MBD4-Associated Neoplasia Syndrome (PDQ®): Genetics - Health Professional Information [NCI]

Introduction

The association between germline, biallelic MBD4 loss-of-function variants and a predisposition to acute myeloid leukemia (AML) was first described in 2018.[1] In this initial report, hallmark mutational features from three patients with biallelic germline MBD4pathogenic variants were described, including an increased somatic variant rate with the accumulation of CG>TG somatic leukemogenic variants in genes frequently mutated in myeloid malignancies. Additional published reports suggest that biallelic MBD4 pathogenic variants may be associated with a multicancer predisposition syndrome, called MBD4-associated neoplasia syndrome (MANS). In addition to increasing the risk of developing AML, MANS increases the risk of gastrointestinal polyposis (comparable to attenuated familial adenomatous polyposis) and may also increase the risk of schwannoma.[2,3] There are conflicting data from a limited number of studies on whether heterozygous germline pathogenic variants in MBD4 increase the risk of developing uveal melanoma.[4,5]

References:

1. Sanders MA, Chew E, Flensburg C, et al.: MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood 132 (14): 1526-1534, 2018.
2. Palles C, West HD, Chew E, et al.: Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. Am J Hum Genet 109 (5): 953-960, 2022.
3. Blombery P, Ryland GL, Fox LC, et al.: Methyl-CpG binding domain 4, DNA glycosylase (MBD4)-associated neoplasia syndrome associated with a homozygous missense variant in MBD4: Expansion of an emerging phenotype. Br J Haematol 198 (1): 196-199, 2022.
4. Repo P, Jäntti JE, Järvinen RS, et al.: Germline loss-of-function variants in MBD4 are rare in Finnish patients with uveal melanoma. Pigment Cell Melanoma Res 33 (5): 756-762, 2020.
5. Derrien AC, Rodrigues M, Eeckhoutte A, et al.: Germline MBD4 Mutations and Predisposition to Uveal Melanoma. J Natl Cancer Inst 113 (1): 80-87, 2021.

Genetics and Molecular Biology of MBD4-Associated Neoplasia Syndrome

The MBD4gene codes for a DNA glycosylase (similar to MUTYH and NTHL1) that is recruited in the base excision repair (BER) pathway. In mouse studies, MBD4 helped repair methylation damage incurred by spontaneous deamination of 5'-methylcytosine to thymine, which is characterized by mismatched CG>TG.[1,2] Individuals with biallelic germline MBD4pathogenic variants lack the ability to use MBD4 for BER of GT mismatches. In turn, cancer risk is increased. Resulting cancers also appear to have elevated mutational burden and are enriched for this specific CG>TG signature.[3]

MBD4 is located at chromosome 3q21.3. Germline disease-causing MDB4 variants described in acute myeloid leukemia are loss-of-function homozygous or compound heterozygous variants. Therefore, MANS has an autosomal recessive inheritance pattern. The types of loss-of-function variants reported include nonsense variants (conferring abnormal splicing), deletions, and duplications.[3]

References:

1. Millar CB, Guy J, Sansom OJ, et al.: Enhanced CpG mutability and tumorigenesis in MBD4-deficient mice. Science 297 (5580): 403-5, 2002.
2. Wong E, Yang K, Kuraguchi M, et al.: Mbd4 inactivation increases Cright-arrowT transition mutations and promotes gastrointestinal tumor formation. Proc Natl Acad Sci U S A 99 (23): 14937-42, 2002.
3. Palles C, West HD, Chew E, et al.: Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. Am J Hum Genet 109 (5): 953-960, 2022.

Clinical Manifestations of MBD4-Associated Neoplasia Syndrome

Acute Myeloid Leukemia (AML) inMBD4-Associated Neoplasia Syndrome

Nine patients with this syndrome have been reported in the literature.[1,2,3] Based on these reports, individuals with germline MBD4-associated AML tend to develop early onset disease, with all reported AML cases (four) occurring between 33 and 49 years. A fifth patient was diagnosed with myelodysplastic syndrome at age 37 years. There are not enough cases to estimate penetrance. Germline genetic testing for MBD4-associated neoplasia syndrome (MANS) may be indicated for patients with AML and the following: 1) increased mutational burden on myeloid neoplasm somatic sequencing, especially when the mutational burden is enriched for CG>GT variants; and/or 2) a personal history of colonic polyposis, schwannomatosis, or uveal melanoma (UVM). Because MANS is autosomal recessive, it may arise in individuals who do not have family histories of leukemia or other MANS-associated manifestations.

Colorectal Polyposis inMBD4-Associated Neoplasia Syndrome

There are nine reported cases of MANS in the scientific literature.[1,2,3] Of these nine individuals, eight underwent colonoscopy at the time these cases were published. Almost all polyps were adenomas, and counts exceeded 20 polyps over multiple colonoscopies. One individual had more than 130 polyps.[1] Another individual had 75 polyps, leading to colectomy at age 32 years.[2] Another individual developed colorectal cancer (CRC) at age 40 years.[1]

One study ran whole-exome or whole-genome sequencing on 309 individuals who previously underwent genetic testing, which did not find a pathogenic variant.[1] These individuals had one of the following: 1) multiple colorectal adenomas, or 2) a family histories of multiple individuals with CRC. Patients with a biallelic loss of MBD4 presented with oligopolyposis. Cancers observed in affected individuals included UVM, CRC, and AML. Most of the adenomas that were found had an accumulation of CG>TG transitions in well-known CRC driver genes like APC, KRAS, and AMER1.

One differential diagnosis for individuals with a history of early onset leukemia and polyposis is a history of receiving total body radiation as a part of a conditioning regimen for hematopoietic stem cell transplantation (HSCT). These individuals are also at an increased risk for gastrointestinal polyps. A case series reported on five patients (all < 1 yr) who underwent HSCT for leukemia after receiving total-body radiation.[4] Every patient developed symptomatic gastrointestinal polyps 0.75 to 5.75 years after HSCT.

Uveal Melanoma inMBD4-Associated Neoplasia Syndrome

It is unclear if MANS is associated with an increased risk for UVM. UVM was reported in two individuals with MANS: one individual developed two primary UVMs at age 38 years and age 45 years, and one individual developed UVM at age 53 years.[1] Interestingly, both individuals with UVM and MANS carried at least one c.939dup MBD4 variant.

Other Manifestations inMBD4-Associated Neoplasia Syndrome

There are two reports of schwannomas in individuals with MANS. One individual had a vestibular schwannoma at age 34 years.[2] Another individual had two schwannomas at age 50 years and also had a meningioma at age 41 years.[1]

References:

1. Palles C, West HD, Chew E, et al.: Germline MBD4 deficiency causes a multi-tumor predisposition syndrome. Am J Hum Genet 109 (5): 953-960, 2022.
2. Blombery P, Ryland GL, Fox LC, et al.: Methyl-CpG binding domain 4, DNA glycosylase (MBD4)-associated neoplasia syndrome associated with a homozygous missense variant in MBD4: Expansion of an emerging phenotype. Br J Haematol 198 (1): 196-199, 2022.
3. Sanders MA, Chew E, Flensburg C, et al.: MBD4 guards against methylation damage and germ line deficiency predisposes to clonal hematopoiesis and early-onset AML. Blood 132 (14): 1526-1534, 2018.
4. Knight B, Anderson L, Lerner D, et al.: Case Series: Development of Polyps as a Late Effect After Total Body Irradiation-based Hematopoietic Cell Transplantation in Children With High-risk Leukemia. J Pediatr Hematol Oncol 43 (8): e1159-e1163, 2021.

Management and Prognosis for MBD4-Associated Neoplasia Syndrome

National Comprehensive Cancer Network (NCCN) guidelines provide management recommendations for individuals with molecularly confirmed MBD4-associated neoplasia syndrome (MANS):[1]

• NCCN recommends colonoscopy beginning at age 18 to 20 years or at the time of diagnosis to screen for colorectal polyps. Colonoscopy can be repeated every 2 to 3 years.
• NCCN recommends annual ophthalmologic exam when the individual is diagnosed with MANS.
• NCCN recommends complete blood count (CBC) when the individual is diagnosed with MANS, but it does not comment on the frequency of CBC afterwards. There is no consensus on the ideal frequency for CBC in patients with MANS.

Individualized treatment recommendations do not yet exist for individuals with MANS.

References:

1. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Genetic/Familial High-Risk Assessment: Colorectal, Endometrial, and Gastric. Version 2.2024. Plymouth Meeting, PA: National Comprehensive Cancer Network, 2024. Available with free registration. Last accessed October 7, 2024.

Latest Updates to This PDQ Summary (10 / 23 / 2024)

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About This PDQ Summary

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This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about MBD4-Associated Neoplasia Syndrome. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

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The lead reviewers for MBD4-Associated Neoplasia Syndrome are:

• Julia Cooper, MS, CGC (Ohio State University)
• Courtney DiNardo, MD, MSC (University of Texas, M.D. Anderson Cancer Center)
• Marcin Wlodarski, MD, PhD (St. Jude Children's Research Hospital)

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Last Revised: 2024-10-23