRAS mutations than polypoid CRNs. Prospective, multicenter studies are needed to clarify the molecular pathways underlying nonpolypoid colorectal carcinogenesis and potential implications for surveillance intervals.
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Tanaka T, Ichikawa K, Maruoka T, Tomita S, Ueda H, Yamaguchi T, Shida Y, Kato H, Nagata H, Kubota K, Akimoto N, Sakamoto C, Imura J, Arita M, Tanaka H, Okamoto Y, Igarashi Y, Fujimori T. Analysis of the anatomic subsites, gender and age in unresectable advanced colorectal carcinomas in Tochigi, Japan suggests a shift in location towards the right side colon in elderly patients treated with cetuximab. Mol Clin Oncol 2013; 1:291-296. [PMID: 24649163 DOI: 10.3892/mco.2013.62] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2012] [Accepted: 12/12/2012] [Indexed: 11/06/2022] Open
Abstract
Colorectal cancer is a frequently occurring cancer whose incidence has shown a marked increase in recent years. Additionally, an increase in right side colon in elderly patients has been identified. Therefore, a clinicopathological study was conducted in 49 patients with unresectable advanced colorectal carcinomas to elucidate the association of clinicopathological characteristics and K-ras mutation. Of the 49 patients included in this study, 24 were aged <60 years with a male/female (M/F) ratio of 16/8 and 25 patients were aged ≥60 years with a M/F ratio of 16/9. Of the patients aged ≥65 years, 15 patients were enrolled as controls and the M/F ratio was 9/6. Results revealed that with regard to the subsite of cancer, unresectable advanced colorectal carcinomas developed in the right-sided colon in 13 patients, left-sided colon in 19 patients and rectum in 17 patients. Right-sided colon carcinomas were commonly identified in the elderly patients aged ≥65 years, with a marked tendency in the female patients (P=0.024). Immunostaining was performed for the epidermal growth factor receptor (EGFR) antibody in 40 patients to determine whether the K-ras gene would yield positive results. The mutant K-ras gene was identified in 8 patients (20%) and the frequency was lower compared with that of the normal colorectal carcinomas. Anti-EGFR antibody (cetuximab) is considered to be a molecularly targeted agent for unresectable advanced colorectal carcinomas. The increase in incidence of right-sided colon carcinomas as well as the increase in the number of patients presenting with colorectal carcinomas means this issue should be addressed. Sessile serrated adenoma/polyp (SSA/P) with b-raf mutation and CIMP (CpG island methylator phenotype) abnormality as a precursor lesion of right-sided colon carcinoma is common and since cetuximab refractory wild-type K-ras/mutant b-raf colorectal carcinoma may increase in elderly patients and patients with right-sided colon carcinoma, a simultaneous examination for the K-ras and b-raf gene abnormalities for the treatment of colorectal cancer using anti-EGFR antibody (cetuximab) is crucial. In addition, the multidisciplinary assessments regarding the effect of such treatments is likely to be determined based on cumulative results, such as the duration of patient survival.
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Affiliation(s)
- Toshio Tanaka
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Kazuhito Ichikawa
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Takashi Maruoka
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Shigeki Tomita
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Hirofumi Ueda
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Takeshi Yamaguchi
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293; ; First Department of Surgery, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Yosuke Shida
- First Department of Surgery, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Hiroyuki Kato
- First Department of Surgery, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Hitoshi Nagata
- Second Department of Surgery, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Keiichi Kubota
- Second Department of Surgery, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
| | - Naohiko Akimoto
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8603
| | - Chouitsu Sakamoto
- Department of Gastroenterology, Nippon Medical School, Graduate School of Medicine, Bunkyo-ku, Tokyo 113-8603
| | - Johji Imura
- Department of Diagnostic Pathology, Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Toyama 930-0194
| | - Munefumi Arita
- Department of Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498
| | - Hiroyuki Tanaka
- Department of Surgery, Jichi Medical University School of Medicine, Shimotsuke, Tochigi 329-0498
| | - Yosuke Okamoto
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293; ; Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University, Omori Medical Center, Ota-ku, Tokyo 143-8541, Japan
| | - Yoshinori Igarashi
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Toho University, Omori Medical Center, Ota-ku, Tokyo 143-8541, Japan
| | - Takahiro Fujimori
- Department of Surgical and Molecular Pathology, Dokkyo Medical University School of Medicine, Shimotsuga-Gun, Tochigi 321-0293
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Comprehensive mutation analysis in colorectal flat adenomas. PLoS One 2012; 7:e41963. [PMID: 22848674 PMCID: PMC3407043 DOI: 10.1371/journal.pone.0041963] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2012] [Accepted: 06/27/2012] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Flat adenomas are a subgroup of colorectal adenomas that have been associated with a distinct biology and a more aggressive clinical behavior compared to their polypoid counterparts. In the present study, we aimed to compare the mutation spectrum of 14 cancer genes, between these two phenotypes. METHODS A consecutive series of 106 flat and 93 polypoid adenomas was analyzed retrospectively for frequently occurring mutations in "hot spot" regions of KRAS, BRAF, PIK3CA and NRAS, as well as selected mutations in CTNNB1 (β-catenin), EGFR, FBXW7 (CDC4), PTEN, STK11, MAP2K4, SMAD4, PIK3R1 and PDGFRA using a high-throughput genotyping technique. Additionally, APC was analyzed using direct sequencing. RESULTS APC mutations were more frequent in polypoid adenomas compared to flat adenomas (48.5% versus 30.3%, respectively, p = 0.02). Mutations in KRAS, BRAF, NRAS, FBXW7 and CTNNB1 showed similar frequencies in both phenotypes. Between the different subtypes of flat adenomas (0-IIa, LST-F and LST-G) no differences were observed for any of the investigated genes. CONCLUSION The lower APC mutation rate in flat adenomas compared to polypoid adenomas suggests that disruption of the Wnt-pathway may occur via different mechanisms in these two phenotypes. Furthermore, in contrast to previous observations our results in this large well-defined sample set indicate that there is no significant association between the different morphological phenotypes and mutations in key genes of the RAS-RAF-MAPK pathway.
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14
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Risk factors for postoperative recurrence in patients with pathologically T1 colorectal cancer. World J Surg 2012; 36:424-30. [PMID: 22187130 DOI: 10.1007/s00268-011-1378-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND The evolution of diagnostic procedures has resulted in an increase in early detection of pathologically T1 (pT1) colorectal cancer (CRC). However, the risk factors affecting long-term outcomes of patients with pT1 CRCs have been unclear. The aim of the present study was to identify risk factors for postoperative recurrence and overall survival in patients with pT1 CRC. METHODS Between January 1990 and January 2003, a total of 284 patients with pT1 CRC underwent radical surgery in the authors' institution. The impact of clinicopathological factors on postoperative recurrence and overall survival was estimated by univariate and multivariate analysis. RESULTS The median follow-up period was 55 months (interquartile range: 47.1 months). Postoperative recurrence occurred in 8 (2.8%) patients. The overall 5-year and 10-year disease-free survival rates were 98.4 and 92.7%. Multivariate analysis showed the presence of lymphatic invasion only was an independent risk factor for postoperative recurrence in pT1 CRC patients (hazard ratio: 11.622; P = 0.003). The 5-year and 10-year disease-free survival rates of the patients in N-ly- group, the N-ly + group, and the N+ group were 99.5%/98.2% and 96.3%/75.2%, and 93.3%/93.3%, respectively. Additionally, 4 of the 8 recurrences were found more than 5 years after the operation. CONCLUSIONS Lymphatic invasion was an independent risk factor for recurrence in pT1 CRC patients.
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Kawamura Y, Ogasawara N, Mizuno M, Sasaki M, Ito Y, Kondo Y, Noda H, Izawa S, Miyachi M, Kasugai K. Small, Depressed-Type Early Colon Cancer Invading Shallow Submucosal Layer With Extensive Lymph Node Metastasis: A Case Report. Gastroenterology Res 2011; 4:131-137. [PMID: 27942329 PMCID: PMC5139820 DOI: 10.4021/gr304w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 04/11/2011] [Indexed: 11/03/2022] Open
Abstract
Early colorectal cancers are defined as invasive tumors that are limited to the mucosal layer or submucosal layer (SM), regardless of the presence or absence of lymph node (LN) metastasis. The reported incidence of LN metastasis of SM1 colon cancers is 0 - 5.9%, but the incidence in SM2 and SM3 colon cancers could be as high as 11.3 - 25.0%, and risk factors for LN metastasis include depth of SM invasion, growth patterns (polypoid or non-polypoid), histological sub-classification (moderate or poor differentiation) and regional lymphatic and vascular invasion. Among colorectal cancers with non-polypoid growth, the malignant potential is higher for depressed, than polypoid types, even for small tumors. Herein, we describe a patient with small, depressed-type early colon cancer with extensive LN metastasis and superficial SM invasion (pSM 450 µm). Six courses of chemotherapy with mFOLFOX6 and bevacizumab reduced the size of the LN metastases, thus eliciting a partial response (PR) according to the response evaluation criteria in solid tumors (RECIST).
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Affiliation(s)
- Yurika Kawamura
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Naotaka Ogasawara
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Mari Mizuno
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Makoto Sasaki
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Yoshitsugi Ito
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Yoshihiro Kondo
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Hisatsugu Noda
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Shinya Izawa
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Masahiko Miyachi
- Department of Surgery, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
| | - Kunio Kasugai
- Department of Gastroenterology, Aichi Medical University School of Medicine, 21 Karimata, Yazako, Nagakute-cho, Aichi 480-1195, Japan
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16
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Kaji E, Kato J, Suzuki H, Akita M, Horii J, Saito S, Higashi R, Ishikawa S, Kuriyama M, Hiraoka S, Uraoka T, Yamamoto K. Analysis of K-ras, BRAF, and PIK3CA mutations in laterally-spreading tumors of the colorectum. J Gastroenterol Hepatol 2011; 26:599-607. [PMID: 21332555 DOI: 10.1111/j.1440-1746.2010.06485.x] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
BACKGROUND AND AIMS Laterally-spreading tumors (LST) are a newly-recognized category of colorectal neoplasia, and are defined as lesions larger than 10 mm in diameter and extending circumferentially rather than vertically. However, genetic features of this new category of tumors are not fully elucidated. The aim of this study was to evaluate genetic alterations in LST. METHODS We examined K-ras, BRAF, and phosphoinositide-3-kinase catalytic-α polypeptide (PIK3CA) mutations in 101 LST, including 68 LST-granular type (LST-G) and 33 LST-non-granular type by direct sequencing. As controls, we examined these gene mutations in 66 protruded colon adenomas (10 mm or larger) and 44 advanced colon cancers. RESULTS K-ras, BRAF, and PIK3CA mutations were observed in 59 (58%), zero (0%), and three (3%) LST, respectively. LST-G morphology in the right-sided colon was significantly correlated with the existence of K-ras mutations, whereas a size of 20 mm or larger was the only predictor of mutations in the left-sided colorectum. The frequency of K-ras mutations in LST was particularly marked in the left-sided colorectum compared to protruded adenomas or advanced cancers (LST vs protruded adenomas, P < 0.001; LST vs advanced cancers, P = 0.002), whereas in the right-sided colon, K-ras mutations were equally frequent. PIK3CA mutations were not familiar in either LST (3%) or advanced cancers (9%). CONCLUSIONS K-ras mutations were involved in colorectal LST in different manners according to tumor location.
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Affiliation(s)
- Eisuke Kaji
- Department of Gastroenterology and Hepatology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
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Kobayashi N, Matsuda T, Sano Y. The natural history of non-polypoid colorectal neoplasms. Gastrointest Endosc Clin N Am 2010; 20:431-435. [PMID: 20656241 DOI: 10.1016/j.giec.2010.03.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Despite their importance, little is known about the natural history of non-polypoid colorectal neoplasms (NP-CRN). This article will summarize the available data to gain some estimates of the natural history of NP-CRN.
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Affiliation(s)
- Nozomu Kobayashi
- Department of Diagnostic Imaging, Tochigi Cancer Center, 4-9-13 Yonan, Utsunomiya, Tochigi 320-0834, Japan.
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18
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Repici A, Pellicano R, Strangio G, Danese S, Fagoonee S, Malesci A. Endoscopic mucosal resection for early colorectal neoplasia: pathologic basis, procedures, and outcomes. Dis Colon Rectum 2009; 52:1502-1515. [PMID: 19617768 DOI: 10.1007/dcr.0b013e3181a74d9b] [Citation(s) in RCA: 93] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Open access endoscopy and screening programs enable detection and removal of an increased number of colon polyps in the early stages of neoplastic transformation. Unfortunately, polyps larger than 3 cm, involving more than one-third of circumference or two haustral folds, or with a flat/depressed morphology are more challenging to remove with standard polypectomy techniques. Endoscopic mucosal resection potentiates the removal, in a minimally invasive way, of certain colonic lesions that would otherwise require surgical or ablative treatment. Because the plane of resection during endoscopic mucosal resection is typically the middle to deep submucosal layer, compared with standard polypectomy, which normally provides resection at a mucosal level, endoscopic mucosal resection offers the advantage of providing en bloc resection specimens for histopathologic analysis. Indications to perform endoscopic mucosal resection are adenoma and small, well-differentiated carcinoma, confined to the mucosa or with minimal invasion to submucosa, and without any invasion to lymphatic channels or vessels. The most frequently reported major complications, such as perforation (0-5%) and bleeding (0.5-6%), may be controlled by endoscopic methods and rarely require surgical treatment. Follow-up postendoscopic mucosal resection is essential because of the risk of neoplastic recurrence.
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Affiliation(s)
- Alessandro Repici
- Department of Gastroenterology and Digestive Endoscopy Unit, Istituto di Recovero e Cura a Carattere Scientifico Istituto Clinico Humanitas, Milano, Italy.
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19
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Koga Y, Yao T, Hirahashi M, Kumashiro Y, Ohji Y, Yamada T, Tanaka M, Tsuneyoshi M. Flat adenoma-carcinoma sequence with high-malignancy potential as demonstrated by CD10 and beta-catenin expression: a different pathway from the polypoid adenoma-carcinoma sequence. Histopathology 2008; 52:569-77. [PMID: 18370954 DOI: 10.1111/j.1365-2559.2008.02996.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
AIMS CD10+ colorectal carcinomas have a high risk of giving rise to liver metastasis. The aim was to examine phenotypic expression in colorectal neoplasia and to elucidate changes in such expression through the adenoma-carcinoma sequence. METHODS AND RESULTS We examined the expression of various proteins immunohistochemically in 111 flat [non-polypoid growth (NPG)] colorectal neoplasms, categorized into 28 low-grade (NPG-LGN), 44 high-grades (NPG-HGN) and 39 cases of invasive neoplasia (NPG-IN), as well as in 96 polypoid [polypoid growth (PG)] neoplasms, categorized into 26 PG-LGN, 39 PG-HGN and 31 PG-IN according to the Vienna classification. CD10 was more frequently expressed in NPG than in PG neoplasia. MUC2 and MUC5AC were more frequently expressed in PG than in NPG neoplasias. Nuclear beta-catenin was more frequently expressed in NPG-LGN than in PG-LGN. No difference in p53 expression was found between NPG and PG neoplasia. CONCLUSIONS From the viewpoint of the expression of CD10 and beta-catenin, it would appear that NPG-LGN differs significantly from PG-LGN, thereby indicating that NPG-LGN is a precursor of CD10+ carcinoma. It is important to ensure that NPG neoplasia is not overlooked if cases of CD10+ carcinoma are to be detected at an early stage.
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Affiliation(s)
- Y Koga
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
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Wang XY, Lai ZS, Yeung CM, Wang JD, Deng W, Li HY, Han YJ, Kung HF, Jiang B, Lin MCM. Establishment and characterization of a new cell line derived from human colorectal laterally spreading tumor. World J Gastroenterol 2008; 14:1204-11. [PMID: 18300345 PMCID: PMC2690667 DOI: 10.3748/wjg.14.1204] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the molecular mechanism of laterally spreading tumor (LST), a cell line [Laterally Spreading Tumor-Rectum 1 (LST-R1)] was derived and the characteristics of this cell line were investigated.
METHODS: A new cell line (LST-R1) originated from laterally spreading tumor was established. Properties of the cell line were characterized using scanning and transmission electron microscopy, immunohistochemistry method, cytogenetic analysis and nude mice xenograft experiments. In vitro invasion assay, cDNA microarray and Western blotting were used to compare the difference between the LST-R1 and other colorectal cancer cell lines derived from prudent colon cancer.
RESULTS: Our study demonstrated that both epithelial special antigen (ESA) and cytokeratin-20 (CK20) were expressed in LST-R1. The cells presented microvilli and tight junction with large nuclei. The karyotypic analysis showed hyperdiploid features with structural chromosome aberrations. The in vivo tumorigenicity was also demonstrated in nude mice xenograft experiments. The invasion assay suggested this cell line has a higher invasive ability. cDNA microarray and Western blotting show the loss of the expression of E-cadherin in LST-R1 cells.
CONCLUSION: We established and characterized a colorectal cancer cell line, LST-R1 and LST-R1 has an obvious malignant tendency, which maybe partially attributed to the changes of the expression of some adhesion molecules, such as E-cadherin. It is also a versatile tool for exploring the original and progressive mechanisms of laterally spreading tumor and the early colon cancer genesis.
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Park DH, Kim HS, Kim WH, Kim TI, Kim YH, Park DI, Kim HJ, Yang SK, Byeon JS, Lee MS, Chung IK, Jung SA, Jeen YT, Choi JH, Choi H, Han DS. Clinicopathologic characteristics and malignant potential of colorectal flat neoplasia compared with that of polypoid neoplasia. Dis Colon Rectum 2008; 51:43-9; discussion 49. [PMID: 18034359 DOI: 10.1007/s10350-007-9091-5] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/01/2006] [Revised: 04/26/2007] [Accepted: 05/26/2007] [Indexed: 12/23/2022]
Abstract
PURPOSE Because of their potential for malignancy, flat colorectal neoplasias are a current topic of debate. This study was designed to investigate the clinicopathologic features of flat neoplasia and to compare them with those of polypoid neoplasia, as well as to identify the determinants of malignant transformation of both flat and polypoid colorectal neoplasia. METHODS A prospective, cross-sectional study of 3,360 patients diagnosed with adenomas via total colonoscopy and polypectomy was performed at 11 tertiary medical centers between July 2003 and July 2004. In this study, potential risk factors for malignant transformation were analyzed. If multiple adenomas were identified, then only the adenoma with the most advanced degree of histology was recorded for the patient. RESULTS Of a total of 3,360 neoplasias identified, we found that the incidence of flat and polypoid neoplasias were 207 (6.2 percent) and 3,153 (93.8 percent), respectively. Patients with flat neoplasias tended to be older (59.6 vs. 57.1, P < 0.01), with the neoplasia located more frequently in the right colon than polypoid neoplasias (49.3 percent vs. 32 percent, P < 0.01). The incidence of high-grade dysplasia or cancer in flat neoplasias was similar to that of polypoid neoplasias (5.4 percent vs. 4.6 percent, P = 0.36). Multivariate analysis revealed that a size of > or =11 mm (odds ratio, 6.8; 95 percent confidence interval, 4.8-9.7) and location in the left colon (odds ratio, 1.6; 95 percent confidence interval, 1.1-2.4) were significant determinants for the malignancy potential of colonic neoplasias. CONCLUSIONS The clinicopathologic indices for the propensity of malignant transformation in colorectal neoplasias were a size > or =11 mm and location in the left colon rather than flat gross morphology.
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Affiliation(s)
- Dong Hun Park
- Department of Internal Medicine and Institute of Lifelong Health, Yonsei University, Wonju College of Medicine, 162 Ilsan-dong, Wonju, South Korea
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22
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Yoshida S, Ikehara N, Aoyama N, Shirasaka D, Sakashita M, Semba S, Hasuo T, Miki I, Morita Y, Tamura T, Azuma T, Yokozaki H, Kasuga M. Relationship of BRAF mutation, morphology, and apoptosis in early colorectal cancer. Int J Colorectal Dis 2008; 23:7-13. [PMID: 17924122 DOI: 10.1007/s00384-007-0349-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 06/14/2007] [Indexed: 02/04/2023]
Abstract
BACKGROUND AND AIMS Many investigators have reported flat and depressed lesions as a new type of precursor of colorectal cancer. In our previous study, we determined that mutations in the BRAF gene may contribute to colorectal carcinogenesis by inhibiting apoptosis. However, the relationship among BRAF mutations, morphology and apoptosis in early colorectal cancer has not been clear. Therefore, gene alternation, morphology, and apoptosis in early colorectal cancer were investigated. MATERIALS AND METHODS Forty-five flat and depressed early colorectal cancer samples and 43 polypoid early colorectal cancer samples were analyzed. Mutations in the BRAF gene and the K-ras gene were examined by direct sequence analysis, and proliferative activity and induction of apoptosis were evaluated using immunohistochemical examination. RESULTS FINDINGS: BRAF mutations were found in 5 (11.1%) of 45 flat and depressed early colorectal cancer samples. No BRAF alteration was found in polypoid early colorectal cancer samples. Mutations in the K-ras gene were detected in 13 (30.2%) of 43 polypoid early colorectal cancer samples. The rate of submucosal invasion of the samples with BRAF mutations was significantly higher than that of the samples with K-ras mutations (p<0.05). INTERPRETATION/CONCLUSIONS BRAF and K-ras mutations were independent factors that influenced morphology in early colorectal cancer. In this study, the relationship between BRAF mutation and apoptosis is not so clear, but BRAF mutations and inhibition in apoptosis may play an important role in the developmental process of flat and depressed early colorectal cancer.
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Affiliation(s)
- Shiei Yoshida
- Division of Diabetes, Digestive and Kidney Diseases, Department of Clinical Molecular Medicine, Kobe University Graduate School of Medicine, Kobe, Japan
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Affiliation(s)
- Kenichi SAITO
- *First Department of Internal Medicine, Gunma University School of Medicine, Gunma, Japan
| | - Akira OGAWA
- **Department of Pathology, Gunma Cancer Center, Gunma, Japan
| | - Ichiro OHKI
- *First Department of Internal Medicine, Gunma University School of Medicine, Gunma, Japan
| | - Masatomo MORI
- *First Department of Internal Medicine, Gunma University School of Medicine, Gunma, Japan
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Flat Colorectal Cancers Are Genetically Determined and Progress to Invasion without Going through a Polypoid Stage. Cancer Res 2007; 67:11594-600. [DOI: 10.1158/0008-5472.can-07-3242] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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25
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SAITO K, OGAWA A, OHKI I. A Study of the Rate of Superficial Cancer Progressing to Advanced Cancer of the Colon and Rectum. Dig Endosc 2007. [DOI: 10.1111/j.1443-1661.1996.tb00439.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
Affiliation(s)
- Kenichi SAITO
- Department of Internal Medicine, Gunma Cancer Center, Gunma, Japan
- First Department of Internal Medicine, Gunma University School of Medicine, Gunma, Japan
| | - Akira OGAWA
- Department of Pathology, Gunma Cancer Center, Gunma, Japan
| | - Ichiro OHKI
- Vice‐President, Gunma Cancer Center, Gunma University School of Medicine, Gunma, Japan
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Nakajima T, Saito Y, Matsuda T, Hoshino T, Yamamoto S, Tamura T, Moriya Y, Saito D. Minute depressed-type submucosal invasive cancer-5 mm in diameter with intermediate lymph-node metastasis: report of a case. Dis Colon Rectum 2007; 50:677-81. [PMID: 17294320 DOI: 10.1007/s10350-006-0843-4] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
We report a rare case of colon cancer in which a depressed-type tumor only 5 mm in diameter invaded the submucosal layer and produced intermediate lymph node metastasis. A 47-year-old male received a total colonoscopy for a depressed-type lesion with marginal elevation in the sigmoid colon. The lesion measured 5 mm in diameter. On chromoendoscopic examination, the depression was clearly demarcated and an irregular pit pattern was identified in the demarcated area by magnification suggesting invasion of the submucosal layer requiring surgery. Laparoscopic-assisted sigmoidectomy was performed and the resected specimen demonstrated well-differentiated adenocarcinoma. The depth of invasion was only 900 microm. There was no lymphovascular invasion although not only paracolic, but also intermediate lymph node metastasis was detected. There have been some reports about small depressed-type colorectal cancer invading the submucosal layer; however, intermediate LN metastasis is very rare in submucosal colorectal cancer. In this case, there were two noteworthy points: 1) despite the small size, submucosal invasion could be estimated preoperatively, therefore, a successful lymph node dissection was performed by laparoscopic surgery; and 2) although this depressed-type cancer invaded the submucosal layer only 900 microm and there was no lymphovascular invasion, intermediate lymph node metastasis was detected.
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Affiliation(s)
- Takeshi Nakajima
- Endoscopy Division 1-1, National Cancer Center Hospital, Tsukiji 5-chome, Chuo-ku, 104-0045, Tokyo, Japan.
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Abstract
This article was presented at the conjoint CSSA and RACS (colorectal section) spring meeting Queensland, Australia, September 2004. The adenoma-carcinoma sequence describes a succession of events from polypoid adenoma to colorectal cancer. However, this model only accounts for up to two-thirds of colorectal cancers. There is growing evidence that flat adenomas are precursor lesions to a flat type of colorectal cancer and certain subtypes of these polyps are at greater risk of malignant transformation. If confirmed, the implications for screening, endoscopic recognition and management will become of increasing importance if we are to decrease the incidence of colorectal cancer.
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Affiliation(s)
- Doug Speake
- Colorectal Unit, Department of Surgery, Manchester Royal Infirmary, Manchester, UK
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Kita H, Hikichi Y, Hikami K, Tsuneyama K, Cui ZG, Osawa H, Ohnishi H, Mutoh H, Hoshino H, Bowlus CL, Yamamoto H, Sugano K. Differential gene expression between flat adenoma and normal mucosa in the colon in a microarray analysis. J Gastroenterol 2006; 41:1053-63. [PMID: 17160516 DOI: 10.1007/s00535-006-1894-y] [Citation(s) in RCA: 43] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/22/2006] [Accepted: 08/14/2006] [Indexed: 02/04/2023]
Abstract
BACKGROUND Flat adenomas in the colon are associated with a relatively higher potential for malignancy. Distinct genes may be involved in the development of flat adenoma. The aim of this study was to profile gene expression changes in flat adenomas in the colon. METHODS A genomewide expression analysis was carried out by using flat adenoma and adjacent normal mucosa in the colon to detect differences in gene expression. Because the right and left colon have different embryonic origins, each sample was classified according to its location, and the gene expression levels between flat adenoma and adjacent normal mucosa were also compared among samples derived from the right or left colon. RESULTS A total of 180 genes were differentially expressed between flat adenoma and normal mucosa in the colon, including matrix metalloproteinase 7 (MMP7), cadherin 3 (CDH3), S100P, and dual oxidase 2 (DUOX2). In addition, a total of 89 and 49 genes were differentially expressed between flat adenoma and normal mucosa among the samples from the right and left colon, respectively. Subsequent quantitative real-time reverse transcriptase-polymerase chain reaction supported the reliability of the expression analysis. Immunohistochemical analysis confirmed differential CDH3 and MMP7 protein expression. CONCLUSIONS This is the first report characterizing the genes differentially expressed in flat adenomas using a microarray analysis. Considerable differences in the gene expression profiles of flat adenomas also exist between the right and left colon. These data should lead to new insights into the pathogenesis of flat adenomas in the colon as well as to new therapeutic strategies.
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Affiliation(s)
- Hiroto Kita
- Department of Gastroenterology, Jichi Medical University, 3311-1 Yakushiji, Shimotsuke 329-0498, Japan
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29
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Lin JK, Chang SC, Wang HS, Yang SH, Jiang JK, Chen WC, Lin TC, Li AFY. Distinctive clinicopathological features of Ki-ras mutated colorectal cancers. J Surg Oncol 2006; 94:234-41. [PMID: 16900509 DOI: 10.1002/jso.20438] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Abstract
BACKGROUND AND OBJECTIVES We explored the relationship between the mutation pattern of Ki-ras and the clinicopathological features of colorectal cancers (CRCs). METHODS Relationships between clinicopathological parameters and Ki-ras mutation status were analyzed in 255 CRC patients using the chi-square and student t-tests. Kaplan-Meier survival curves were compared using the log-rank test. RESULTS Ki-ras mutation occurred in 43.9% of tumors, and 83% affected codon 12. The most frequent mutations were GGT->GAT (Gly->Asp) (37.5%), followed by GGT->GTT (Gly->Val) (31.3%), both in codon 12. The frequency of Ki-ras mutation was similar for different tumor stages (38.2-47.8%). The mucin component of tumors was significantly associated with Ki-ras mutation. The 4-year overall and disease-free survival was 61% and 54%, respectively, for patients with Ki-ras mutated tumors, and 73% and 60% for patients with nonmutated tumors (not statistically significant). Patients with Ki-ras mutated tumors had lower plasma folate (24 ng/dl) than those bearing nonmutated tumors (37 ng/dl). Patients with G->T Ki-ras mutations had the lowest folate level (22 ng/dl), followed by those with G->A mutations (25 ng/dl). CONCLUSIONS Ki-ras mutated colorectal tumors have a higher mucin production and higher differentiation, and are associated with lower plasma folate levels and a relatively poorer disease outcome.
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Affiliation(s)
- Jen-Kou Lin
- Division of Colon & Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, National Yang-Ming University, Taipei, Taiwan.
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30
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Goto H, Oda Y, Murakami Y, Tanaka T, Hasuda K, Goto S, Sasaki Y, Sakisaka S, Hattori M. Proportion of de novo cancers among colorectal cancers in Japan. Gastroenterology 2006; 131:40-6. [PMID: 16831588 DOI: 10.1053/j.gastro.2006.04.010] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/18/2005] [Accepted: 03/23/2006] [Indexed: 01/12/2023]
Abstract
BACKGROUND & AIMS Adenomatous polyps are main precursors of colorectal cancers (CRCs). In Japan, de novo cancers, which do not arise from preexisting adenomas, are considered to account for a substantial number of CRCs, but the relative importance of de novo carcinogenesis remains controversial. This study estimated the proportion of de novo cancers among CRCs in Japan. METHODS The subjects were persons 40-79 years of age who were relatively similar to those in the general population. The subjects underwent colonoscopy between 1997 and 2001. Early cancers among CRCs detected in this study were classified as de novo cancers or polyp cancers derived from adenomas. The age-specific incidence of the early CRCs was calculated, and the proportion of de novo cancers was estimated. The lifetime risk of early CRCs was estimated. RESULTS The study group comprised 14,817 persons. CRCs were diagnosed in 189 subjects, including 83 early cancers. There were no differences with regard to size and location between de novo cancers and polyp cancers, but morphology differed. Eighty-four percent (16/19) of de novo cancers were flat elevated or depressed. The expected lifetime risk of developing early CRCs was 5.27% for men and 3.21% for women. Among persons with early cancers, the expected probabilities of developing de novo cancer were 18.6% for men, 27.4% for women. CONCLUSIONS De novo cancers account for a considerable proportion in Japan. This information suggests that the recommended interval for colonoscopic examination in Japan should be shorter than that in the United States.
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Affiliation(s)
- Hideyo Goto
- Hattori GI Endoscopy and Oncology Clinic, Kumamoto, Japan.
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31
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Smith D, Ballal M, Hodder R, Selvachandran SN, Cade D. The adenoma carcinoma sequence: an indoctrinated model for tumorigenesis, but is it always a clinical reality? Colorectal Dis 2006; 8:296-301. [PMID: 16630233 DOI: 10.1111/j.1463-1318.2005.00936.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
OBJECTIVE Evidence exists to support alternative pathways to the adenoma carcinoma sequence. Some mutations in key onco-suppressor genes relate to the anatomical site of the tumour. This link is typified by microsatellite instability and proximal neoplasia. However, rectal tumours are rarely considered separately. We hypothesized that tumour behaviour in the rectum may differ in terms of pathogenesis and malignant propensity. Therefore, we aimed to look for an association between the histopathological features of adenomas and their anatomical location as compared with the distribution of cancers. METHODS A single centre prospective study was undertaken over a four-year period. Patients referred to a colorectal assessment clinic with bowel symptoms underwent a minimum investigation of flexible sigmiodoscopy. Neoplastic lesions were either biopsied or removed after noting distance from the anal margin. Adenomas, differentiated by size, villous architecture and degree of dysplasia were compared to both early and advanced carcinomas. RESULTS Of 4089 patients, polyps were identified in 8.0% and cancer in 4.2%. There was a clear difference between the distribution of cancer and adenomas > 1 cm, P < 0.001. All degrees of dysplasia in large adenomas were more prevalent in the sigmoid colon as compared to cancer, P < 0.001. Seventy-five percent of high risk diminutive adenomas were rectal in origin. CONCLUSION Our data provides indirect evidence to support the concept that a significant proportion of rectal cancers may arise via an alternative pathway to the Vogelstein model. Polyp behaviour along with malignant propensity may actually be site dependent, with rectal polyps harbouring a more aggressive phenotype.
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Affiliation(s)
- D Smith
- Leighton Hospital, Crewe, UK.
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32
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Kaihara T, Fu KI, Sano Y, Yamashita K, Ochiai A, Yoshida S, Fujimori T. Depressed-type early invasive colon cancer in a patient treated with cyclooxygenase-2 inhibitor. Dig Dis Sci 2006; 51:885-8. [PMID: 16773432 DOI: 10.1007/s10620-006-9339-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2005] [Accepted: 04/12/2005] [Indexed: 12/09/2022]
Affiliation(s)
- Tsukasa Kaihara
- Division of Digestive Endoscopy and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Chiba, Japan
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33
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Konishi K, Takimoto M, Kaneko K, Makino R, Hirayama Y, Nozawa H, Kurahashi T, Kumekawa Y, Yamamoto T, Ito H, Yoshikawa N, Kusano M, Nakayama K, Rembacken BJ, Ota H, Imawari M. BRAF mutations and phosphorylation status of mitogen-activated protein kinases in the development of flat and depressed-type colorectal neoplasias. Br J Cancer 2006; 94:311-7. [PMID: 16404419 PMCID: PMC2361104 DOI: 10.1038/sj.bjc.6602911] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Although some molecular differences between flat-depressed neoplasias (FDNs) and protruding neoplasias (PNs) have been reported, it is uncertain if the BRAF mutations or the status of phosphorylated mitogen-activated protein kinase (p-MAPK) are different between theses two groups. We evaluated the incidence of BRAF and KRAS mutations, high-frequency microsatellite instability (MSI-H), and the immunohistochemical status of p-MAPK in the nonserrated neoplasias (46 FDNs and 57 PNs). BRAF mutations were detected in four FDNs (9%) and none of PNs (P=0.0369 by Fisher's exact test). KRAS mutations were observed in none of FDNs and in 14 PNs (25%; P=0.0002 by Fisher's exact test). MSI-H was detected in seven out of 44 FDNs (16%) and in one out of 52 of PNs (2%) (P=0.022 by Fisher's exact test). Type B and C immunostaining for p-MAPK was observed in 34 out of 46 FDNs (72%), compared with 24 out of 55 PNs (44%; P=0.0022 by χ2 test). There was no significant difference in the type B and C immunostaining of p-MAPK between FDNs with and without BRAF mutations. BRAF and KRAS mutations are mutually exclusive in the morphological characteristics of colorectal nonserrated neoplasia. Abnormal accumulation of p-MAPK protein is more likely to be implicated in the tumorigenesis of FDNs than of PNs. However, this abnormality in FDNs might occur via the genetic alteration other than BRAF or KRAS mutation.
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Affiliation(s)
- K Konishi
- Second Department of Internal Medicine, Showa University School of Medicine, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan.
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34
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Kashida H, Kudo SE. Early colorectal cancer: concept, diagnosis, and management. Int J Clin Oncol 2006; 11:1-8. [PMID: 16508722 DOI: 10.1007/s10147-005-0550-5] [Citation(s) in RCA: 69] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2005] [Indexed: 01/13/2023]
Abstract
In colorectal cancers, although flat and depressed-type lesions are found by regular endoscopic view, magnification and pit-pattern observation are vital parts of the precise diagnosis of the lesion. The depressed-type lesions appear to have a prominent tendency to show malignant characteristics, and the recognition and timely treatment of such lesions is important for improving the morbidity and mortality of colorectal cancer. Chromoscopy is mandatory for an accurate diagnosis of these lesions. The pit-pattern classification correlates well with actual histological findings and can provide important additional information prior to endoscopic treatment of the lesion.
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Affiliation(s)
- Hiroshi Kashida
- Digestive Disease Center, Showa University Northern Yokohama Hospital, 35-1 Chigasaki-chuo, Yokohama, 224-8503, Japan.
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35
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Orita H, Sakamoto N, Ajioka Y, Terai T, Hino O, Sato N, Shimoda T, Kamano T, Tsurumaru M, Fujii H. Allelic loss analysis of early-stage flat-type colorectal tumors. Ann Oncol 2006; 17:43-9. [PMID: 16249214 DOI: 10.1093/annonc/mdj017] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Flat-type colorectal tumors are rare, but are known for their unusual flat morphology and aggressive clinical behavior despite their small size. To identify distinct genetic alterations, loss of heterozygosity (LOH) analysis was performed on microdissected tissues. MATERIALS AND METHODS DNA was extracted from multiple microdissected foci in 43 cases of early-stage flat-type colorectal tumors and LOH analysis was performed on 2q, 4q, 5q, 12q, 14q, 15q, 17p, 18q, 18p and 22q. RESULTS LOH patterns were detected in one of two forms: (i) homogeneous LOH throughout the microdissected foci, which indicated the early acquisition of LOH; and (ii) heterogeneous LOH, which were detected in a part of analyzed foci. Homogeneous and heterogeneous LOH were most frequently detected on 17p (92%) followed by 18q (81%), 18p (81%), 5q (61%), 22q (51%), 14q (44%), 15q (41%), 2q (39%), 12q (36%) and 4q (32%). Homogeneous LOH was detected most frequently on 17p (68%) followed by 18p (53%), 18q (53%), 22q (34%) and 12q (27%). The average fractional allelic loss (FAL) for heterogeneous and homogeneous LOH was 0.57 and the average FAL for homogeneous LOH was 0.37. CONCLUSIONS Early flat-type colorectal tumors frequently shows the early occurrence of multiple LOH including 17p, 18p, 18q and 22q, which is coupled with additional LOH of other loci either simultaneously or in the early clonal progression phase. The extent and sequences of LOH may be the mechanisms responsible for the aggressive clinical behaviors of these tumors.
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Affiliation(s)
- H Orita
- Department of Surgery, Juntendo University, Tokyo, Japan
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36
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Sung JJY, Lau JYW, Goh KL, Leung WK. Increasing incidence of colorectal cancer in Asia: implications for screening. Lancet Oncol 2005; 6:871-876. [PMID: 16257795 DOI: 10.1016/s1470-2045(05)70422-8] [Citation(s) in RCA: 597] [Impact Index Per Article: 29.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Many Asian countries, including China, Japan, South Korea, and Singapore, have experienced an increase of two to four times in the incidence of colorectal cancer during the past few decades. The rising trend in incidence and mortality from colorectal cancer is more striking in affluent than in poorer societies and differs substantially among ethnic groups. Although changes in dietary habits and lifestyle are believed to be the reasons underlying the increase, the interaction between these factors and genetic characteristics of the Asian populations might also have a pivotal role. Non-polypoidal (flat or depressed) lesions and colorectal neoplasms arising without preceding adenoma (de novo cancers) seem to be more common in Asian than in other populations. The absence of polypoid growth preceding malignancy has posed difficulties in screening for early colorectal cancer by radiological imaging or even endoscopic techniques. Although epidemiological data are scanty, most Asian populations are not aware of the growing problem of colorectal cancer. More work is needed to elucidate the magnitude of the problem in Asia.
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Affiliation(s)
- Joseph J Y Sung
- Institute of Digestive Diseases, Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, Hong Kong.
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37
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Mukawa K, Fujii S, Takeda J, Kitajima K, Tominaga K, Chibana Y, Fujita M, Ichikawa K, Tomita S, Ono Y, Imura J, Kawamata H, Chiba T, Hiraishi H, Terano A, Fujimori T. Analysis of K-ras mutations and expression of cyclooxygenase-2 and gastrin protein in laterally spreading tumors. J Gastroenterol Hepatol 2005; 20:1584-90. [PMID: 16174078 DOI: 10.1111/j.1440-1746.2005.03897.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/09/2022]
Abstract
BACKGROUND AND AIM Recent advances in colonoscopic techniques have led to the increased detection of, and interest in, superficial type colorectal tumors, and a new category, the 'laterally spreading tumor (LST)', has been proposed. However, the characteristics of the genetic alterations in these LSTs have not yet been fully determined. We therefore classified LSTs as LST-granular (LST-G) or LST-non-granular (LST-NG), according to their macroscopic appearance, and examined the genetic alterations in these two tumor groups compared with those in protruded type tumors. METHODS We obtained a total of 62 colorectal tumors, including 26 protruded type, 17 LST-G and 19 LST-NG, from specimens resected surgically or endoscopically. We examined K-ras codon 12 mutations by using the polymerase chain reaction-restriction fragment length polymorphism method and by fluorescence direct sequencing. We also performed immunohistochemistry to analyze cyclooxygenase (COX)-2 and gastrin abnormalities. RESULTS The incidence of K-ras mutation was 50.0% in protruded type tumors, 76.5% in LST-G, and 26.3% in LST-NG. The frequencies of COX-2 overexpression were 73.1, 88.2, and 31.6%, respectively, and those of gastrin overexpression were 61.5, 82.4, and 26.3%, respectively. Therefore, LST-G is similar to protruded type tumors in that the incidence of K-ras mutation and the frequencies of COX-2 and gastrin overexpression are high. LST-NG differs from both of these tumor types in that the values of these three indicators are all low. CONCLUSIONS These results show that LST-G and LST-NG have different genetic alterations.
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Affiliation(s)
- Kenichiroh Mukawa
- Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Tochigi, Japan
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Nishikawa M, Oshitani N, Matsumoto T, Nishigami T, Arakawa T, Inoue M. Accumulation of mitochondrial DNA mutation with colorectal carcinogenesis in ulcerative colitis. Br J Cancer 2005; 93:331-7. [PMID: 15956973 PMCID: PMC2361569 DOI: 10.1038/sj.bjc.6602664] [Citation(s) in RCA: 51] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
We recently reported that oxidative stress elicited by chronic inflammation increases the mutation of mitochondrial DNA (mtDNA) and possibly correlates with precancerous status. Since severe oxidative stress is elicited in the colorectal mucosa of individuals with ulcerative colitis (UC), the possible occurrence of an mtDNA mutation in the inflammatory colorectal mucosa and colitic cancer was investigated. Colorectal mucosal specimens were obtained from individuals with UC with and without colitic cancer and from control subjects. The frequency of mtDNA mutations was higher in colorectal mucosal specimens from patients with UC than that from control subjects. The levels of 8-hydroxy-2′-deoxyguanosine, a DNA adduct by reactive oxygen species, were significantly higher in UC than in control. Specimens from patients with colitic cancer contained a significantly higher number of mtDNA mutations. The present observations suggest that the injury followed by the regeneration of colorectal mucosal cells associated with chronic inflammation causes accumulation of mtDNA mutations. The increased instability of genes, including those on the mtDNA, is consistent with the high and multicentric incidence of colorectal cancer in individuals with UC. Thus, analysis of mtDNA could provide a new criterion for the therapeutic evaluation, and may be useful for the prediction of risk of carcinogenesis.
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Affiliation(s)
- M Nishikawa
- Department of Biochemistry & Molecular Pathology, Osaka City University Medical School, Osaka 545-8585, Japan.
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39
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Abstract
Although flat and depressed-type lesions are found by regular endoscopic view, magnification and pit pattern observation are vital parts of a precise diagnosis of the lesion. The depressed-type lesions have a prominent tendency to show malignant character, and the recognition and timely treatment of this lesion is inevitable in improving the morbidity and mortality from colorectal cancer. A magnifying colonoscope has the capability of a regular colonoscope with an additional feature: magnification. With chromoscopic techniques, the surface pattern of the mucosal pits can be observed. The pit-pattern classification correlates well with actual histologic findings and provides important additional information before endoscopic treatment of the lesion.
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Affiliation(s)
- Shin-ei Kudo
- Digestive Disease Center, Showa University Northern Yokohama Hospital, Japan.
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40
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Kinoshita H, Yanagisawa A, Watanabe T, Nagawa H, Oya M, Kato Y, Muto T. Increase in the frequency of K-ras codon 12 point mutation in colorectal carcinoma in elderly males in Japan: the 1990s compared with the 1960s. Cancer Sci 2005; 96:218-20. [PMID: 15819719 PMCID: PMC11160025 DOI: 10.1111/j.1349-7006.2005.00037.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
The incidence of colorectal carcinomas has been increasing over the last 50 years in Japan. In order to determine whether adenoma-carcinoma sequence (ACS) or de novo cancer development, generally considered to be two separate genetic pathways, might be responsible, K-ras codon 12 mutations, good markers for ACS, were examined in 59 and 84 cases of advanced colorectal cancer surgically resected in Cancer Institute Hospital of the Japanese Foundation for Cancer Research in 1960-1969 and in 1990-1999, respectively. There was no significant difference of K-ras codon 12 mutation between the 25.4% (15/59) in the 1960s and 36.9% (31/84) in the 1990s (P = 0.148), and the reference of distal colon cancer also showed no significant difference between 24.4% (11/45) and 36.4% (20/55). Yet elderly males showed a significant difference: 27.3% (6/22) in the 1960s and 59.3% (16/27) in the 1990s. The references of males, elderly patients (over 75 years old) and distal colon cancer in the 1990s were significantly more likely to demonstrate mutations than their counterparts in the 1960s. There was no variation with the tumor location. The results suggest that the ACS pathway might have primarily contributed to the increased incidence of colorectal cancer in elderly males in Japan.
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Affiliation(s)
- Hirokatsu Kinoshita
- Department of Pathology, The Cancer Institute of the Japanese Foundation for Cancer Research, 3-10-6, Ariake, Kotoku, Tokyo 135-8550
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41
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Okamoto M, Kawabe T, Yamaji Y, Kato J, Ikenoue T, Togo G, Watabe H, Yoshida H, Shiratori Y, Omata M. Flat-type early colorectal cancer preferentially develops in right-sided colon in older patients. Dis Colon Rectum 2005; 48:101-7. [PMID: 15690665 DOI: 10.1007/s10350-004-0754-1] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Flat-type colorectal cancer is frequently reported in Japan and Europe, but its clinical features remain obscure. Thus, we investigated the clinical features of flat-type early colorectal cancer with respect to tumor location and patient age and compared them with those of polypoid-type early and advanced cancer. METHODS Between January 1999 and June 2001, total colonoscopy was performed in 6,178 patients (mean age, 61 years; 4,290 males and 1,888 females). Of these patients, 402 patients with 429 colorectal cancers were found: 202 at advanced stage (invading beyond muscularis propria) and 227 at early stage (carcinoma in situ or invading within submucosa). Early-stage cancer was classified into two macroscopic subgroups: flat-type and polypoid-type. RESULTS Out of 227 early cancers, 44 were flat type and 183 were polypoid. Flat-type early cancer was more frequently located in the right colon (57 percent, 25/44) than polypoid-type cancer (19 percent, 35/183; P < 0.001). Adenomatous component in flat-type early cancer was less frequent than in polypoid-type cancer (23 percent vs. 92 percent, P < 0.001). The proportion of right-sided colon in flat-type early cancer increased with age (33 percent in patients < or = 59 years, 50 percent in patients between 60 and 69 years, and 72 percent in patients > or = 70 years), whereas polypoid-type early cancer showed minimal change (16 percent, 18 percent, and 25 percent, respectively). An increase in the proportion of right-sided colon with age was also found in advanced cancer (20 percent, 38 percent, and 52 percent, respectively). CONCLUSION The incidence of flat-type early cancer in right-sided colon increased with age, similar to the pattern of advanced cancer. This suggests that flat-type early cancer may be a precursor of advanced cancer in the right colon, especially in older people.
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Affiliation(s)
- Makoto Okamoto
- Department of Gastroenterology, Faculty of Medicine, University of Tokyo, Tokyo, Japan
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42
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Yokoyama Y, Tamura S, Onishi S. FREQUENT K-RAS MUTATIONS AMONG LATERALLY SPREADING TUMORS WITH GRANULAR COMPONENTS AND THEIR SIGNIFICANCE FOR RECTAL CARCINOMAS. Dig Endosc 2005. [DOI: 10.1111/j.1443-1661.2005.00465.x] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/23/2023]
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Okada K, Satoh T, Fujimoto K, Tokunaga O. Interaction between morphology and angiogenesis in human early colorectal cancers. Pathol Int 2004; 54:490-7. [PMID: 15189502 DOI: 10.1111/j.1440-1827.2004.01650.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Morphologically, early colorectal cancers are divided into two types: polypoid cancers and non-polypoid cancers. They vary in growth pattern, progression, and genetic alteration. Angiogenesis between polypoid and non-polypoid cancers may also be different. Therefore, the present study aims to evaluate angiogenesis in the early stages of colorectal malignancy, with particular attention to the morphological differences. The serial slides of all materials (48 polypoid cancers, 10 non-polypoid cancers, 20 adenomas and 10 normal tissues) were immunohistochemically stained for three endothelial cell markers (CD31, von Willebrand factor and CD105), counted for the number of microvessels in the same hot spots, and the angiogenic status was estimated. Polypoid cancers had higher microvessel counts and were more predominantly supplied by activated (CD105-positive, newly forming) microvessels than non-polypoid cancers. The present study indicated the possibility that the difference in growth pattern might be explained by the difference in angiogenesis between polypoid and non-polypoid cancers.
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Affiliation(s)
- Keiichiro Okada
- Department of Pathology and Biodefense, Saga Medical School, Saga, Japan
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44
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Sakamoto N, Terai T, Ajioka Y, Abe S, Kobayasi O, Hirai S, Hino O, Watanabe H, Sato N, Shimoda T, Fujii H. Frequent hypermethylation of RASSF1A in early flat-type colorectal tumors. Oncogene 2004; 23:8900-7. [PMID: 15480433 DOI: 10.1038/sj.onc.1207993] [Citation(s) in RCA: 39] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Flat colorectal tumors, characterized by high-grade dysplasia from early small flat mucosal lesions, exhibit a relatively aggressive clinical behavior and are known for their infrequent K-ras mutations. In this study, we investigated the methylation status of the RASSF1A promoter in association with 3p LOH and K-ras mutations in 48 flat colorectal tumors (39 early carcinomas and nine intramucosal high-grade dysplasias). RASSF1A hypermethylation was detected in 39 of 48 (81.3%) tumors and RASSF1A methylation was also detected in 19 of 39 (49%) normal colonic mucosal tissues. 3p21.3 LOH was detected in 20 of 42 (47.6%) cases, but RASSF1 methylation was detected in cases with LOH (14 cases) and retention of 3p21.3 (20 cases). K-ras mutations were detected in seven of 48 (14.6%) tumors and the concordant occurrence of K-ras mutation and RASSF1A methylation was detected in three of 48 cases (6.3%). Overall, there was a statistically significant mutually exclusive relationship between K-ras mutations and RASSF1A methylation. In conclusion, promoter hypermethylation of RASSF1A is a frequent event and may start early in the background normal mucosa in this tumor type. An alternative cascade of abnormalities in RAS transduction pathways may be responsible for the flat morphology and aggressive nature of flat colorectal neoplasms.
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Affiliation(s)
- Naoto Sakamoto
- Department of Pathology(II), Juntendo University, Juntendo University School of Medicine, 2-1-1 Hongo, Tokyo 113-8421, Japan
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45
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46
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Noro A, Sugai T, Habano W, Nakamura SI. Analysis of Ki-ras and p53 gene mutations in laterally spreading tumors of the colorectum. Pathol Int 2004; 53:828-36. [PMID: 14629748 DOI: 10.1046/j.1440-1827.2003.01564.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
A laterally spreading tumor (LST) is considered to be a specific subtype of superficial colorectal tumors, in view of its characteristic clinicopathological features. We attempted to compare genetic alterations found in LST (>10 mm) with those found in IIa-type adenomas (10 mm or less (small superficial elevated lesion)) and conventional polypoid adenomas (>10 mm). In addition, multiple sampling by microdissection was performed for 14 LST to examine genetic heterogeneity in the Ki-ras and p53 gene mutation patterns. Polymerase chain reaction, single-strand conformation polymorphism and direct sequencing were used to analyze Ki-ras and p53 gene mutations in 73 sporadic colorectal adenomas: 28 LST; 22 IIa-type adenomas; and 23 polypoid adenomas. Ki-ras gene mutations were found more frequently in LST (6/28 tumors) and polypoid adenomas (6/23 tumors) than in IIa-type adenomas (2/22 tumors), although this difference was not statistically significant. The frequency of p53 gene mutations in the 28 LST was 25% (7/28), which was significantly higher than that found in IIa-type adenomas (P < 0.05). However, although p53 gene mutations were found more frequently in LST than in polypoid adenomas, this difference was not statistically significant. Seven LST exhibited a combination of wild-type and mutant-type tumor cells having the p53 gene mutation pattern, whereas a pattern of different Ki-ras gene mutations was found in two of three LST that exhibited Ki-ras gene mutation heterogeneity. We suggest that the LST exhibited a characteristic pattern in terms of the Ki-ras as well as the p53 gene mutation pattern, thereby supporting the hypothesis that LST is a specific subtype of colorectal tumors.
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Affiliation(s)
- Akihiro Noro
- Division of Pathology, Central Clinical Laboratory, Iwate Medical University, Morioka, Japan
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47
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The Paris endoscopic classification of superficial neoplastic lesions: esophagus, stomach, and colon: November 30 to December 1, 2002. Gastrointest Endosc 2003; 58:S3-43. [PMID: 14652541 DOI: 10.1016/s0016-5107(03)02159-x] [Citation(s) in RCA: 1309] [Impact Index Per Article: 59.5] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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48
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Richter H, Slezak P, Walch A, Werner M, Braselmann H, Jaramillo E, Ost A, Hirata I, Takahama K, Zitzelsberger H. Distinct chromosomal imbalances in nonpolypoid and polypoid colorectal adenomas indicate different genetic pathways in the development of colorectal neoplasms. THE AMERICAN JOURNAL OF PATHOLOGY 2003; 163:287-94. [PMID: 12819033 PMCID: PMC1868156 DOI: 10.1016/s0002-9440(10)63652-8] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
Cytogenetic changes are widely unknown for nonpolypoid (synonymously termed as "flat" or "depressed") colorectal adenomas. A comparison with polypoid adenomas will contribute to the discussion whether different genetic pathways for colorectal tumorigenesis depending on its origin from nonpolypoid or polypoid adenomas exist. Tissue samples of nonpolypoid (n = 22), polypoid (n = 28) adenomas, carcinomas ex-nonpolypoid adenomas (n = 9), carcinomas ex-polypoid adenomas (n = 14), and normal colonic mucosa (n = 9) were investigated by comparative genomic hybridization of whole genomic DNA. Chromosomal imbalances were detected from average comparative genomic hybridization profiles for each entity. Nonpolypoid adenomas show recurrent chromosomal losses on chromosomes 16, 17p, 18, 20, and 22 and gains on chromosomes 2q, 4q, 5, 6, 8q, 12q, and 13q. In polypoid adenomas losses of whole chromosomes 16, 18, and 22 and gains of chromosomes 7q and 13 were detected. The frequency of copy number changes was higher in nonpolypoid compared to polypoid adenomas and early onset of chromosomal changes became apparent in low-grade dysplasias of nonpolypoid adenomas. Gains on chromosomes 2q, 5, 6, 8q, and 12q and losses on chromosomes 17p and 20 occurred exclusively in nonpolypoid adenomas, whereas 16p deletions are significantly more frequent in nonpolypoid than in polypoid adenomas. Carcinomas ex-nonpolypoid adenomas are characterized by more complex aberration patterns compared to nonpolypoid adenomas exhibiting frequent losses on chromosomes 8p, 12q, 14, 15q, 16, 17p, 18, and 22 and gains on 3q, 5, 6, 7, 8q, 12q, and 13, respectively. Normal colonic mucosa showed no chromosomal imbalances. Distinct differences of chromosomal imbalances between nonpolypoid and polypoid colorectal adenomas have been characterized that support the hypothesis that different genetic pathways may exist in the development of colorectal adenomas exhibiting nonpolypoid and polypoid phenotype.
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Affiliation(s)
- Hedwig Richter
- Institute of Molecular Radiobiology, GSF-Forschungszentrum für Umwelt und Gesundheit GmbH, Neuherberg, Germany
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Sugai T, Uesugi N, Nakamura SI, Habano W, Jiao YF, Noro A, Takahashi H, Akasaka I, Higuchi T. Evolution of DNA ploidy state and DNA index in colorectal adenomas and carcinomas using the crypt isolation technique: new hypothesis in colorectal tumorigenesis. Pathol Int 2003; 53:154-62. [PMID: 12608896 DOI: 10.1046/j.1440-1827.2003.01448.x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The evolution of DNA diploid, aneuploid and multiploid (diploid and aneuploid) states that represent DNA types that are independent of genetic alterations in colorectal tumors were examined. Changes in the DNA index (DI) accompanying tumor development from adenoma to carcinoma were assessed. In colorectal adenomas and early cancers, the DNA was diploid or multiploid. A pure aneuploid state was observed in advanced carcinomas only, whereas the aneuploid DI values of adenomas were characterized by two distinct peaks. The DI values for the carcinomas were randomly distributed. However, in advanced carcinomas, aneuploid carcinomas tended to have lower DI whereas aneuploid populations within multiploid carcinomas tended to have higher DI. Early cancers were subdivided into two groups: a cancer region associated with an adenomatous region (group A tumors) and a cancer region that exhibited an absence of or a very limited adenomatous region (group B tumors). Group A tumor DI were lower than group B. It is suggested that low DI adenomas might transform into group A tumors, which consequently progress to advanced aneuploid carcinomas. In addition, group B tumors might derive predominantly from high DI adenomas or from group A tumors by high DI evolution, and might progress into advanced multiploid carcinomas. Therefore, the evolution of the DNA index might play an important role in the development of colorectal tumors.
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Affiliation(s)
- Tamotsu Sugai
- Division of Pathology, Central Clinical Laboratory, First Department of Internal Medicine and First Department of Surgery, School of Medicine, Iwate Medical University, Morioka, Japan
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Abstract
An increasing body of literature is available showing the existence of flat and depressed colorectal neoplasms in Western countries. The appreciation that colorectal neoplasms may present as flat or depressed lesions has important implications, as the risk of adenocarcinoma in depressed lesions has been found to be markedly higher than in flat or protruding lesions of similar size. There is concern that flat or depressed colorectal neoplasms might be easily missed during a colonoscopy and subsequently diagnosed as cancer within a few years after a clearing examination. In this review, we appraise advances in the study of flat and depressed colorectal cancers based on the English literature published in 2000 and subsequently, with emphasis on their epidemiology, diagnosis, and therapy.
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Affiliation(s)
- Roy M Soetikno
- Veterans Affairs, Palo Alto Health Care System and Stanford University, Palo Alto, California, USA.
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