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Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 790-796

A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer

Department of Pathology, ShandongProvincial Hospital Affiliated to Shandong First Medical University; Department of Pathology, Shandong Provincial Hospital, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China

Date of Submission04-Feb-2021
Date of Acceptance07-May-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Xi-Chao Sun
Department of Pathology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/jcrt.jcrt_214_21

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 > Abstract 

Objectives: The objective of the study is to provide an efficient and practical screening strategy to distinguish a broader spectrum of Lynch syndrome (LS) and LS mimics-associated colorectal cancer (CRC), including Lynch-like syndrome (LLS), constitutional mismatch repair-deficiency, familial CRC type X (FCCTX), and polymerase proofreading-associated polyposis syndrome.
Materials and Methods: 1294 cases of CRC samples were detected mismatch repair (MMR) status using immunohistochemistry (IHC) staining, in which the cases with MLH1-deficient CRC underwent BRAF mutation analysis by IHC. Following the personal and/or family history survey, next-generation sequencing (NGS) was used to detect gene variants.
Results: 1294 CRC patients were dichotomized into tumors caused by a deficient MMR (dMMR) system and a proficient MMR (pMMR) system after MMR status analysis. 45 patients with suspected sporadic dMMR CRC were then separated from MLH1-deficient CRC though BRAF mutation status analysis by IHC. Following the personal and/or family history survey for 1294 patients, as well as germline genetic testing by NGS, 34 patients were diagnosed as LS (8 cases), SLS (13 cases), LLS ( 6 cases), FCCTX (3 cases), and sporadic CRC (4 cases).
Conclusions: Our screening strategy, which consists of clinical and molecular analyses, is expected to improve the screening efficiency and management for the LS and LS mimics.

Keywords: DNA mismatch repair, familial colorectal cancer, hereditary nonpolyposis colorectal cancer, Lynch syndrome, Lynch-like syndrome

How to cite this article:
Yao ZG, Lv BB, Jing HY, Su WJ, Li JM, Fan H, Zhao MQ, Qin YJ, Sun XC. A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer. J Can Res Ther 2021;17:790-6

How to cite this URL:
Yao ZG, Lv BB, Jing HY, Su WJ, Li JM, Fan H, Zhao MQ, Qin YJ, Sun XC. A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer. J Can Res Ther [serial online] 2021 [cited 2021 Jul 29];17:790-6. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/790/321024

 > Introduction Top

The term 'hereditary nonpolyposis colorectal cancer (HNPCC) was once considered equal to Lynch syndrome (LS).[1] Currently, HNPCC is recommended to refer to a broader spectrum of familial colorectal cancer (CRC) without a polyposis phenotype encompassing disorders that can mimic some clinical features of LS.[2],[3] These HNPCC conditions can broadly be divided into tumors caused by an underlying deficient mismatch repair (dMMR) system, such as LS, Lynch-like syndrome (LLS), and constitutional mismatch repair-deficiency (CMMRD) and those that develop in families with similar patterns of heredity but with proficient MMR (pMMR) system, including familial CRC type X (FCCTX) and polymerase proofreading-associated polyposis (PPAP).[3] These HNPCC conditions share similar clinical features, such as strong personal or family history of cancer, diagnosis of colorectal neoplasia at young ages. In clinical practice, it is important to distinguish LS and its mimics as the approach to surveillance for patients and their family members with high risk differs according to risks for colonic and extracolonic cancers associated with each syndrome. Various clinical screening criteria, immunohistochemistry (IHC), and/or microsatellite instability (MSI) detection are recommended for LS identification in CRC.[4] In this study, we proposed a screening strategy to differentiate these HNPCC conditions from 1294 CRC patients through MMR IHC, BRAF IHC combined the personal and/or family history survey of patients. Accordingly, we selected 34 patients as the candidates for germline genetic testing using next-generation sequencing (NGS). We tried to develop a CRC patient's stratification algorithm for differentiating LS and LS mimics.

 > Materials and Methods Top

Study population and procedures

A total of 1294 patients who received surgical operations at Shandong Provincial Hospital between January 2017 and December 2018 were identified retrospectively. The patients' clinical data, such as age, personal medical history, and family history, were collected from medical records. All study participants provided written informed consent in the prescribed document. This project was approved by the Institutional Review Board of Shandong Provincial Hospital.


IHC was performed on formalin-fixed paraffin-embedded (FFPE) CRC specimens by using a BenchMark®XT autostainer (Roche, USA). Rabbit anti-MLH1, PMS2, MSH2, and MSH6 monoclonal antibodies were purchased from ZSGB-Bio (Beijing, China). Mouse anti-BRAF V600E (clone VE1) monoclonal antibody was purchased from Ventana Medical Systems, Inc. (Roche Diagnostics, USA). The following antibodies and dilutions were applied: (1) MLH1 monoclonal antibody (clone ES05) 1:200; (2) PMS2 monoclonal antibody (clone EP51) 1:200; (3) MSH2 monoclonal antibody (clone RED2) 1:100; (4) MSH6 monoclonal antibody (clone EP49) 1:100; and (5) BRAF V600E monoclonal antibody (clone VE1) 1:100. Adjacent normal colorectal mucosa and lymphocytes in the slides were used as an internal control. We judged the complete absence of nuclear staining in the tumor cells as the loss of MMR protein expression.

Targeted next-generation sequencing

Genomic DNA was extracted from FFPE-negative surgical margins of the intestinal walls through microscopic examination according to the manufacturer's standard procedure of DNA FFPE Tissue Kit (Qiagen, Germany). Then, the genomic DNA was fragmented by Covaris LE220 (Covaris, Inc., USA) to generate paired-end library (200–250 bp) and constructed into the libraries. Libraries were hybridized to custom-designed biotinylated oligonucleotide probes (Invitrogen, USA) targeting 114 cancer-related genes, including MMR genes. The products were then subjected to Agilent 2100 Bioanalyzer and ABI StepOne to estimate the magnitude of enrichment. After quality control, captured library sequencing was carried out on Illumina HiSeq X Ten Analyzers (Illumina, USA) for 150 cycles per read to generate paired-end reads. Image analysis, error estimation, and base calling were performed using Illumina Pipeline software (Illumina Inc., San Diego, USA) to generate raw data. For bioinformatics processing and data analysis, we using AfterQC to generate “clean reads” for further analysis.[5] The “clean reads” (with a length of 150 bp) derived from targeted sequencing and filtering were then aligned to the human genome reference (hg19) using the Burrows Wheeler Aligner software.[6] After alignment, the output files were used to perform sequencing coverage and depth. We used Genome Analysis Toolkit software (https://software.broadinstitute.org/gatk) to detect SNVs and indels. All SNVs and indels were filtered and estimated via multiple databases, including 1000 Genomes (1000 human genome dataset), Genome AD (Genome Aggregation Database dataset), and ExAC (The Exome Aggregation Consortium dataset). We used dbNSFP to predict the effect of missense variants.[7] The Human Gene Mutation Database and Clinvar Database were used to screen mutations reported in published studies. Variants classification was done according to the InSiGHT MMR genes variant classification criteria (https://www.insight-group.org). Sequencing data were generated from a multigene panel, which contained MLH1, MLH3, MSH2, MSH3, MSH6, PMS1, PMS2, POLB, POLD1, POLE, EPCAM, APC, MUTYH, STK11, TP53, and SMAD4. Variants were classified as: Class 5: pathogenic; Class 4: likely pathogenic; Class 3: variant of uncertain significance (VUS); Class 2: likely benign; Class 1: benign/polymorphism, following the 2007 guidelines from the American College of Medical Genetic and Genomics.[8] Reports with Class 5 and Class 4 were considered positive for many analyses in this study, and those with only benign or likely benign variants were considered negative.[9]

 > Results Top

As shown in [Figure 1], among the 1294 CRCs examined, IHC staining showed 5.6% (73/1294) CRCs displayed dMMR, including 4.5% (58/1294) patients with MLH1 and/or PMS2 absence, and 1.2% (15/1294) patients with MSH2 and/or MSH6 absence. Rarely, 2 patients showed single PMS2 loss and 2 patients showed single MSH6 loss. BRAF immunostaining was carried out in 56 patients lacking the expression of MLH1. The results revealed that 48 (85.7%) of these MLH1/PMS2-deficient CRCs displayed positive BRAF V600E staining. Using our screening strategy, 11 patients with MLH1/PMS2 deficiency, including 3 patients of BRAF V600E mutation and 8 patients of intact BRAF, displayed personal history and/or family history. The remaining 45 patients (93.5%) having MLH1/PMS2 deficiency and BRAF mutation without personal medical history and family history were considered as sporadic CRC (SCRC). In addition, 2 patients with single loss of PMS2, 15 patients with MSH2 and/or MSH6 absence, and 6 patients with pMMR were also shown the personal history and/or family history. These 34 patients underwent NGS and the corresponding genetic testing.
Figure 1: Summary of screening strategy to differentiate LS and LS mimics. CRC = Colorectal cancer, FCCTX = Familial colorectal cancer type X, IHC = Immunohistochemistry, LLS = Lynch-like syndrome, LS = Lynch syndrome, MMR = Mismatch repair, pMMR = Proficient MMR, SCRC = Sporadic CRC, SLS = Suspected Lynch syndrome

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The clinical information and the gene details of the NGS results are shown in [Table 1]. For 8 patients with MLH1 and PMS2 protein deficiency and intact BRAF, pathogenic mutations of MLH1 were found in 5 patients (Cases 1–5), suggesting the diagnosis of LS. For 15 patients with MSH2 and MSH6 protein deficiency, 3 patients (Cases 6–8) with (likely) pathogenic mutations of MSH2 were classified as LS. 13 patients (Cases 9–21), including 6 cases with MLH1 and/or PMS2 protein deficiency and 7 cases with MSH2 and/or MSH6 protein deficiency, were classified as suspected LS (SLS) according personal and/or family history and VUS genetic results of MMR genes. Although no pathogenic or likely pathogenic MMR gene mutation, 4 patients (Cases 16–19) with MSH2 and MSH6 protein deficiency were temporarily identified as SLS considering personal and/or family history, which need further EPCAM deletion analysis. 6 patients (Cases 22–27), including one case with MLH1 and PMS2 protein deficiency and 5 cases with MSH2 and/or MSH6 protein deficiency, were preliminary identified as LLS because of no pathogenic or likely benign MMR gene mutation. There was no pathogenic abnormality in the MMR genes for the 6 tested patients (Cases 28–33) with pMMR CRC, of which 3 patients (Cases 28–30) were regarded as FCCTX because of prominent family history. The other 3 patients (Cases 31–33) with no detected MMR variants were identified as SCRC. For 3 patients with MLH1 deficiency and BRAF mutation, 2 patients (Cases 9 and 11) aged <50 years carried VUS in PMS1 gene. Coupled with family history, we tended to classify these 2 patients as SLS before functional studies and pedigree studies of mutational genes. Although one patient (Case 34) carried VUS in PMS2 gene, we classified him as SCRC considering the absence of family history. In addition, no pathogenic POLB, POLD1, or POLE variants were found. No suspected pathogenic mutation of EPCAM gene was found in all MSH2 protein-deficient patients. Moreover, NGS showed no underlying mutation in other genes, including APC, MUTYH, STK11, TP53, and SMAD4.
Table 1: The clinical information and gene details detected by next-generation sequencing of the 34 patients

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 > Discussion Top

In this study, we devised a practical screening strategy for LS and LS mimics in CRC. The strategy consists of clinical characters and molecular analyses. First, tumor analysis for MMR IHC can dichotomize for the clinician conditions with dMMR or pMMR, allowing a focused differential diagnosis. Tumors of patients with LS, LLS, and CMMRD and 15% of all SCRC characteristically demonstrate MMR deficiency.[10] The cellular hallmarks of these disorders are loss of expression of the MMR protein (detected via IHC). The finding of the absence of MMR protein expression is the basis for differentiating familial CRC patients associated with LS from other HNPCC conditions, such as FCCTX and PPAP.[11] Accordingly, 73 patients, including 58 patients with MLH1 and/or PMS2 loss and 15 patients with MSH2 and/or MSH6 loss, contained LS, SLS, LLS, and SCRC. Moreover, the most common mechanism of dMMR in SCRC is via epigenetic silencing of MLH1 by promoter hypermethylation in tumors.[12] It has been demonstrated that BRAF testing for the V600E mutation is an alternative molecular approach to distinguish between SCRC and LS-associated CRC.[13],[14] Clinically, BRAF testing by IHC has become routine in the evaluation of CRC and is technically less demanding and less costly than assays of MLH1 promoter methylation.[15] Given that HNPCC is much more likely to have personal or family history compared with SCRC, our screening criteria focused on personal medical history and family history of patients. Accordingly, 45 patients with loss of MLH1 immunostaining, positive BRAF mutation, and absence of personal and/or family history are considered as SCRC. In contrast, 3 patients with negative MLH1 immunostaining will receive genetic testing because of personal/family history, even they were positive for BRAF mutation detection. Totally, 34 patients including dMMR and pMMR met the history screening criteria as candidates for gene testing by NGS.

NGS results confirmed 8 cases of LS, including 7 patients with pathogenic MLH1 or MSH2 genes and one patient with likely pathogenic MSH2 gene. 10 patients with VUS of MMR genes and family history are temporarily classified as SLS. Although VUS has not been considered clinically actionable, it can create concern for patients and clinicians. Therefore, these genetic mutations require further investigation in family pedigrees. 2 patients (Cases 9 and 11) aged <50 years with family history and negative MLH1 immunostaining were classified as SLS, even both were positive for BRAF mutation detection. It has been demonstrated that BRAF mutation testing for the exclusion of LS is misleading in MSI CRC patients <50 years.[16] In addition, MMR IHC showed isolated loss of PMS2 in 2 patients. Dudley et al. reported that approximately 24% of LS patients with isolated loss of PMS2 expression harbor germline MLH1 mutation.[17] Furthermore, a subset of MLH1 mutations results in functionally inactive MLH1 protein that is antigenically intact and will be detected by the commonly used anti-MLH1 antibodies. Such germline MLH1 mutations will lead to decreased MLH1 protein stability and/or quantity, compromised stability of MLH1-PMS2 complexes, and subsequent PMS2 degradation.[18] Accordingly, germline MLH1 mutation analysis in individuals with isolated loss of PMS2 expression was recommended. In our study, however, 2 patients with isolated loss of PMS2 showed no MMR gene variants, considering as SLS. According to our strategy, one patient (Case 22) with negative MLH1/PMS2 expression, lacked MLH1 methylation and germline mutations in MMR genes is identified as LLS, regardless of personal and/or family history. 5 patients with negative MSH2 and/or MSH6 immunostaining were classified as LLS, according to the negative pathogenic MMR genes by NGS. LLS may account for as much as 70% of SLS patients.[19] In view of 17.4% of LS cases showed large genomic deletions/duplications of MMR genes, the dMMR patients in our study with no germline mutation should be further evaluated the MMR and EPCAM genes status by multiplex ligation dependent probe amplification (MLPA).[20]

In our study, pathogenic germline mutations of MSH2 were found in LS patients with dual loss of MSH2 and MSH6 expression. However, approximately 20%–25% of patients suspected of having a mutation in MSH2 but in which a germline mutation is not detected.[21] These patients can be accounted for germline deletions at the 3' end of EPCAM (TACSTD1), which locates upstream of MSH2. Deletions eliminate the transcription termination signal of the EPCAM gene and lead to the expression of an EPCAM–MSH2 fusion transcript, resulting in silencing MSH2.[21],[22] Further testing of the EPCAM status among patients with negative MSH2 immunostaining and no pathogenic germline mutation will contribute to differentiate EPCAM-associate LS from LS mimics.

In our study, the functions and pedigree status of mutational genes need further investigation. Indeed, there are difficulties and limitations in obtaining a thorough family history in daily clinical practice. 3 patients (Cases 28–30) with significant family history showed no MMR genes mutation and no extracolonic cancers. These 3 patients were identified as FCCTX. Clinically, approximately half of CRC patients who meet Amsterdam criteria are classified as FCCTX.[23] The genetic etiology for FCCTX is largely unknown and may constitute more than one genetic etiologies. In addition, NGS results displayed three VUS of PMS1 gene in 2 patients (Cases 9 and 10) having MLH1 and PMS2 protein deficiency. These 2 patients were identified as SLS considering the presence of family history. A truncating germline mutation of PMS1 gene in one LS patient has been described.[24]

In our study, there is no clinical feature and molecular genetic finding to support the diagnosis of CMMRD and PPAP. CMMRD syndrome is a distinct childhood cancer predisposition syndrome that results from biallelic germline mutations in one of the four MMR genes, MLH1, MSH2, MSH6, or PMS2.[25] PPAP is a rare autosomal dominantly inherited syndrome in which the exonuclease domain of POLE or POLD1 is mutated in the germline.[26] Although two patients (Cases 10 and 26) showed VUS of POLB and POLE, respectively, we preferred to classify the case as SLS before understanding the mechanism of the dual absence of MSH2 and MSH6.

In our screening strategy, we did not restrict the age of patients considering the older mean age of onset for LLS and FCCTX than LS (50–60 vs. 40 years).[27],[28] On the other hand, about 5% of CRC with MSI showed full expression of MMR. Potential reasons for this include the loss of uncommon MMR genes, such as MLH3 and MSH3, or that the MMR gene is expressed but not functioning normally, perhaps due to a missense mutation.[29] Our screening strategy of personal history and family history combined with high-throughput sequencing panels will improve the sensitivity of dMMR. However, our study has some limitations that should be considered. First, deletions in the EPCAM gene for the patients with no MSH2 expression should be further detected using additional methods to differentiate EPCAM-associated LS from SLS. Indeed, Case 16 in our study possesses a large deletion in the EPCAM detected by MLPA (data not shown).[30] Second, the quality and quantity of DNA extracted from FFPE samples used in our study might influence the sequencing results. Compared with fresh tissues, the treatment of samples with formalin and paraffin, along with sample storage and extraction procedures, can result in significant fragmentation, denaturation, and chemical modifications of nucleic acids.[31] These changes may lead to sequencing artifacts. Third, the Sanger sequencing validation of NGS detected variants is mandatory in the future research.[32]

 > Conclusions Top

We developed a CRC patient's stratification algorithm for differentiating LS and LS mimics. The growing complex clinical and molecular phenotypes demonstrated heterogeneity of hereditary CRC. Our screening strategy, which consists of clinical and molecular analyses, is expected to improve the screening efficiency and management for the LS and LS mimics.

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Conflicts of interest

There are no conflicts of interest.

 > References Top

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