Shigeki Sekine1,2, Satoshi Yamashita3, Masayoshi Yamada4, Taiki Hashimoto5, Reiko Ogawa6, Hiroshi Yoshida5, Hirokazu Taniguchi5, Motohiro Kojima7, Toshikazu Ushijima3, Yutaka Saito4. 1. Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. ssekine@ncc.go.jp. 2. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan. ssekine@ncc.go.jp. 3. Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan. 4. Endoscopy Division, National Cancer Center Hospital, Tokyo, Japan. 5. Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo, 104-0045, Japan. 6. Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan. 7. Division of Pathology, Research Center for Innovative Oncology, National Cancer Center, Kashiwa, Chiba, Japan.
Abstract
BACKGROUND: Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity. METHODS: We examined the spectra of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs. RESULTS: Sequencing analyses identified BRAF V600E, BRAF non-V600E, KRAS, and NRAS mutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including RSPO fusions/overexpression, RNF43 mutations, ZNRF3 mutations, APC mutations, and CTNNB1 mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored GNAS mutations. There was significant interdependence between the altered MAPK and WNT pathway genes. RSPO fusions/overexpression was significantly associated with KRAS mutations (31/47, 66%), whereas most RNF43 mutations coexisted with the BRAF V600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the BRAF V600E mutation (71%) and those with RNF43 mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with RSPO fusions/overexpression (58%) and those with GNAS mutations (100%). CONCLUSIONS: Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.
BACKGROUND: Traditional serrated adenoma (TSA) is the least common type of colorectal serrated polyp, which exhibits considerable morphological and molecular diversity. METHODS: We examined the spectra of alterations in MAPK and WNT pathway genes and their relationship with clinicopathological features in 128 TSAs. RESULTS: Sequencing analyses identified BRAFV600E, BRAF non-V600E, KRAS, and NRAS mutations in 77, 3, 45, and 1 lesion, respectively. Collectively, 124 lesions (97%) had mutations in MAPK pathway genes. Alterations in WNT pathway genes were identified in 107 lesions (84%), including RSPO fusions/overexpression, RNF43 mutations, ZNRF3 mutations, APC mutations, and CTNNB1 mutations in 47, 45, 2, 13, and 2 lesions, respectively. Ten lesions (8%) harbored GNAS mutations. There was significant interdependence between the altered MAPK and WNT pathway genes. RSPO fusions/overexpression was significantly associated with KRAS mutations (31/47, 66%), whereas most RNF43 mutations coexisted with the BRAFV600E mutation (40/45, 89%). Histologically, extensive slit-like serration was more common in lesions with the BRAFV600E mutation (71%) and those with RNF43 mutations (87%). Prominent ectopic crypt formation was more prevalent in lesions with RSPO fusions/overexpression (58%) and those with GNAS mutations (100%). CONCLUSIONS: Our observations indicate that TSAs mostly harbor various combinations of concurrent WNT and MAPK gene alterations. The associations between genetic and morphological features suggest that the histological diversity of TSA reflects the underlying molecular heterogeneity.
Entities:
Keywords:
MAPK pathway; Traditional serrated adenoma; WNT pathway
Authors: Homer O Wiland; Bonnie Shadrach; Daniela Allende; Paula Carver; John R Goldblum; Xiuli Liu; Deepa T Patil; Lisa A Rybicki; Rish K Pai Journal: Am J Surg Pathol Date: 2014-09 Impact factor: 6.394
Authors: Sangeetha N Kalimuthu; Stefano Serra; Sara Hafezi-Bakhtiari; Richard Colling; Lai Mun Wang; Runjan Chetty Journal: Histopathology Date: 2017-05-05 Impact factor: 5.087
Authors: Douglas K Rex; Dennis J Ahnen; John A Baron; Kenneth P Batts; Carol A Burke; Randall W Burt; John R Goldblum; José G Guillem; Charles J Kahi; Matthew F Kalady; Michael J O'Brien; Robert D Odze; Shuji Ogino; Susan Parry; Dale C Snover; Emina Emilia Torlakovic; Paul E Wise; Joanne Young; James Church Journal: Am J Gastroenterol Date: 2012-06-19 Impact factor: 10.864
Authors: Kevin J Spring; Zhen Zhen Zhao; Rozemary Karamatic; Michael D Walsh; Vicki L J Whitehall; Tanya Pike; Lisa A Simms; Joanne Young; Michael James; Grant W Montgomery; Mark Appleyard; David Hewett; Kazutomo Togashi; Jeremy R Jass; Barbara A Leggett Journal: Gastroenterology Date: 2006-08-18 Impact factor: 22.682
Authors: Michael J O'Brien; Shi Yang; Charline Mack; Huihong Xu; Christopher S Huang; Elizabeth Mulcahy; Mark Amorosino; Francis A Farraye Journal: Am J Surg Pathol Date: 2006-12 Impact factor: 6.394