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Patients with tumors displaying high microsatellite instability (MSI-H) but no germline MMR inactivation are suspected for Lynch-like syndrome (LLS). To explore the involvement of acquired somatic MMR alteration as a cause, we screened 113 patient tumor samples for MMR gene variations and loss of heterozygosity. Somatic MMR alterations were found in 85.8% of patients including "double hits" in 63.7% of patients, mainly diagnosed with colon and endometrial cancers. Interestingly, 37.5% of them were under the age of 50, and seven patients were under 30. Somatic alterations were mainly attributed to the MLH1, MSH2 genes, likely reflecting the functional importance of these key MMR genes. Pathogenic variants co-existed in other cancer genes in particular the APC gene displaying a characteristic MMR deficiency-related "mutational signature", indicating that it may be inactivated owing to MMR deficiency. We speculated that APC inactivation could trigger an accelerated malignant transformation underlying early-onset cancers. Our findings provide further insight into the mechanisms underlying LLS, somatic MMR inactivation being a major cause for early-onset LLS through pathways differing from those involved in late-onset sporadic cases.

The POLD1 gene is involved in DNA proofreading to ensure accurate DNA replication. Some germline alterations in its exonuclease domain are associated with predisposition to cancers and colonic polyps. Only a few pathogenic variants have been clearly identified so far. Here we report a novel variant: c.1458GT p.(Lys486Asn) that we classified as pathogenic, detected in two putatively unrelated families. The cancer spectrum was very similar to Lynch syndrome, implying an overlapped tissue susceptibility. The common presence of colonic polyps in carriers and the MMR proficient phenotype in tumors were distinctive features suggesting POLD1 implication. Some clinical characteristics observed in the carriers of this variant differed from those reported previously, suggesting a potential genotype/phenotype correlation, and very likely in relation to the functional importance of affected residues. Our findings provide further insight into understanding the role of POLD1 in cancer-related risk.

Heterozygous germlineWe report 200Genomic rearrangements account for 18% of alterations. The c.137GT variant was observed in 18% of the patients, but a founder effect could not be clearly identified by haplotype analysis. Among class-4/5 variant carriers, the median age at first tumour onset was 49 years with a predominance of colorectal (80%) and endometrial (8.1%) cancers. Seven patients developed colorectal cancers before the age of 30 with the youngest at the age of 21. Only 6.2% of class-4/5 carriers had a family history fulfilling Amsterdam I/II criteria among patients with available data. Tumours fromOur results provide further insight into the role of the