From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

Lepore Signorile, Martina; Disciglio, Vittoria; Di Carlo, Gabriella; Pisani, Antonio; Simone, Cristiano; Ingravallo, Giuseppe

doi:10.3390/ijms22136767

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From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

by

Martina Lepore Signorile

¹,

Vittoria Disciglio

¹,

Gabriella Di Carlo

²

,

Antonio Pisani

³,

Cristiano Simone

^1,4,* and

Giuseppe Ingravallo

^2,*

¹

Medical Genetics, National Institute for Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy

²

Department of Emergency and Organ Transplantation, Section of Pathology, University of Bari Aldo Moro, 70124 Bari, Italy

³

Gastroenterology and Digestive Endoscopy Unit, National Institute for Gastroenterology, IRCCS “S. de Bellis” Research Hospital, 70013 Castellana Grotte, Italy

⁴

Medical Genetics, Department of Biomedical Sciences and Human Oncology (DIMO), University of Bari Aldo Moro, 70124 Bari, Italy

^*

Authors to whom correspondence should be addressed.

Int. J. Mol. Sci. 2021, 22(13), 6767; https://doi.org/10.3390/ijms22136767

Submission received: 28 April 2021 / Revised: 18 June 2021 / Accepted: 21 June 2021 / Published: 23 June 2021

(This article belongs to the Special Issue Molecular Alterations in GastroIntestinal Pre-invasive Lesions)

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Abstract

Lynch syndrome is a hereditary cancer-predisposing syndrome caused by germline defects in DNA mismatch repair (MMR) genes such as MLH1, MSH2, MSH6, and PMS2. Carriers of pathogenic mutations in these genes have an increased lifetime risk of developing colorectal cancer (CRC) and other malignancies. Despite intensive surveillance, Lynch patients typically develop CRC after 10 years of follow-up, regardless of the screening interval. Recently, three different molecular models of colorectal carcinogenesis were identified in Lynch patients based on when MMR deficiency is acquired. In the first pathway, adenoma formation occurs in an MMR-proficient background, and carcinogenesis is characterized by APC and/or KRAS mutation and IGF2, NEUROG1, CDK2A, and/or CRABP1 hypermethylation. In the second pathway, deficiency in the MMR pathway is an early event arising in macroscopically normal gut surface before adenoma formation. In the third pathway, which is associated with mutations in CTNNB1 and/or TP53, the adenoma step is skipped, with fast and invasive tumor growth occurring in an MMR-deficient context. Here, we describe the association between molecular and histological features in these three routes of colorectal carcinogenesis in Lynch patients. The findings summarized in this review may guide the use of individualized surveillance guidelines based on a patient’s carcinogenesis subtype.

Keywords: Lynch syndrome; CRC; early detection; MMR genes

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MDPI and ACS Style

Lepore Signorile, M.; Disciglio, V.; Di Carlo, G.; Pisani, A.; Simone, C.; Ingravallo, G. From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome. Int. J. Mol. Sci. 2021, 22, 6767. https://doi.org/10.3390/ijms22136767

AMA Style

Lepore Signorile M, Disciglio V, Di Carlo G, Pisani A, Simone C, Ingravallo G. From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome. International Journal of Molecular Sciences. 2021; 22(13):6767. https://doi.org/10.3390/ijms22136767

Chicago/Turabian Style

Lepore Signorile, Martina, Vittoria Disciglio, Gabriella Di Carlo, Antonio Pisani, Cristiano Simone, and Giuseppe Ingravallo. 2021. "From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome" International Journal of Molecular Sciences 22, no. 13: 6767. https://doi.org/10.3390/ijms22136767

APA Style

Lepore Signorile, M., Disciglio, V., Di Carlo, G., Pisani, A., Simone, C., & Ingravallo, G. (2021). From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome. International Journal of Molecular Sciences, 22(13), 6767. https://doi.org/10.3390/ijms22136767

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From Genetics to Histomolecular Characterization: An Insight into Colorectal Carcinogenesis in Lynch Syndrome

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