Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition
(2019) In Genetics in Medicine 21(8). p.1868-1873- Abstract
Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of... (More)
Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.
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- author
- Olkinuora, Alisa ; Nieminen, Taina T. ; Mårtensson, Emma LU ; Rohlin, Anna LU ; Ristimäki, Ari ; Koskenvuo, Laura ; Lepistö, Anna ; Gebre-Medhin, Samuel LU ; Nordling, Margareta and Peltomäki, Päivi
- author collaboration
- organization
- publishing date
- 2019
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- biallelic germline variant, MLH3, polyposis
- in
- Genetics in Medicine
- volume
- 21
- issue
- 8
- pages
- 1868 - 1873
- publisher
- Nature Publishing Group
- external identifiers
-
- pmid:30573798
- scopus:85058847175
- ISSN
- 1098-3600
- DOI
- 10.1038/s41436-018-0405-x
- language
- English
- LU publication?
- yes
- id
- 0cf75b50-8d5b-45b2-8f25-b93adf228254
- date added to LUP
- 2019-01-14 10:41:30
- date last changed
- 2024-10-15 16:19:15
@article{0cf75b50-8d5b-45b2-8f25-b93adf228254, abstract = {{<p>Purpose: Some 10% of familial adenomatous polyposis (FAP) and 80% of attenuated polyposis (AFAP) cases remain molecularly unexplained. We scrutinized such cases by exome-wide and targeted methods to search for novel susceptibility genes. Methods: Exome sequencing was conducted on 40 unexplained (mainly sporadic) cases with FAP or AFAP from Finland. The DNA mismatch repair (MMR) gene MLH3 (MutL Homolog 3) was pinpointed and prompted a subsequent screen of ~1000 Swedish patients referred to clinical panel sequencing for colon tumor susceptibility. Results: Three homozygous carriers of a truncating variant in MLH3, c.3563C>G, p.Ser1188Ter, were identified among the index cases from the Finnish series. An additional biallelic carrier of the same variant was present in the Swedish series. All four patients shared a 0.8-Mb core haplotype around MLH3, suggesting a founder variant. Colorectal polyps from variant carriers showed no instability at mono-, di-, tri-, or tetranucleotide repeats, in agreement with previous findings of a minor role of MLH3 in MMR. Multiple loci were affected by loss of heterozygosity, suggesting chromosomal instability. Conclusion: Our results show that a biallelic nonsense variant of MLH3 underlies a novel syndrome with susceptibility to classical or attenuated adenomatous polyposis and possibly extracolonic tumors, including breast cancer.</p>}}, author = {{Olkinuora, Alisa and Nieminen, Taina T. and Mårtensson, Emma and Rohlin, Anna and Ristimäki, Ari and Koskenvuo, Laura and Lepistö, Anna and Gebre-Medhin, Samuel and Nordling, Margareta and Peltomäki, Päivi}}, issn = {{1098-3600}}, keywords = {{biallelic germline variant; MLH3; polyposis}}, language = {{eng}}, number = {{8}}, pages = {{1868--1873}}, publisher = {{Nature Publishing Group}}, series = {{Genetics in Medicine}}, title = {{Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition}}, url = {{http://dx.doi.org/10.1038/s41436-018-0405-x}}, doi = {{10.1038/s41436-018-0405-x}}, volume = {{21}}, year = {{2019}}, }