Insertion of an <scp>SVA</scp> element in <scp><i>MSH2</i></scp> as a novel cause of Lynch syndrome

Yang, Ciyu; Li, Yirong; Trottier, Magan; Farrell, Michael; Vikas, K; Salo‐Mullen, Erin; Gallagher, David J.; Stadler, Zsofia K.; Klift, Heleen M. van der; Zhang, Liying

doi:10.1002/gcc.22950

Cited by 7 publications

(3 citation statements)

References 27 publications

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“…Such variants include tandem exon duplications, disruptions due to mobile element insertions, and identification of variants that lead to monoallelic RNA expression due to disruption of RNA regulatory elements. [31][32][33] These additional use cases further highlight the importance of DNA-RNA paired testing in uncovering the full landscape of clinically relevant variants in Mendelian diseases.…”

Section: Discussionmentioning

confidence: 97%

Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing

Young,

Horton,

Grzybowski

et al. 2024

JCO Precis Oncol

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PURPOSE Patients with germline pathogenic variants (PVs) in APC develop tens (attenuated familial adenomatous polyposis [AFAP]) to innumerable (classic FAP) adenomatous polyps in their colon and are at significantly increased lifetime risk of colorectal cancer. Up to 10% of FAP and up to 50% of patients with AFAP who have undergone DNA-only multigene panel testing (MGPT) do not have an identified PV in APC. We seek to demonstrate how the addition of RNA sequencing run concurrently with DNA can improve detection of germline PVs in individuals with a clinical presentation of AFAP/FAP. METHODS We performed a retrospective query of individuals tested with paired DNA-RNA MGPT from 2021 to 2022 at a single laboratory and included those with a novel APC PV located in intronic regions infrequently covered by MGPT, a personal history of polyposis, and family medical history provided. All clinical data were deidentified in this institutional review board-exempt study. RESULTS Three novel APC variants were identified in six families and were shown to cause aberrant splicing because of the creation of a deep intronic cryptic splice site that leads to an RNA transcript subject nonsense-mediated decay. Several carriers had previously undergone DNA-only genetic testing and had received a negative result. CONCLUSION Here, we describe how paired DNA-RNA MGPT can be used to solve missing heritability in FAP families, which can have important implications in family planning and treatment decisions for patients and their families.

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Section: Discussionmentioning

confidence: 97%

Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing

Young,

Horton,

Grzybowski

et al. 2024

JCO Precis Oncol

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“…SVA repeats have been shown to be involved in pathogenic SV formation [ 35 ]. More specifically, SVA transposition events in MSH2, MSH6 and PMS2 , have been reported to cause LS [ 44 – 46 ]. In the patients reported in the present study, the MSH2 insertion point and donor MSH6 site contain the SVA D retrotransposon repeat element (SINE-VNTR-Alu, subfamily D) [ 35 ].…”

Section: Discussionmentioning

confidence: 99%

A 39 kb structural variant causing Lynch Syndrome detected by optical genome mapping and nanopore sequencing

Bjørnstad,

Aaløkken,

Åsheim

et al. 2023

Eur J Hum Genet

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Lynch Syndrome (LS) is a hereditary cancer syndrome caused by pathogenic germline variants in one of the four mismatch repair (MMR) genes MLH1, MSH2, MSH6 and PMS2. It is characterized by a significantly increased risk of multiple cancer types, particularly colorectal and endometrial cancer, with autosomal dominant inheritance. Access to precise and sensitive methods for genetic testing is important, as early detection and prevention of cancer is possible when the variant is known. We present here two unrelated Norwegian families with family histories strongly suggestive of LS, where immunohistochemical and microsatellite instability analyses indicated presence of a pathogenic variant in MSH2, but targeted exon sequencing and multiplex ligation-dependent probe amplification (MLPA) were negative. Using Bionano optical genome mapping, we detected a 39 kb insertion in the MSH2 gene. Precise mapping of the insertion breakpoints and inserted sequence was performed by low-coverage whole-genome sequencing with an Oxford Nanopore MinION. The same variant was present in both families, and later found in other families from the same region of Norway, indicative of a founder event. To our knowledge, this is the first diagnosis of LS caused by a structural variant using these technologies. We suggest that structural variant detection be performed when LS is suspected but not confirmed with first-tier standard genetic testing.

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“…Lynch syndrome or hereditary non-polyposis colorectal cancer (HNPCC) is characterized by germline inactivation of one allele of genes involved in the mismatch repair system, namely MLH1, MSH2, MSH6, PMS2 or EPCAM and have received prominent clinical and research attention and since 1985 (1,2). More than 1500 variants of Lynch syndrome alleles have been identified including: retrotransposition and Alu-like element insertion events (3)(4)(5), splice site mutations and large exonic deletions (6)(7)(8). However, inactivation of MLH1 or PMS2 alleles are the most frequent ones and are associated with approximately 80% of Lynch syndrome cases (9,10).…”

Section: Introductionmentioning

confidence: 99%

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

et al. 2021

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Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome – a hereditary cause of dMMR – confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability – high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.

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Insertion of an SVA element in MSH2 as a novel cause of Lynch syndrome

Cited by 7 publications

References 27 publications

Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing

Solving Missing Heritability in Patients With Familial Adenomatous Polyposis With DNA-RNA Paired Testing

A 39 kb structural variant causing Lynch Syndrome detected by optical genome mapping and nanopore sequencing

Lynch Syndrome and MSI-H Cancers: From Mechanisms to “Off-The-Shelf” Cancer Vaccines

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