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Declining Detection Rates for APC and Biallelic MUTYH Pathogenic Variants in Polyposis Patients, Implications for DNA Testing Policy

26 Pages Posted: 15 Apr 2019

See all articles by Diantha Terlouw

Diantha Terlouw

Leiden University - Department of Clinical Genetics

Manon Suerink

Leiden University - Department of Clinical Genetics

Sunny Singh

Erasmus University Rotterdam (EUR) - Department of Internal Medicine

J. T. van Wezel

Leiden University, Medical Center (LUMC), Department of Pathology

J. J. P. Gille

VU University Amsterdam - Department of Clinical Genetics

Y. J. Vos

University of Groningen - University Medical Center Groningen (UMCG)

F. J. Hes

Leiden University - Department of Clinical Genetics

A. M. J. Langers

Leiden University - Medical Center (LUMC)

Hans Morreau

Leiden University, Medical Center (LUMC), Department of Pathology

H. F. A. Vasen

Leiden University - Medical Center (LUMC)

C. M. Tops

Leiden University - Department of Clinical Genetics

S. W. ten Broeke

Leiden University - Department of Clinical Genetics

Maartje Nielsen

Leiden University - Department of Clinical Genetics

More...

Abstract

Background: This study aimed to determine the prevalence of APC-associated familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP) in a large cohort, taking into account several factors including adenoma count and year of diagnosis.

Methods: All application forms used to send patients in for APC and MUTYH mutation analysis between 1992 and 2017 were collected (n=2082). Using this data, possible predictive factors were examined using multivariate multinomial logistic regression analysis in SPSS.

Findings: The prevalence of APC mutations significantly increases with adenoma count while MAP shows a peak prevalence in individuals with 50-99 adenomas. Logistic regression analysis shows significant odds ratios for adenoma count, age at diagnosis and having a first degree family member with more than 10 polyps. Moreover, the chance of finding an APC or MUTYH mutation steadily declined over the past 23 years. Mutations in APC and MUTYH were found in 22% (43/200) of patients with FAP-related extracolonic manifestations, such as duodenal polyps and desmoid tumors. Mutation detection rate were 40% and 10% for respectively patients with >10 adenomas under age 60 and >20 adenomas under age 70. Mutation carriers not falling into these criteria, had FAP-related extracolonic manifestations, colorectal cancer (CRC) below the age of 40, somatic KRAS c.34G>T variant in the tumor or a first-degree family member with >10 adenomas.

Interpretation: Adenoma count, age at diagnosis of the adenomas and year of analysis are important predictive factors for APC and MUTYH mutations. Based on our results, APC and MUTYH testing is advised in patients >10 adenomas under age 60 and >20 adenomas under age 70. Almost all FAP and MAP patients who did not meet these criteria showed other characteristics that can be used as an indication to prompt genetic testing.

Funding Statement: The authors declare: "N/A."

Declaration of Interests: The authors state: "No competing interest to declare."

Ethics Approval Statement: The study was approved by local ethics review boards (P01.019).

Keywords: Polyposis, APC, Familial adenomatous polyposis, MUTYH associated polyposis, Colorectal carcinoma

Suggested Citation

Terlouw, Diantha and Suerink, Manon and Singh, Sunny and van Wezel, J. T. and Gille, J. J. P. and Vos, Y. J. and Hes, F. J. and Langers, A. M. J. and Morreau, Hans and Vasen, H. F. A. and Tops, C. M. and ten Broeke, S. W. and Nielsen, Maartje, Declining Detection Rates for APC and Biallelic MUTYH Pathogenic Variants in Polyposis Patients, Implications for DNA Testing Policy (April 12, 2019). Available at SSRN: https://ssrn.com/abstract=3371080

Diantha Terlouw

Leiden University - Department of Clinical Genetics

Leiden
Netherlands

Manon Suerink

Leiden University - Department of Clinical Genetics

Leiden
Netherlands

Sunny Singh

Erasmus University Rotterdam (EUR) - Department of Internal Medicine

Doctor Molewaterplein 40
Rotterdam, South Holland 3015 GD
Netherlands

J. T. Van Wezel

Leiden University, Medical Center (LUMC), Department of Pathology

Leiden
Netherlands

J. J. P. Gille

VU University Amsterdam - Department of Clinical Genetics

Amsterdam
Netherlands

Y. J. Vos

University of Groningen - University Medical Center Groningen (UMCG)

Hanzeplein 1
Groningen, 9713
Netherlands

F. J. Hes

Leiden University - Department of Clinical Genetics

Leiden
Netherlands

A. M. J. Langers

Leiden University - Medical Center (LUMC)

Albinusdreef 2
Leiden, South Holland 2333 ZA
Netherlands

Hans Morreau

Leiden University, Medical Center (LUMC), Department of Pathology

Leiden
Netherlands

H. F. A. Vasen

Leiden University - Medical Center (LUMC)

Albinusdreef 2
Leiden, South Holland 2333 ZA
Netherlands

C. M. Tops

Leiden University - Department of Clinical Genetics

Leiden
Netherlands

S. W. Ten Broeke

Leiden University - Department of Clinical Genetics

Leiden
Netherlands

Maartje Nielsen (Contact Author)

Leiden University - Department of Clinical Genetics

Leiden
Netherlands

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