Heterozygous APC germline mutations impart predisposition to colorectal cancer

Abstract Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisi...

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Autores principales:	Livia Preisler, Aline Habib, Guy Shapira, Liron Kuznitsov-Yanovsky, Yoav Mayshar, Ilana Carmel-Gross, Mira Malcov, Foad Azem, Noam Shomron, Revital Kariv, Dov Hershkovitz, Dalit Ben-Yosef
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/1cd322207da747e2ac2ab6d15bbd29d1
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spelling	oai:doaj.org-article:1cd322207da747e2ac2ab6d15bbd29d12021-12-02T15:53:58ZHeterozygous APC germline mutations impart predisposition to colorectal cancer10.1038/s41598-021-84564-42045-2322https://doaj.org/article/1cd322207da747e2ac2ab6d15bbd29d12021-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-84564-4https://doaj.org/toc/2045-2322Abstract Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.Livia PreislerAline HabibGuy ShapiraLiron Kuznitsov-YanovskyYoav MaysharIlana Carmel-GrossMira MalcovFoad AzemNoam ShomronRevital KarivDov HershkovitzDalit Ben-YosefNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Livia Preisler Aline Habib Guy Shapira Liron Kuznitsov-Yanovsky Yoav Mayshar Ilana Carmel-Gross Mira Malcov Foad Azem Noam Shomron Revital Kariv Dov Hershkovitz Dalit Ben-Yosef Heterozygous APC germline mutations impart predisposition to colorectal cancer
description	Abstract Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.
format	article
author	Livia Preisler Aline Habib Guy Shapira Liron Kuznitsov-Yanovsky Yoav Mayshar Ilana Carmel-Gross Mira Malcov Foad Azem Noam Shomron Revital Kariv Dov Hershkovitz Dalit Ben-Yosef
author_facet	Livia Preisler Aline Habib Guy Shapira Liron Kuznitsov-Yanovsky Yoav Mayshar Ilana Carmel-Gross Mira Malcov Foad Azem Noam Shomron Revital Kariv Dov Hershkovitz Dalit Ben-Yosef
author_sort	Livia Preisler
title	Heterozygous APC germline mutations impart predisposition to colorectal cancer
title_short	Heterozygous APC germline mutations impart predisposition to colorectal cancer
title_full	Heterozygous APC germline mutations impart predisposition to colorectal cancer
title_fullStr	Heterozygous APC germline mutations impart predisposition to colorectal cancer
title_full_unstemmed	Heterozygous APC germline mutations impart predisposition to colorectal cancer
title_sort	heterozygous apc germline mutations impart predisposition to colorectal cancer
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/1cd322207da747e2ac2ab6d15bbd29d1
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_version_	1718385497788645376

Heterozygous APC germline mutations impart predisposition to colorectal cancer

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