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

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.

Keywords

lynch syndrome - PMS2 deficiency - mismatch repair gene - colorectal cancer

Introduction

Lynch syndrome (LS) is an autosomal dominant disorder due to germline pathogenic variants in DNA mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and post-meiotic segregation increased 2 (PMS2).[1] [2] [3] [4] The EpCam, a neighboring gene of MSH2, is also responsible for LS. Classically, the condition is not associated with polyps.

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]

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 and Methods

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 (Illumina, Inc, San Diego, California, United States) in Ogenetics facility. Library was prepared using the Oto Inherited Cancer panel kit (Ogenetics Inh Ca). The panel includes the following genes: BMPR1A, SMAD4, STK11, PTEN, APC, MUTYH, NF1, MLH1, MSH2, MSH6, PMS2, EPCAM, RET, ATM, BARD1, BRCA1, BRCA2, TP53, BRIP1, CDH1, CDK4, CDKn2A, CHEK2, ELAC2, FANCC, HRAS1, MEN1, MET, NBN, NTRK1, PALLD, PTCH, RAD50, RAD51, RAD51C, RAD51D, VHL, MRE11A, PALB2.

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 ulcero-budding, 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.

Fig. 1 Family pedigree of the index patient with a deleterious PMS2 mutation. (c.2192_2196delTAACT). Note three successive affected generations (vertical transmission). The index patient had colorectal cancer (CRC) at the age of 51 years and three family members also had cancer. His daughter (first-degree) 22-years old had breast cancer (BC). His sister at the age of 40 years, and his father (first-degree) died from CCR. CCT, clinical complete response.

Fig. 2 Macroscopic tumor per colonoscopy. Note hemorrhagic appearance of the tumor and presence of colonic polyps.

Next Generation sequencing of multigene panel identified a heterozygous pathogenic frameshift variant in PMS2, NM_000535.7: c.2192_2196delTAACT; p. Leu731Cysfs*3 (rs63750695) ([Fig. 3]), a variant previously described in LS patients [PMID: 26845104, PMID: 20186688, PMID: 15872200, PMID: 15256438, PMID: 16472587, PMID: 24033266].

Fig. 3 PMS2 mutation. Mutation in exon 13 of PMS2 by deletion of five dinucleotides: thymine (T), adenines (A), cytosine (C), at position 2192 to 2196, defined as « c.2192_2196delTAACT ». This mutation is at the origin of a predictive pathogenic variant « p. Leu731Cysfs*3 »: codon substitution leucine position 731 in cysteine and premature stop codon, 3 amino acids later the substitution. rg, reference genome; pg, patient genome.

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.

Discussion

PMS2 gene is located in 7p22.1 chromosomal segment with 38,125 base pairs, 15 exons and the encoded protein contains 862 amino acids (GRCh38/hg38).[11] PMS2 protein contains ATPase and endonuclease domains. The last domain acts with MLH1 to give a protein complex that interacts with other proteins to repair DNA errors during replication.

Heterozygous mutation in the PMS2 gene (MIM 600259) are responsible for hereditary nonpolyposis CRC-4 (HNPCC4) (MIM 614337), which is a form of LS. This syndrome is the most common hereditary form of clinical complete response (CCR) due to inherited mutations in the MMR genes.

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*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.

Table 1 Examples of recurrent PMS2 pathogenic variants in individuals with cancers (ClinVar)

Nucleotide change	Protein change	E	Cancers site	Age Ds /Gender	Countries	References
c.736_741del6ins11	p.Pro246_Pro247 delinsCysValTer	7	Colon, Cecum, Rectosigmoid, Stomach	28–74; M, F	United States Australia	8; 15; 19
c.903G > T	p.Lys301Asn	8	Colon, Endometrium	54–61; M, F	United States	8
c.862_863del	p.Gln288fs	8	Colon	54	United States	19
c.949C > T	p.Gln317Ter	9	Colon, Brain	39		3; 8
c.943C > T	p.Arg315Ter	9	Ovaries	F	Chine	24
c.904_1144del		9	Colon, Cecum, Rectum	M, F	Australia	15
c.137G > T	p.Ser46Ile	10	Small bowel, Transverse colon, Cecum, Sigmoid	32–67; M, F	France United States	3; 8; 17
Exon 10 deletion		10	Colon, Cecum, Rectum, Endometrium	30–60; M, F	United States	8; 19
c.1021delA	p.Arg341fs	10	Esophagium, Colon, Rectum, Breast, Skin, Endometrium	45–66; M, F	Australia	16
c.2444C > T	p.Ser815Leu	14	–	–	Netherlands	18; 19
c.903 + 1G > A		8	Colon, Cecum, Rectum	32–40; M, F	United States	19
c.1500del	p.Val501TrpfsTer94	11	Colon, Brain Ovaries, Endometrium	10–37; F	Pakistan	9
c.2182_2184delACTinsG	p.Thr728Alafs	13	Colon, Rectum	F, M	United States	8; 14
c.2192_2196delTAACT	p.Leu731Cysfs*3	13	Transverse colon	22–23; M	United States	8; 19; 20
			Left colon, Rectum	51; M	Congo	Present study

Abbreviations: Age Ds, age of diagnosis (years); E, exon; F, female; M, male.

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.

Conflict of Interest

None declared.

Acknowledgments

The authors would like to thank the patient and clinician DG who provided the photos.

Authors' Contributions

H.P. and D.G. designed the study. L.B.B., A.L., D.G., and H.P. performed the research and analyzed the data. A.M.-O. contributed materials and tools. H.P. and A.L. wrote the paper. All authors contributed and approved the final manuscript.

Ethic Approval and Consent to Participate

Not applicable.

Consent for Publication

Obtained.

Availability of Data and Material

Not applicable.

• References

• 1 Lepore Signorile M, Disciglio V, Di Carlo G, Pisani A, Simone C, Ingravallo G. From genetics to histomolecular characterization: an insight into colorectal carcinogenesis in Lynch syndrome. Int J Mol Sci 2021; 22 (13) 6767
• 2 Bucksch K, Zachariae S, Aretz S. et al; German Consortium for Familial Intestinal Cancer. Cancer risks in Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X: a prospective cohort study. BMC Cancer 2020; 20 (01) 460
• 3 Rosenblum RE, Ang C, Suckiel SA. et al. Lynch syndrome-associated variants and cancer rates in an ancestrally diverse biobank. JCO Precis Oncol 2020; 4 (04) 1429-1444
• 4 Roberts ME, Jackson SA, Susswein LR. et al. MSH6 and PMS2 germ-line pathogenic variants implicated in Lynch syndrome are associated with breast cancer. Genet Med 2018; 20 (10) 1167-1174
• 5 Bernstedt SW, Björk J, Fritzell K, Spigelman AD, Björck E, Backman AS. Room for improvement: one third of Lynch syndrome patients presenting for genetic testing in a highly specialised centre in Stockholm already have cancer. Hered Cancer Clin Pract 2021; 19 (01) 18
• 6 Poaty H, Aba Gandzion C, Soubeyran I. et al. The identification of Lynch syndrome in Congolese colorectal cancer patients. Bull Cancer 2017; 104 (10) 831-839
• 7 Niessen RC, Kleibeuker JH, Westers H. et al. PMS2 involvement in patients suspected of Lynch syndrome. Genes Chromosomes Cancer 2009; 48 (04) 322-329
• 8 Senter L, Clendenning M, Sotamaa K. et al. The clinical phenotype of Lynch syndrome due to germ-line PMS2 mutations. Gastroenterology 2008; 135 (02) 419-428
• 9 Ramchander NC, Ryan NAJ, Crosbie EJ, Evans DG. Homozygous germ-line mutation of the PMS2 mismatch repair gene: a unique case report of constitutional mismatch repair deficiency (CMMRD). BMC Med Genet 2017; 18 (01) 40
• 10 Poaty H, Batamba Bouya L, Ondima IPL. et al. BMPR1A and SMAD4 mutations in juvenile polyposis syndrome: clinicopathological and genetic data from two congolese patients. Gene Rep 2021; 23: 101141
• 11 Blount J, Prakash A. The changing landscape of Lynch syndrome due to PMS2 mutations. Clin Genet 2018; 94 (01) 61-69
• 12 Zhu F, Pan D, Zhang H, Ye Q, Xu P, Pan J. Single-center study of Lynch syndrome screening in colorectal polyps. Hered Cancer Clin Pract 2019; 17: 9
• 13 Burt RW. Colonic polyps in lynch syndrome. Dis Colon Rectum 2015; 58 (04) 371-372
• 14 Eleftheriadis N, Inoue H, Ikeda H, Onimaru M, Maselli R, Kudo SE. Polyps in Lynch syndrome. Differences in quality of colonoscopy between Western and Eastern endoscopists. Endoscopy 2015; 47 (01) 89
• 15 Guindalini RS, Win AK, Gulden C. et al. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology 2015; 149 (06) 1446-1453
• 16 Talseth-Palmer BA, McPhillips M, Groombridge C, Spigelman A, Scott RJ. MSH6 and PMS2 mutation positive Australian Lynch syndrome families: novel mutations, cancer risk and age of diagnosis of colorectal cancer. Hered Cancer Clin Pract 2010; 8 (01) 5
• 17 Worthley DL, Walsh MD, Barker M. et al. Familial mutations in PMS2 can cause autosomal dominant hereditary nonpolyposis colorectal cancer. Gastroenterology 2005; 128 (05) 1431-1436
• 18 Wang Q, Leclerc J, Bougeard G. et al; French Consortium of Oncogenetic laboratories for colorectal cancers, Unicancer Cancer Genetic Group (GGC). Characterisation of heterozygous PMS2 variants in French patients with Lynch syndrome. J Med Genet 2020; 57 (07) 487-499
• 19 van der Klift HM, Mensenkamp AR, Drost M. et al. Comprehensive mutation analysis of PMS2 in a large cohort of probands suspected of Lynch syndrome or constitutional mismatch repair deficiency syndrome. Hum Mutat 2016; 37 (11) 1162-1179
• 20 Goodenberger ML, Thomas BC, Riegert-Johnson D. et al. PMS2 monoallelic mutation carriers: the known unknown. Genet Med 2016; 18 (01) 13-19
• 21 Hampel H, Frankel WL, Martin E. et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352 (18) 1851-1860
• 22 Nakagawa H, Lockman JC, Frankel WL. et al. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 2004; 64 (14) 4721-4727
• 23 Dominguez-Valentin M, Sampson JR, Seppälä TT. et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the prospective Lynch syndrome database. Genet Med 2020; 22 (01) 15-25
• 24 Liu YL, Cadoo KA, Maio A. et al. Early age of onset and broad cancer spectrum persist in MSH6- and PMS2-associated Lynch syndrome. Genet Med 2022; 24 (06) 1187-1195
• 25 Guo X, Wu W, Gao H. et al. PMS2 germline mutation c.943C>T (p.Arg315*)-induced Lynch syndrome-associated ovarian cancer. Mol Genet Genomic Med 2019; 7 (06) e721
• 26 Sheehan M, Heald B, Yanda C. et al. Investigating the link between Lynch syndrome and breast cancer. Eur J Breast Health 2020; 16 (02) 106-109

Publication History

Received: 02 September 2022

Accepted: 25 October 2022

Article published online:
11 January 2023