PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps

Background  Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1 , MSH2 , MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods  The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results  The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion  Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

The carriers of MMR deficiency are at high risk for gastrointestinal cancers, particularly colorectal cancer (CRC) and other primary malignancies in diverse sites at young age (endometrial, ovaries, brain, lung, skin, small bowel, pancreas, and cervix). 1,3,5 The Amsterdam criteria and Bethesda guidelines are useful clinical tools, for the identification of individuals and families at high risk of LS. 6,7 Keywords ► lynch syndrome ► PMS2 deficiency ► mismatch repair gene ► colorectal cancer

Abstract
Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.
Deleterious variants in PMS2 may be monoallelic (heterozygous) in LS or biallelic (homozygous) in constitutional MMR deficiency syndrome. 8,9 In comparison with others MMR genes (MLH1, MSH2, MSH6), there is less data reported on PMS2 mutations thus far. Here, we report one young African individual affected by CRC with colorectal polyps and a PMS2 germline pathogenic variant.

Patient
The proband is a 51 year-old-Congolese male, recruited at the Gastroenterology and Cancerology Services of the Brazzaville Teaching Hospital, Congo in the frame of a research study hereditary on CRC in Brazzaville. 6,10 He had personal medical problems evolving for 8 years. It all started with diarrhea and abdominal pains, followed by rectal bleeding, significant weight loss, and anemia.

Methods
The study was performed based on Amsterdam II clinical criteria for LS, pedigree to detect a family history of cancers, colonoscopy examination, and anatomical-pathological analysis in search of polyps and to confirm the malignancy. The final diagnosis was provided by DNA sequencing to identify the germline mutation.
Genomic DNA was extracted from peripheral lymphocytes, using the magnetic beads technique on Chemagic 360 from PerkinElmer. A gene panel of 39 genes involved in hereditary CRC resulting from polyposis or nonpolyposis hereditary syndromes was sequenced in PE100 on a HiSeq Hundred percent of the target was covered with >600 reads. A vcf file was returned and analyzed with Moon (Diploid, Heverlee, Belgium), using cancer (HP:0002664) and intestinal polyposis (HP:0200008) as HPO terms.
The study required the Ethics Committee approval (Medical Congo Ethics Commission approval, 00171/DGRST/CERSSA).

Results
The phenotypic pedigree (►Fig. 1) revealed a family history of cancers. His daughter had breast cancer, whereas his sister and father died from CRC. Colonoscopy showed ulcerobudding, infiltrating, and hemorrhagic lesion (►Fig. 2), with multiple sessile polyps located on the left side of the colon and rectum. Histopathological analysis performed on a tumor biopsy diagnosed a colorectal adenocarcinoma. The patient fulfilled the Amsterdam II criteria.
Next Generation sequencing of multigene panel identified a heterozygous pathogenic frameshift variant in PMS2, We concluded to LS-associated CRC with a pathogenic PMS2 mutation. The patient underwent chemotherapy and surgical cure. Two years later, he left for Europe.

LS and Polyps
Individuals with LS can have polyps in their life, 12,13 and the sessile-type adenomatous polyps as observed in our case predispose to the dysplasia and cancer. 14 The polyps, located on all sites of colon increase the risk of CRC and they are associated with MMR gene deficiencies including PMS2 mutations (OMIM#614337). 8,12 The localization of the polyps in our patient was consistent with those previous reports. In contrast, our patient had more than 10 polyps at the time of diagnostic, which is higher than the number usually reported, less than 10.

PMS2 Mutations
Globally, PMS2 mutations cause LS in approximately 8 to 15% of cases. 5,11,15 That incidence is variable according to the countries and methods performed to establish diagnosis of LS: PCR, microsatellite instability and IHC or DNA sequencing. It should be noted than some of the PMS2 mutations are recurrent. 3,[15][16][17] The heterozygous PMS2 mutations are known to be responsible for LS in 5 to 15% of cases. 18,19 However, in one study looking at 61 LS due to PMS2 deficiency, heterozygous PMS2 mutations occurred in 90.16% (55/61) while the homozygous PMS2 mutations occurred in 9.83% (6/61) of LS. 8 The heterozygous mutation c.2192_2196delTAACT detected in our patient has been already identified in African Americans and in Caucasian Americans patients at young age. 8,[20][21][22] It is predicted to cause the substitution of the amino acid leucine 731 and the premature termination of the protein 3 amino acids downstream, p. Leu731Cysfs Ã 3. This variant is predicted to cause loss of normal function through truncated protein. This mutation is one of the PMS2 pathogenic variants listed in the International Society for Gastrointestinal Hereditary Tumors (InSiGHT) database (http:// www.insight database.org/classifications /gene). The colonic cancer caused by this pathogenic variant is often located in transverse or left colon. 8,20,21

PMS2 Cancer Predispositions
In LS, the risk for any cancer by the age of 70 years is 63.7% and the syndrome is responsible of 2 to 5% of all CRCs. 2,15 Regarding cancer predisposition in PMS2 mutation carriers, cumulative risk for any cancer in both sex is approximately 10% at the age 50 to 55 years. 23 Various types of cancers are observed: CRC, endometrial, ovarian, prostate, lung, brain, kidney pancreas, skin, small bowel, cervix. 1,4,11,18,24,25 CRC risk is 5.2 times higher than in healthy persons. The age-related risk for CCR is 22% for persons in their 50s. 11 One cohort study reported that the most frequent cancer in PMS2 mutations was CRC (in 80% of cases) followed by endometrial cancer (in 8.1% of cases). 18 As observed in our pedigree, PMS2 deficiency is also associated with increased risk of breast cancer and cumulative risk at the age of 60 years is 37.7%. 4 Sheehan et al 26 reported an increased prevalence of breast cancer among women carrying LS due to mutations in PSM2 as compared with those carrying mutations in MLH1, MSH2, and MSH6 genes.
In our patient, family history is compatible with cancer predisposition with the sister and father affected with CRC and his daughter with breast cancer.
The ►Table 1 reports some recurrent PMS2 deleterious mutations detected in individuals (of diverse populations) affected by LS-associated cancers, mainly the CCR.

Conclusion
Our report and published papers underline the notion that LS is also associated with multiple polyps. In addition, our data in accordance with the review highlights that the recurrent heterozygous PMS2 pathogenic variants can be identified in diverse patient populations (Caucasian, Africa). They are associated with an increased risk for CRC at young age. This report also supports the need for more study into the association between LS and breast cancer, especially in African patients.

What Does This Article Bring New?
First, we report the first Central African patient with a known LS-associated pathogenic variant, who also has multiple colonic polyps. Second, our results provide additional information about the clinical phenotype of the deleterious PMS2 mutation « c.2192_2196delTAACT » that contributes to colorectal carcinogenesis in Caucasian and also in African populations. Ethic Approval and Consent to Participate Not applicable.

Consent for Publication
Obtained.

Availability of Data and Material
Not applicable.

Funding
None.

Conflict of Interest
None declared.