Biallelic germline nonsense variant of MLH3 underlies polyposis predisposition

Abstract

PurposeSome 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.MethodsExome 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.ResultsThree 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.ConclusionOur 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.

Molecular Basis of Mismatch Repair Protein Deficiency in Tumors from Lynch Suspected Cases with Negative Germline Test Results

“…Tertiary analysis was carried out with VarSeq ® (v1.3.2, Golden Helix) and analyzed according to the principles used by Olkinuora et al [5]. Briefly, only high-quality (Phred-scale likelihood >70), rare (variant allele frequency <0.003 in the ExAC and GnomAD databases), and nonsynonymous variants (frameshift, stop gained/lost, missense, disrupting donor/acceptor site variants) were considered.…”

“…Heterozygous pathogenic variants in the DNA mismatch repair (MMR) genes, namely MLH1, MSH2, MSH6, and PMS2 and less frequently, deletions in the 3 end of EPCAM cause predisposition to LS [3]. Other MMR genes may contribute to cancer susceptibility with lower penetrance (MLH3) or predispose to polyposis (MSH3, MLH3) [4,5]. It is generally thought that a 'second hit', a somatic mutation, in the wild-type allele of the affected MMR gene is required for triggering tumorigenesis.…”

Current status of the genetic susceptibility in attenuated adenomatous polyposis

“…The MLH3 gene is located in the long arm of chromosome 14 (14q24.3), consists of 13 exons, and encodes a 1,453 amino acid protein. The homozygous truncating germline variant S1188* was first detected in an unexplained Swedish AAP case[21], and more recently in one more AAP and two CAP subjects from Finland, suggesting a founder effect[16] (Figure 1G). Authors hypothesize the involvement of a defective DNA damage response and/or recombination-related processes in the pathogenesis of these cases[16].…”

“…Under this scenario, the elucidation of genetic susceptibility, which could explain the etiology of the disease and improve the accuracy of genetic counseling, has become a priority for scientists and clinicians. Thanks to the advance of sequencing technologies, new genes have been recently associated with primary predisposition to the development of adenomas by genome/exome sequencing studies in unexplained AP cohorts[13-16]. In the same way, other genetic alterations not detected by conventional coding germline DNA sequencing screening strategies have also been described in the APC gene, such as mutations in the promoter[17] or introns[18], large inversions[19] or mosaicism phenomes[20].…”

Contribution to colonic polyposis of recently proposed predisposing genes and assessment of the prevalence of NTHL1 ‐ and MSH3 ‐associated polyposes

“…Autosomal recessive forms of polyposis are caused by biallelic inactivation of the base excision repair genes MUTYH and NTHL1 and of the DNA mismatch repair genes MSH3 , PMS2 , MSH6 , MSH2 , MLH1 , and MLH3 . Other genes, such as GREM1 and RNF43 have been associated with mixed and serrated polyposis respectively, and different forms of hamartomatous polyposes are caused by germline mutations in SMAD4 and BMPR1A (Juvenile polyposis), STK11 (Peutz Jeghers), or PTEN (PTEN‐hamartoma‐tumor syndromes) (reviewed by Olkinuora et al, ; Valle, ).…”