Four g.MMR genes (MLH1, MSH2, MSH6, and PMS2) were analyzed by next generation sequencing in 1058 cancer patients (614 male, 444 female; mean age 65.6 years) without past diagnosis of LS.
Lynch syndrome (LS) is an autosomal dominant inherited disorder that is associated with an increased predisposition to certain cancers caused by loss-of-function mutations in one of four DNA mismatch repair (MMR) genes (MLH1, MSH2, MSH6, or PMS2).
Inherited mutations in DNA mismatch repair (MMR) genes, MLH1, MSH2, and MSH6, account for approximately 90% of LS, while a relatively small number of LS families segregate a PMS2 mutation.
We highlight an <i>MLH1</i> variant in the colonic adenomas in an obligate Lynch syndrome carrier that resulted in PMS2 protein loss in the absence of mutations of the <i>PMS2</i> gene.
Fifty-six subjects had pathogenic variants associated with Lynch syndrome (25 with mutations in MSH2, 24 with mutations in MLH1, 5 with mutations in MSH6, and 2 with mutations in PMS2) and 10 subjects had pathogenic variants associated with familial adenomatous polyposis.
In a genetic analysis of 84 colorectal tumors, we found tumors from patients with PMS2-associated Lynch syndrome to be distinct from colorectal tumors associated with defects in other mismatch repair genes.
Lynch Syndrome (LS) is associated with germline mutations in one of the mismatch repair (MMR) genes, including MutL homolog 1 (MLH1), MutS homolog 2 (MSH2), MSH6, PMS1 homolog 2, mismatch repair system component (PMS2), MLH3 and MSH3.
Lynch syndrome (LS) patients with isolated PMS2 loss in the colon cancer, while intact MMR in the prostate cancer, are exceedingly rare.Herein, we report such a case.
Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF <sup>wild type</sup>/normal MLH1 sequence.
Hereditary cancer screening (HCS) for germline variants in the 3' exons of PMS2, a mismatch repair gene implicated in Lynch syndrome, is technically challenging due to homology with its pseudogene PMS2CL.
PMS2 and MSH6 protein expression in metastatic and matched primary tumor was assessed using clinically validated immunohistochemistry methods for Lynch syndrome screening.
Lynch syndrome (LS) is the most common hereditary colorectal cancer syndrome, caused by germline mutations in one of the major genes involved in mismatch repair (MMR): MLH1, MSH2, MSH6 and more rarely, PMS2.
These methods enable efficient and sensitive Lynch syndrome screening for 3' PMS2 copy-number mutations and may be applied similarly to other genomic regions with highly homologous pseudogenes.
When losses of both MLH1 and PMS2 proteins are observed by IHC, MLH1 promoter methylation analysis is conducted to distinguish Lynch syndrome-associated endometrial cancer from sporadic cancer.