Germline Mutations In MMR Genes Research Articles

Validation and Implementation of Long Mononucleotide Repeat Testing for the Detection of Microsatellite Instability: A Single Institution Experience

Introduction: Microsatellites are short, repetitive portions of DNA that are error prone during replication; several mismatch repair proteins recognize and repair these errors. Deficient MMR (dMMR) results in microsatellite instability (MSI), a well-recognized carcinogenic pathway. In Lynch syndrome (LS), germline mutations in MMR genes predispose to colorectal (CRC) and endometrial carcinoma (EC), among others. Immune checkpoint inhibitors (ICI), such as pembrolizumab, are approved to treat dMMR or MSI-high (MSI-H) cancers regardless of tumor type. Therefore, sensitive and specific methods to detect MSI are of critical importance to patient care. Multiple methods are used to detect MSI status, including immunohistochemistry (IHC) for MMR proteins and molecular assays. The Detroit Medical Center utilizes both IHC and PCR-based assays to maximize MSI detection sensitivity. We attempted validation of a new fluorescent PCR-based assay for MSI tumor testing which compares allelic profiles of microsatellite markers from matching normal and tumor samples. The assay utilizes four traditional MSI markers in addition to four long mononucleotide repeat (LMR) markers. LMR markers produce more pronounced fragment length changes, and thus may improve detection of MSI. Methods: Our validation set included 46 carcinoma patient samples with prior PCR-based MSI and MMR IHC testing. These included MSI-high, MSI-low (MSI-L), and microsatellite stable (MSS) cases. DNA was isolated from formalin-fixed, paraffin embedded (FFPE) tissue and amplified. Stutter peak patterns were analyzed, comparing allele sizes and stutter patterns. All cases were reviewed by two directors, with any discrepancies discussed and reviewed to achieve consensus. MSS samples showed identical stutter patterns between tumor and normal pairs. MSI-L samples had a single discrepant marker, whereas MSI-H samples had 2 or more discrepant markers. The results of the LMR assay were compared with the original PCR-based MSI and IHC results to determine test concordance. Results: 42 cases were successfully amplified and included in our results. Fourteen cases were classified as MSI-H by consensus, with a range of 3 to 8 unstable markers out of 8 total markers. IHC results for the MSI-H cases were available in 13/14 cases; thirteen were classified as abnormal. Notably, in one EC MSI-H case, a normal IHC result was reported. Three cases were classified as MSI-L. All were CRC samples, and 2 of 3 were also designated MSI-L using the traditional PCR MSI assay. The remaining MSI-L case was formerly interpreted as MSS. The IHC results for the MSI-L cases were all available and reported as normal. The remaining cases were designated as MSS. IHC results were normal in all but one EC case. Conclusions: Our study validated the LMR MSI Analysis System for detection of MSI; it is now used in clinical practice in our molecular laboratory at DMC, and challenging real-world cases from our assay rollout will be presented graphically. Our validation results demonstrate high concordance (42/42 cases) between the LMR and traditional MSI panels, highlighting the reliability of LMR markers. IHC and PCR results were largely concordant, with occasional discrepancies revealing the importance of a combination approach for MSI detection.

HGG-11. TRANS-SPECIES STUDY OF IDH-MUTANT REPLICATION-REPAIR DEFICIENT HIGH-GRADE GLIOMAS (RRD-HGG) AND RESPONSE TO COMBINED TARGETED AND IMMUNOTHERAPY: AN IRRDC STUDY

Abstract BACKGROUND IDH-mutant gliomas comprise <10% of HGG in children. RRD-HGG comprise 5-10% of childhood HGG, demonstrate high mutation burden (TMB) and respond to immune-checkpoint inhibition (ICI). The impact of RRD with childhood IDH-mutant gliomas, and effective therapeutic options for these patients are not well-established. METHODS Clinical and multi-omic analyses were performed on IDHmut-RRD-HGG registered to the IRRDC and the glioma taskforce. Tumor development and genomic data were studied from a novel IDHmut-RRD-HGG immunocompetent mouse model. Outcome following ICI and targeted therapy were evaluated. RESULTS IDH mut-RRD-HGG accounted for >60% of childhood IDH-mutant-HGG. Conversely, IDH1-mutations were detected in 20% of RRD-HGG. All patients (n=48) harboured germline mutations in MMR genes (CMMRD: 62%, Lynch syndrome: 38%). Contrary to sporadic IDH-mutant-gliomas, the majority (>90%) were high-grade. Diffuse/multifocal involvement, predominantly involving the frontal lobe, was frequent. TMB was lower than IDH-wildtype RRD-HGG (median: 28 mutations/Mb, p<0.05). Secondary POLE/POLD1 mutations were absent. TP53 and ATRX were frequent somatic hits. Copy number changes, particularly loss of CDKN2A/2B, were common. CD8-T-cell infiltration (immunohistochemistry) and tumor inflammation score (transcriptome) were lower than IDH-wildtype RRD-HGG (p<0.05). A novel mouse model (Olig2Cre+/Msh2LoxP/LSL-Idh1R132H) revealed similar lower TMB, diffuse cerebral involvement, slower growth, and low immune infiltrates as compared with IDH-wildtype RRD-HGG models. IDHmut-RRD-HGG demonstrated worse survival as compared to sporadic IDH-mutant-HGG (p<0.001). Within RRD-HGG, ICI monotherapy resulted in inferior survival in IDHmut-RRD-HGG vs IDH-wildtype RRD-HGG (p<0.05). Five patients developed metachronous IDHmut-RRD-HGG while on anti-PD1 treatment for IDH-wildtype RRD-HGG, suggesting intrinsic resistance. Interestingly, an IDH-inhibitor demonstrated objective response in 4/8 IDHmut-RRD-HGG. Furthermore, for IDHmut-RRD-HGG on ICI treatment, the addition of an IDH-inhibitor prolonged survival at 12-months in comparison to those without (p=0.01). CONCLUSION Hypermutant RRD-HGG with IDH1;p.R132H harbour unique immuno-biology and do not respond to anti-PD1 monotherapy. The addition of IDH-inhibition demonstrated favourable responses, supporting need for evaluation of the combination in clinical trials.

Abstract 1445: Emergence of frameshift mutations during tumorigenesis in VCMsh2 mouse model of Lynch syndrome

Abstract Monoallelic germline mutations in MMR genes (e.g., MLH1, MSH2, MSH6, and PMS2) predispose individuals to Lynch syndrome (LS) with microsatellite instability (MSI) throughout the genome. Mutations at coding mononucleotide repeats (MNR) usually result in frameshift mutations (FSMs). Recurrent FSMs are thought to play a central role in the increased risk of different types of cancer. Neoantigens produced by FSMs have been shown to elicit immune responses, which is the basis for frameshift neoantigen-based vaccines. To develop a prophylactic vaccine and prevention strategy for this high-risk population, we assessed FSMs during tumorigenesis from histologically normal mucosa and fecal DNA of a LS mouse model using targeted sequencing and a panel of FSMs in MNR regions. Msh2LoxP/LoxP;Villin-Cre mice (VCMsh2) started developing detectable tumors at 7-8 months and median survival was 11.5 months with 100% penetrance. Interestingly, FSMs were detectable not only in tumors and mucosa at 7-8 months, but also in young mice (1 month), embryos and pups although FSMs detected and variant allele frequency (VAF) were very low, indicating that FSMs accumulated over time, and FSMs alone may be not sufficient for tumorigenesis since tumors emerge at older age. To determine whether Msh2 was absent in embryos and pups, immunohistochemical (IHC) analysis was performed. Msh2 was lost in almost all intestine epithelial cells in 2-month-old mice but still present in young pups and embryos with very few cells absent of Msh2, indicating that emerging FSMs in these young pups may be due to decreased Msh2 expression because of delayed Cre function. To determine whether low Msh2 expression could lead to the emergence of FSMs, intestine mucosa from 8-, 10-, and 12-month-old Msh2LoxP/+;Villin-Cre heterozygous mice was sequenced. FSMs were detectable with low VAF, although they didn’t develop tumors. IHC staining revealed that Msh2 was absent in only a few intestine epithelial cells in these heterozygous mice, suggesting that loss of heterozygosity was a late event and rare at 12 months. To determine whether MSI emerged in young VCMsh2 pups and heterozygous mice due to haploinsufficiency of Msh2, MSI was assessed using seven markers and fragment size analysis. One marker (mBat67) showed instability in the intestinal mucosa of heterozygous mice and three showed instability in fecal DNA of one month old VCMsh2 mice. Interestingly, mucosal and fecal samples from a time course study in VCMsh2 mice showed progressive increase in MSI with a good correlation between MSI and FSMs during the tumorigenesis process. In summary, FSMs emerged at an early stage of tumorigenesis in VCMsh2 mice, which correlated with MSI status. Our data indicates that FSMs and MSI status can be used to monitor the tumor development of LS colorectal cancer. Funded by the National Cancer Institute, National Institutes of Health, under Contract No. HHSN261201500003I Citation Format: Yurong Song, Lei Wei, Shaneen S. Baxter, Brandon Somerville, Holli Loomans-Kropp, Chelsea Sanders, Ryan N. Baugher, Stephanie D. Mellott, Todd B. Young, Heidi E. Lawhorn, Teri M. Plona, Qiang Hu, Song Liu, Alan Hutson, Simone Difilippantonio, Ligia Pinto, Steven M. Lipkin, Matthias Kloor, Shizuko Sei, Robert H. Shoemaker. Emergence of frameshift mutations during tumorigenesis in VCMsh2 mouse model of Lynch syndrome [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1445.

A rare case of sporadic mismatch repair deficient pancreatic ductal adenocarcinoma that responded to ipilimumab and nivolumab combination treatment: case report.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignant disease with a poor prognosis. Despite high efficacy in multiple cancers, immunotherapy has had very little success in treating PDAC due to unfavorable characteristics such as low tumor mutational burden (TMB), low microsatellite instability (MSI), and non-immunogenic tumor microenvironment. Recently, however, there have been reports of rare PDAC cases with high TMB and DNA mismatch repair deficiency (dMMR) that have demonstrated positive response to immunotherapy. All these cases have also presented with Lynch Syndrome, or germline mutations in MMR genes. Here, we report a 57-year-old male with stage IV PDAC whose tumor profile revealed high TMB, high MSI, and dMMR, but no germline mutations in genes associated with hereditary cancers including those associated with Lynch Syndrome. After a series of ineffective treatments, the patient showed positive response to combined ipilimumab and nivolumab immunotherapy. To our knowledge, this is the first report of an advanced PDAC case with sporadic dMMR, high TMB, and no Lynch Syndrome having a good response to immunotherapy. This case further supports TMB and high MSI/dMMR being possible biomarkers for immunotherapy of PDAC as well as highlights the importance of both germline and somatic testing of patients with PDAC.

The utility of evaluating mismatch repair proteins in endometrial carcinoma: an experience from a tertiary referral centre in North India.

SummaryBackgroundEndometrial cancer (EC) is a common gynecological malignancy. Around 25-30% patients have mismatch repair deficiency (MMRd). Lynch syndrome is caused by germline mutations in MMR genes. Lynch-associated tumours have better prognosis, however implications for prognosis and survival is less known. Microsatellite insufficiency (MSI) is associated with high neoantigen loads and number of tumor infiltrating lymphocytes, which overexpresses PD-1 and PD-L1 and are excellent candidates for PD-1-targeted immunotherapies. In this study, we aim to evaluate the utility of MMR in patients with EC and its clinico-pathological correlation.MethodsEighty-two cases of EC which underwent MMR evaluation over a period of five years at our centre were included. Demographics, clinical details including family history, histopathological and immunohistochemical (IHC) parameters were recorded. Tumors with loss-of at least one protein were considered MMR deficient (MMRd) and those with intact expression were MMR proficient (MMRp).ResultsOf 82 cases tested, 27 (33%) were MMRd. Frequencies of IHC MMR loss of expression were: MLH1/PMS2: 17 (21%), MSH6 loss only: 3 (4%), MSH2/MSH6 loss: 3 (4%), PMS2 loss: 2 (2%). In MMRd cases, most common histologic tumor type was endometrioid adenocarcinoma (70%). Loss of expression was significantly (p < 0.001) more frequent in lower uterine segment involvement and positive family history.ConclusionsMSI plays an important role in the progression of endometrial cancer. Lower uterine segment involvement and positive family history are significant predictor of MMR loss. Routine testing of MMR proteins in endometrial cancer can contribute to screening of Lynch syndrome families and make immunotherapy available as a treatment option.

Abstract PS5-04: Therapeutic considerations in microsatellite instability high (MSI- H) breast cancers (BC) identified by comprehensive genomic profiling (CGP)

Abstract Background: Non-colorectal MSI-H tumors are increasingly identified by CGP. Rare types such as MSI-H BC remain poorly defined with an evidence gap on how to optimally sequence or combine with standard of care treatment. MSI can be measured by either IHC, PCR, or CGP and can be caused by both sporadic and germline variants within different tumor types. Prior studies in BC have shown evidence of dMMR by IHC cases MSS based on PCR. This could be due to intra-tumor heterogeneity, specific microsatellite loci evaluated, or penetrance of germline, somatic, or epigenetic alterations. Published data suggests carriers of germline pathogenic MMR variants have a BC risk equivalent to the normal population and currently germline testing is recommended only for BRCA. Currently in advanced BC, standard tumor biomarker testing includes IHC, PCR, and FISH; however, with increasing use of CGP we demonstrate additional actionable biomarkers as well as potential germline variants in MSI-H BC. Methods: DNA was extracted and hybrid capture CGP was performed on 29,160 BC cases. TMB was determined on 0.8-1.2 Mb of DNA and MSI status on 95-114 loci. Genomic LOH was also evaluated. Comparative analysis was done with 101 MSI-H BC, 841 MSS BC and 4,988 non-breast MSI-H cancers. Histological subtype was obtained from the pathology along with orthogonal testing for ER/PR/HER2 status. Somatic-germline-zygosity (SGZ) status was predicted using a published research use algorithm. Select case reports with clinical outcomes will be presented. Results: We identified 101 (0.35% of total) MSI-H BC cases: 29 ER+/HER2-, 5 HER2+, 29 TNBC, and 28 unknown. Amongst BC cases with known subtype, TNBC was enriched for MSI-H vs MSS (53.4 vs 35.8%, p=0.005). The median TMB in MSI-H BC (26.1 mut/Mb, IQR 17.4;42.8) was significantly lower than that of MSI-H colon (46.1mut/MB) and higher than that of MSI-H uterine tumors (22.6mut/Mb) in our comparison group (p&amp;lt;0.001 for both, Kruskal-Wallis test). Pathogenic variants in an MMR gene were found in 61.4% of MSI-H BC with MLH1 loss being the most common (13.6%) and much higher vs. the non-breast MSI-H cohort (2.4%, p&amp;lt;0.0001). Germline mutations in MMR genes in BC are rare yet 5/52 MMR short variants identified in 101 MSI-H BCs were predicted to be germline, 34 somatic, and 13 could not be determined. We identified 21 MSI-H BC patients with a total of 25 pathogenic BRCA1/2 alterations of which 4 were likely germline, 10 were homozygous, and were enriched in TNBC. These were mainly frameshift mutations, including BRCA2 T3033fs* in 5/18 (28%) cases; however, 7/25 were deletions, rearrangements, or nonsense mutations. Median gLOH was significantly higher in BRCA altered (19.7%) compared to BRCA wild-type MSI-H BC cases (9.6%) (p=0.007, Wilcox test). Additional potentially targetable biomarkers included 26 CDx eligible PIK3CA mutations, 11 ERBB2 activating point mutations in the TKD or ECD domain, 1 FGFR2 rearrangement, and 6 AKT1 E17K mutations. Four cases also had concurrent (CD274) PD-L1 amplifications. Conclusion: MSI-H BC is rare but CGP can identify additional therapeutic options for rational combination with targeted therapies such as PI3K, PARP, and HER2 inhibitors. BRCA alterations may be of germline or somatic origin and they may be targetable, as demonstrated by gLOH, rather than passenger mutations. Further characterization of these tumors and comparison to both MSS BC and non-breast MSI-H tumor types, combined with treatment outcomes, can provide insights on rationale combinations and/or sequencing of therapeutic agents. Citation Format: Kimberly McGregor, Natalie Danzinger, Jeffrey S. Ross, Kyle Gowen, Alexa B. Schrock, Garrett M. Frampton, Dean C. Pavlick, Jan W. Davis, Carl R. Gray, Jeffrey M. Venstrom. Therapeutic considerations in microsatellite instability high (MSI- H) breast cancers (BC) identified by comprehensive genomic profiling (CGP) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-04.

RARE-19. PEDIATRIC HIGH GRADE GLIOMA WITH DNA REPAIR PATHWAY ABERRATIONS, CLINICAL CHARACTERISTICS AND OUTCOME

DNA mismatch repair machinery is an integral part of the human genome and its defect has been involved in tumorigenesis and treatment resistance. Heterozygous monoallelic germline loss of function in MLH-1, MSH-2, MSH-6 or PMS-2 is involved in Lynch syndrome, whereas biallelic mutations cause constitutional mismatch repair deficiency (CMMRD) which is associated with hematologic malignancies and glioblastoma. We report here the clinical characterization and molecular analyses of 7 patients who presented with gliomas and MMR machinery aberrations. Two patients had a clinical diagnosis of NF-1 with dermatologic stigmata, of whom one patient has CMMRD and the other has Lynch syndrome. Two patients had a known family history of Lynch syndrome upon their diagnosis of glioma. Three patients with high-grade glioma and negative family history, 2 had germline mutations in MMR genes, and one had numerous mutations including MMR genes with microsatellite instability. Patients were initially treated with chemotherapy and radiation for high-grade gliomas (HGG); 5/7 had progression. Median time to progression was 12 months (range: 5–52), and median time from progression to death was 7 months (range: 2–25). One patient had low-grade glioma initially but progressed to HGG and is currently on therapy. Another patient treated with temozolomide and radiation is currently receiving maintenance therapy without any disease recurrence. Although the literature data on brain tumors with MMR deficiency is limited, these consistently show that MMRD-associated gliomas are treatment-resistant and have a dismal outcome. Collaborative efforts are needed to better understand this subgroup of pediatric HGG and to define optimal treatment strategy.

Immune checkpoint inhibitor response in mismatch repair-deficient colorectal cancer and other solid tumors: is it truly disease-agnostic?

Immune checkpoint inhibitor response in mismatch repair-deficient colorectal cancer and other solid tumors: is it truly disease-agnostic?

Abstract CT111: Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa

Abstract Patients diagnosed with germline mutations in MMR genes (Lynch Syndrome, LS) have up to 70-80% lifetime risk of colorectal cancer. Therefore, this high-risk population has the potential to benefit from effective chemopreventive strategies. Naproxen is an NSAID widely used for pain treatment with an excellent safety profile that has demonstrated to be more efficacious preventing colorectal cancer compared to aspirin in vivo using an intestinal tissue-specific mouse model of LS (VC-Msh2-LoxP). The ‘Naproxen trial' was designed to evaluate the modulation of PGE2 levels in colorectal mucosa, evaluate safety and tolerability, and discover novel molecular pathways involved in the chemopreventive activity of naproxen in LS patients. Methods: Participants were randomized to naproxen 440 mg (HD), 220 mg (LD) and placebo by mouth daily for 6 months. Modulation of prostaglandin levels, number of adverse events (AEs) observed in each treatment arm and gene expression profiles by next-generation sequencing (mRNAseq) in normal colorectal mucosa of LS patients after 6 months of intervention were examined. Results: Eighty participants diagnosed with LS were randomized, 25 participants to HD, 27 to LD, and 28 to placebo. From these patients, 54 were considered evaluable per-protocol analysis: 16 in the HD group, 15 in the LD and 23 in placebo. The level of prostaglandin E2 in the colorectal mucosa decreased significantly after treatment with both LD and HD naproxen when compared to placebo (-91.2%±14.1, -93.6%±7.9, and 23.8%±108.4, P-value&amp;lt;0.001, respectively). Moreover, levels of PGE2 urinary metabolite (PGE-M) were significantly changed in both treatment groups when compared to placebo (-47.7%±56.9, -41.1%±40.5, 7.6%±94.3, P-Value&amp;lt;0.018). The intervention was well tolerated, no severe AEs related to treatment were reported, and the total number of AEs was not different across treatment arms. LD and HD naproxen promoted the activity of the immune system by activating different immune cell types without any effect on lymphoid cellularity and changed the expression patterns of the intestinal crypt towards epithelial differentiation and stem cell regulation. Conclusions: Naproxen is a promising strategy for immune interception in LS that induces immune-modulation coupled with changes in the dynamics of the intestinal crypt. We have also discovered naproxen-induced gene expression profiles for their potential use as predictive biomarkers of drug activity. Citation Format: Laura Reyes Uribe, Wenhui Wu, Ozkan Gelincik, Prashant V. Bommi, Alejandro Francisco-Cruz, Luisa M. Solis, Patrick M. Lynch, Ramona Lim, Elena Stoffel, Priyanka Kanth, N. Jewel Samadder, Maureen E. Mork, Melissa W. Taggart, Ginger L. Milne, Lawrence J. Marnett, Lana Vornik, Diane D. Liu, Maria Revuelta, Kyle Chang, Y. Nancy You, Levy Kopelovich, Ignacio I. Wistuba, J. Jack Lee, Shizuko Sei, Robert H. Shoemaker, Eva Szabo, Ellen Richmond, Asad Umar, Marjorie Perloff, Powell H. Brown, Steven M. Lipkin, Eduardo Vilar. Naproxen chemoprevention promotes immune activation in Lynch syndrome colorectal mucosa [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr CT111.

EPID-09. CMMRD (CONSTITUTIONAL MISMATCH REPAIR DEFICIENCY) ASSOCIATED-BRAIN TUMORS: REPORT FROM THE EUROPEAN C4CMMRD CONSORTIUM

BACKGROUND Constitutional mismatch repair deficiency (CMMRD) is a rare childhood cancer predisposition syndrome (OMIM#276300) due to biallelic germline mutations in MMR genes, leading to a broad spectrum of childhood malignancies including brain, hematologic and colorectal cancers associated with cafe-au-lait macules (CALM).

Whole-Genome Sequencing Reveals Breast Cancers with Mismatch Repair Deficiency.

Mismatch repair (MMR)-deficient cancers have been discovered to be highly responsive to immune therapies such as PD-1 checkpoint blockade, making their definition in patients, where they may be relatively rare, paramount for treatment decisions. In this study, we utilized patterns of mutagenesis known as mutational signatures, which are imprints of the mutagenic processes associated with MMR deficiency, to identify MMR-deficient breast tumors from a whole-genome sequencing dataset comprising a cohort of 640 patients. We identified 11 of 640 tumors as MMR deficient, but only 2 of 11 exhibited germline mutations in MMR genes or Lynch Syndrome. Two additional tumors had a substantially reduced proportion of mutations attributed to MMR deficiency, where the predominant mutational signatures were related to APOBEC enzymatic activity. Overall, 6 of 11 of the MMR-deficient cases in this cohort were confirmed genetically or epigenetically as having abrogation of MMR genes. However, IHC analysis of MMR-related proteins revealed all but one of 10 samples available for testing as MMR deficient. Thus, the mutational signatures more faithfully reported MMR deficiency than sequencing of MMR genes, because they represent a direct pathophysiologic readout of repair pathway abnormalities. As whole-genome sequencing continues to become more affordable, it could be used to expose individually abnormal tumors in tissue types where MMR deficiency has been rarely detected, but also rarely sought. Cancer Res; 77(18); 4755-62. ©2017 AACR.

Identification et prise en charge du syndrome HNPCC ( hereditary non polyposis colon cancer). Prédisposition héréditaire aux cancers du côlon, du rectum et de l'utérus

Background The HNPCC syndrome (hereditary nonpolyposis colon cancer) is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for small intestine, urothelial, ovary, stomach and biliary tract carcinomas. HNPCC syndrome is responsible for 5% of colorectal cancers. Identification and management of this disease are part of a multidisciplinary procedure. Methods Twelve experts have been mandated by the French Health Ministry to analyze and synthesize their consensus position, and the resulting document has been reviewed by an additional group of 4 independent experts. Main recommendations The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a 2-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks, but other organs being at low lifetime risk, no specific surveillance will be proposed.

Prédisposition héréditaire au cancer colorectal et inactivation de la fonction de réparation des mésappariements de l'ADN

The hereditary non-polyposis colorectal cancer (HNPCC) syndrome is an inherited condition characterized by clinical and genealogical criteria (Amsterdam criteria), caused by germline mutations in MMR genes in about 70% of cases. In this situation, tumor cells exhibit an MSI phenotype that is evidenced by genotyping of a reference panel of 5 monucleotidic sequences. Gene carriers are at high-risk of developing colorectal, endometrial, urothelial and small intestine carcinomas, and at moderate risk of ovary, stomach and biliary tract carcinomas. Genetic counseling is based on the presence of a carcinoma belonging to one of these locations, diagnosed before the age of 40, or before 60 years in case of MSI phenotype or an affected first degree relative. Identification of germline MMR gene is an important step for recommendations of subsequent surveillance and follow-up, focused on main cancer risks, i.e. colorectum and endometrium.

Le syndrome HNPCC (hereditary non polyposis colon cancer) : identification et prise en charge

Background. – The hereditary non-polyposis colon cancer (HNPCC) syndrome is an inherited condition defined by clinical and genealogical information, known as Amsterdam criteria. In about 70% of cases, HNPCC syndrome is caused by germline mutations in MMR genes, leading to microsatellite instability of tumor DNA (MSI phenotype). Patients affected by the disease are at high risk for colorectal and endometrial carcinomas, but also for other organs tumors. HNPCC syndrome is responsible for 5% of colorectal cancers. Major aspects. – The lack of sensitivity of Amsterdam criteria in recognizing patients carrying a MMR germline mutation led to an enlargement of these criteria for the recruitment of possible HNPCC patients, and to a two-steps strategy, asking first for a tumor characterization according to MSI phenotype, especially in case of early-onset sporadic cases. Further developments. – The identification of germline MMR mutations has no major consequence on the cancer treatments, but influences markedly the long-term follow-up and the management of at-risk relatives. Gene carriers will enter a follow-up program regarding their colorectal and endometrial cancer risks; other organs being at low lifetime risk, no specific surveillance will be proposed.