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Mismatch repair cancer syndrome 3(MMRCS3)

MedGen UID:
1733656
•Concept ID:
C5436807
•
Disease or Syndrome
Synonyms: mismatch repair cancer syndrome 3; MMRCS3
 
Gene (location): MSH6 (2p16.3)
 
Monarch Initiative: MONDO:0030841
OMIM®: 619097

Definition

Mismatch repair cancer syndrome-3 (MMRCS3) is an autosomal recessive childhood cancer predisposition syndrome characterized by brain tumors, hematologic malignancy, and gastrointestinal tumors. Multiple cafe-au-lait spots, axillary freckling, and, rarely, Lisch nodules reminiscent of neurofibromatosis type I (NF1; 162200) may be present (Hegde et al., 2005, Ostergaard et al., 2005). Microsatellite instability may be detected in tumor samples (Hegde et al., 2005). For a discussion of genetic heterogeneity of mismatch repair cancer syndrome, see MMRCS1 (276300). [from OMIM]

Clinical features

From HPO
Lymphoma
MedGen UID:
44223
•Concept ID:
C0024299
•
Neoplastic Process
A cancer originating in lymphocytes and presenting as a solid tumor of lymhpoid cells.
See: Feature record | Search on this feature
T-cell lymphoma
MedGen UID:
86957
•Concept ID:
C0079772
•
Neoplastic Process
A type of lymphoma that originates in T-cells.
See: Feature record | Search on this feature
Colon cancer
MedGen UID:
2839
•Concept ID:
C0007102
•
Neoplastic Process
A primary or metastatic malignant neoplasm that affects the colon. Representative examples include carcinoma, lymphoma, and sarcoma.
See: Feature record | Search on this feature
Neoplasm of the rectum
MedGen UID:
11148
•Concept ID:
C0034885
•
Neoplastic Process
A benign or malignant neoplasm that affects the rectum. Representative examples of benign neoplasms include lipoma and leiomyoma. Representative examples of malignant neoplasms include carcinoma, lymphoma, and sarcoma. Rectal adenomas always exhibit epithelial dysplasia and are considered premalignant neoplasms.
See: Feature record | Search on this feature
Astrocytoma
MedGen UID:
438
•Concept ID:
C0004114
•
Neoplastic Process
Astrocytoma is a neoplasm of the central nervous system derived from astrocytes. Astrocytes are a type of glial cell, and thus astrocytoma is a subtype of glioma.
See: Feature record | Search on this feature
Glioblastoma multiforme
MedGen UID:
301585
•Concept ID:
C1621958
•
Neoplastic Process
A tumor arising from glia in the central nervous system with macroscopic regions of necrosis and hemorrhage. Microscopically, glioblastoma multiforme is characterized by regions of pseudopalisading necrosis, pleomorphic nuclei and cells, and microvascular proliferation.
See: Feature record | Search on this feature
Axillary freckling
MedGen UID:
348082
•Concept ID:
C1860335
•
Finding
The presence in the axillary region (armpit) of an increased number of freckles, small circular spots on the skin that are darker than the surrounding skin because of deposits of melanin.
See: Feature record | Search on this feature
Cafe au lait spots, multiple
MedGen UID:
396266
•Concept ID:
C1861975
•
Finding
The presence of six or more cafe-au-lait spots.
See: Feature record | Search on this feature
Lisch nodules
MedGen UID:
395461
•Concept ID:
C1860334
•
Finding
The presence of pigmented, oval and dome-shaped raised hamartomatous nevi of the iris..
See: Feature record | Search on this feature
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Professional guidelines

PubMed

Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment.
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM
Eur J Cancer 2022 Nov;175:136-157. Epub 2022 Sep 14 doi: 10.1016/j.ejca.2022.07.020. PMID: 36115290
Challenges in the diagnosis of neurofibromatosis type 1 (NF1) in young children facilitated by means of revised diagnostic criteria including genetic testing for pathogenic NF1 gene variants.
Kehrer-Sawatzki H, Cooper DN
Hum Genet 2022 Feb;141(2):177-191. Epub 2021 Dec 20 doi: 10.1007/s00439-021-02410-z. PMID: 34928431Free PMC Article
Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group.
Aronson M, Colas C, Shuen A, Hampel H, Foulkes WD, Baris Feldman H, Goldberg Y, Muleris M, Wolfe Schneider K, McGee RB, Jasperson K, Rangaswami A, Brugieres L, Tabori U
J Med Genet 2022 Apr;59(4):318-327. Epub 2021 Feb 23 doi: 10.1136/jmedgenet-2020-107627. PMID: 33622763

Recent clinical studies

Etiology

Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment.
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM
Eur J Cancer 2022 Nov;175:136-157. Epub 2022 Sep 14 doi: 10.1016/j.ejca.2022.07.020. PMID: 36115290
Immune checkpoint blockades in gynecological cancers: A review of clinical trials.
Peng H, He X, Wang Q
Acta Obstet Gynecol Scand 2022 Sep;101(9):941-951. Epub 2022 Jun 25 doi: 10.1111/aogs.14412. PMID: 35751489Free PMC Article
Diagnostic criteria for constitutional mismatch repair deficiency (CMMRD): recommendations from the international consensus working group.
Aronson M, Colas C, Shuen A, Hampel H, Foulkes WD, Baris Feldman H, Goldberg Y, Muleris M, Wolfe Schneider K, McGee RB, Jasperson K, Rangaswami A, Brugieres L, Tabori U
J Med Genet 2022 Apr;59(4):318-327. Epub 2021 Feb 23 doi: 10.1136/jmedgenet-2020-107627. PMID: 33622763
Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.
André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators
N Engl J Med 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699. PMID: 33264544
Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations.
Dinarvand P, Davaro EP, Doan JV, Ising ME, Evans NR, Phillips NJ, Lai J, Guzman MA
Arch Pathol Lab Med 2019 Nov;143(11):1382-1398. Epub 2019 May 9 doi: 10.5858/arpa.2018-0570-RA. PMID: 31070935

Diagnosis

Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment.
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM
Eur J Cancer 2022 Nov;175:136-157. Epub 2022 Sep 14 doi: 10.1016/j.ejca.2022.07.020. PMID: 36115290
Mismatch repair deficiency: The what, how and why it is important.
Olave MC, Graham RP
Genes Chromosomes Cancer 2022 Jun;61(6):314-321. Epub 2021 Dec 9 doi: 10.1002/gcc.23015. PMID: 34837268
Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations.
Dinarvand P, Davaro EP, Doan JV, Ising ME, Evans NR, Phillips NJ, Lai J, Guzman MA
Arch Pathol Lab Med 2019 Nov;143(11):1382-1398. Epub 2019 May 9 doi: 10.5858/arpa.2018-0570-RA. PMID: 31070935
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr
Science 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8 doi: 10.1126/science.aan6733. PMID: 28596308Free PMC Article
Practical guidance for mismatch repair-deficiency testing in endometrial cancer.
Stelloo E, Jansen AML, Osse EM, Nout RA, Creutzberg CL, Ruano D, Church DN, Morreau H, Smit VTHBM, van Wezel T, Bosse T
Ann Oncol 2017 Jan 1;28(1):96-102. doi: 10.1093/annonc/mdw542. PMID: 27742654

Therapy

γδ T cells are effectors of immunotherapy in cancers with HLA class I defects.
de Vries NL, van de Haar J, Veninga V, Chalabi M, Ijsselsteijn ME, van der Ploeg M, van den Bulk J, Ruano D, van den Berg JG, Haanen JB, Zeverijn LJ, Geurts BS, de Wit GF, Battaglia TW, Gelderblom H, Verheul HMW, Schumacher TN, Wessels LFA, Koning F, de Miranda NFCC, Voest EE
Nature 2023 Jan;613(7945):743-750. Epub 2023 Jan 11 doi: 10.1038/s41586-022-05593-1. PMID: 36631610Free PMC Article
Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment.
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM
Eur J Cancer 2022 Nov;175:136-157. Epub 2022 Sep 14 doi: 10.1016/j.ejca.2022.07.020. PMID: 36115290
Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.
André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators
N Engl J Med 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699. PMID: 33264544
Immunotherapy, Inflammation and Colorectal Cancer.
Lichtenstern CR, Ngu RK, Shalapour S, Karin M
Cells 2020 Mar 4;9(3) doi: 10.3390/cells9030618. PMID: 32143413Free PMC Article
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr
Science 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8 doi: 10.1126/science.aan6733. PMID: 28596308Free PMC Article

Prognosis

Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment.
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM
Eur J Cancer 2022 Nov;175:136-157. Epub 2022 Sep 14 doi: 10.1016/j.ejca.2022.07.020. PMID: 36115290
Mismatch repair deficiency: The what, how and why it is important.
Olave MC, Graham RP
Genes Chromosomes Cancer 2022 Jun;61(6):314-321. Epub 2021 Dec 9 doi: 10.1002/gcc.23015. PMID: 34837268
Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations.
Dinarvand P, Davaro EP, Doan JV, Ising ME, Evans NR, Phillips NJ, Lai J, Guzman MA
Arch Pathol Lab Med 2019 Nov;143(11):1382-1398. Epub 2019 May 9 doi: 10.5858/arpa.2018-0570-RA. PMID: 31070935
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr
Science 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8 doi: 10.1126/science.aan6733. PMID: 28596308Free PMC Article
Practical guidance for mismatch repair-deficiency testing in endometrial cancer.
Stelloo E, Jansen AML, Osse EM, Nout RA, Creutzberg CL, Ruano D, Church DN, Morreau H, Smit VTHBM, van Wezel T, Bosse T
Ann Oncol 2017 Jan 1;28(1):96-102. doi: 10.1093/annonc/mdw542. PMID: 27742654

Clinical prediction guides

γδ T cells are effectors of immunotherapy in cancers with HLA class I defects.
de Vries NL, van de Haar J, Veninga V, Chalabi M, Ijsselsteijn ME, van der Ploeg M, van den Bulk J, Ruano D, van den Berg JG, Haanen JB, Zeverijn LJ, Geurts BS, de Wit GF, Battaglia TW, Gelderblom H, Verheul HMW, Schumacher TN, Wessels LFA, Koning F, de Miranda NFCC, Voest EE
Nature 2023 Jan;613(7945):743-750. Epub 2023 Jan 11 doi: 10.1038/s41586-022-05593-1. PMID: 36631610Free PMC Article
Deficient mismatch repair/microsatellite unstable colorectal cancer: Diagnosis, prognosis and treatment.
Taieb J, Svrcek M, Cohen R, Basile D, Tougeron D, Phelip JM
Eur J Cancer 2022 Nov;175:136-157. Epub 2022 Sep 14 doi: 10.1016/j.ejca.2022.07.020. PMID: 36115290
Mismatch repair deficiency: The what, how and why it is important.
Olave MC, Graham RP
Genes Chromosomes Cancer 2022 Jun;61(6):314-321. Epub 2021 Dec 9 doi: 10.1002/gcc.23015. PMID: 34837268
Pembrolizumab in Microsatellite-Instability-High Advanced Colorectal Cancer.
André T, Shiu KK, Kim TW, Jensen BV, Jensen LH, Punt C, Smith D, Garcia-Carbonero R, Benavides M, Gibbs P, de la Fouchardiere C, Rivera F, Elez E, Bendell J, Le DT, Yoshino T, Van Cutsem E, Yang P, Farooqui MZH, Marinello P, Diaz LA Jr; KEYNOTE-177 Investigators
N Engl J Med 2020 Dec 3;383(23):2207-2218. doi: 10.1056/NEJMoa2017699. PMID: 33264544
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Le DT, Durham JN, Smith KN, Wang H, Bartlett BR, Aulakh LK, Lu S, Kemberling H, Wilt C, Luber BS, Wong F, Azad NS, Rucki AA, Laheru D, Donehower R, Zaheer A, Fisher GA, Crocenzi TS, Lee JJ, Greten TF, Duffy AG, Ciombor KK, Eyring AD, Lam BH, Joe A, Kang SP, Holdhoff M, Danilova L, Cope L, Meyer C, Zhou S, Goldberg RM, Armstrong DK, Bever KM, Fader AN, Taube J, Housseau F, Spetzler D, Xiao N, Pardoll DM, Papadopoulos N, Kinzler KW, Eshleman JR, Vogelstein B, Anders RA, Diaz LA Jr
Science 2017 Jul 28;357(6349):409-413. Epub 2017 Jun 8 doi: 10.1126/science.aan6733. PMID: 28596308Free PMC Article

Recent systematic reviews

Outcome of Patients With Early-Stage Mismatch Repair Deficient Colorectal Cancer Receiving Neoadjuvant Immunotherapy: A Systematic Review.
Chakrabarti S, Grewal US, Vora KB, Parikh AR, Almader-Douglas D, Mahipal A, Sonbol MBB
JCO Precis Oncol 2023 Aug;7:e2300182. doi: 10.1200/PO.23.00182. PMID: 37595183
Mismatch-repair deficiency, microsatellite instability, and lynch syndrome in ovarian cancer: A systematic review and meta-analysis.
Mitric C, Salman L, Abrahamyan L, Kim SR, Pechlivanoglou P, Chan KKW, Gien LT, Ferguson SE
Gynecol Oncol 2023 Mar;170:133-142. Epub 2023 Jan 20 doi: 10.1016/j.ygyno.2022.12.008. PMID: 36682091
Unexplained mismatch repair deficiency: Case closed.
Eikenboom EL, Moen S, van Leeuwen L, Geurts-Giele WRR, Tops CMJ, van Ham TJ, Dinjens WNM, Dubbink HJ, Spaander MCW, Wagner A
HGG Adv 2023 Jan 12;4(1):100167. Epub 2022 Dec 14 doi: 10.1016/j.xhgg.2022.100167. PMID: 36624813Free PMC Article
The prevalence of mismatch repair deficiency in ovarian cancer: A systematic review and meta-analysis.
Atwal A, Snowsill T, Dandy MC, Krum T, Newton C, Evans DG, Crosbie EJ, Ryan NAJ
Int J Cancer 2022 Nov 1;151(9):1626-1639. Epub 2022 Jul 6 doi: 10.1002/ijc.34165. PMID: 35792468Free PMC Article
Adjuvant Therapy for Stage II Colon Cancer: ASCO Guideline Update.
Baxter NN, Kennedy EB, Bergsland E, Berlin J, George TJ, Gill S, Gold PJ, Hantel A, Jones L, Lieu C, Mahmoud N, Morris AM, Ruiz-Garcia E, You YN, Meyerhardt JA
J Clin Oncol 2022 Mar 10;40(8):892-910. Epub 2021 Dec 22 doi: 10.1200/JCO.21.02538. PMID: 34936379

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