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Lynch syndrome 4(LYNCH4)

MedGen UID:
325005
Concept ID:
C1838333
Disease or Syndrome
Synonyms: Colorectal cancer, hereditary nonpolyposis, type 4; Hereditary non-polyposis colorectal cancer, type 4; LYNCH4
 
Gene (location): PMS2 (7p22.1)
 
Monarch Initiative: MONDO:0013699
OMIM®: 614337

Definition

Lynch syndrome-4 (LYNCH4), or hereditary nonpolyposis colorectal cancer type 4 (HNPCC4), is an autosomal dominant disorder characterized primarily by the development of early-onset colorectal cancer. It is associated with the development of a variety of epithelial tumors that include endometrial cancer, stomach cancer, and ovarian cancer (summary by Thompson et al., 2004). [from OMIM]

Additional description

From MedlinePlus Genetics
People with Lynch syndrome may occasionally have noncancerous (benign) growths in the colon, called colon polyps. In individuals with this disorder, colon polyps occur at a younger age but not in greater numbers than they do in the general population.

Lynch syndrome, often called hereditary nonpolyposis colorectal cancer (HNPCC), is an inherited disorder that increases the risk of many types of cancer, particularly cancers of the colon (large intestine) and rectum, which are collectively referred to as colorectal cancer. People with Lynch syndrome also have an increased risk of cancers of the stomach, small intestine, liver, gallbladder ducts, urinary tract, brain, and skin. Additionally, women with this disorder have a high risk of cancer of the ovaries and lining of the uterus (endometrial cancer). Women with Lynch syndrome have a higher overall risk of developing cancer than men with the condition because of these cancers of the female reproductive system. In individuals with Lynch syndrome who develop cancer, the cancer typically occurs in their forties or fifties.  https://medlineplus.gov/genetics/condition/lynch-syndrome

Clinical features

From HPO
Ovarian neoplasm
MedGen UID:
181539
Concept ID:
C0919267
Neoplastic Process
A tumor (abnormal growth of tissue) of the ovary.
Endometrial carcinoma
MedGen UID:
96903
Concept ID:
C0476089
Neoplastic Process
A carcinoma of the endometrium, the mucous lining of the uterus.
Hereditary nonpolyposis colorectal carcinoma
MedGen UID:
870541
Concept ID:
C4024989
Neoplastic Process

Professional guidelines

PubMed

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
Ballester V, Cruz-Correa M
Gastroenterology 2018 Oct;155(4):955-959. Epub 2018 Aug 24 doi: 10.1053/j.gastro.2018.08.031. PMID: 30148981
Kurland G, Deterding RR, Hagood JS, Young LR, Brody AS, Castile RG, Dell S, Fan LL, Hamvas A, Hilman BC, Langston C, Nogee LM, Redding GJ; American Thoracic Society Committee on Childhood Interstitial Lung Disease (chILD) and the chILD Research Network
Am J Respir Crit Care Med 2013 Aug 1;188(3):376-94. doi: 10.1164/rccm.201305-0923ST. PMID: 23905526Free PMC Article

Curated

UK NICE Guideline NG151, Colorectal cancer, 2021

UK NICE Diagnostics Guidance DG42, Testing strategies for Lynch syndrome in people with endometrial cancer, 2020

American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, MLH1, MSH2, MSH6, PMS2, EPCAM Pathogenic Variants, Lynch Syndrome (Hereditary Non-polyposis Colon Cancer [HNPCC]), 2019

Recent clinical studies

Etiology

González Peña T, Huang M
Clin Obstet Gynecol 2024 Dec 1;67(4):660-665. Epub 2024 Oct 7 doi: 10.1097/GRF.0000000000000894. PMID: 39371029
Maratt JK, Stoffel E
Gastrointest Endosc Clin N Am 2022 Jan;32(1):45-58. doi: 10.1016/j.giec.2021.09.002. PMID: 34798986
Bateman AC
J Clin Pathol 2021 Apr;74(4):264-268. Epub 2021 Feb 17 doi: 10.1136/jclinpath-2020-207281. PMID: 33597222
Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, Middha S, Hechtman J, Zehir A, Dubard-Gault M, Tran C, Stewart C, Sheehan M, Penson A, DeLair D, Yaeger R, Vijai J, Mukherjee S, Galle J, Dickson MA, Janjigian Y, O'Reilly EM, Segal N, Saltz LB, Reidy-Lagunes D, Varghese AM, Bajorin D, Carlo MI, Cadoo K, Walsh MF, Weiser M, Aguilar JG, Klimstra DS, Diaz LA Jr, Baselga J, Zhang L, Ladanyi M, Hyman DM, Solit DB, Robson ME, Taylor BS, Offit K, Berger MF, Stadler ZK
J Clin Oncol 2019 Feb 1;37(4):286-295. Epub 2018 Oct 30 doi: 10.1200/JCO.18.00283. PMID: 30376427Free PMC Article
Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S
Gastroenterology 2015 Sep;149(3):604-13.e20. Epub 2015 May 14 doi: 10.1053/j.gastro.2015.05.006. PMID: 25980754Free PMC Article

Diagnosis

González Peña T, Huang M
Clin Obstet Gynecol 2024 Dec 1;67(4):660-665. Epub 2024 Oct 7 doi: 10.1097/GRF.0000000000000894. PMID: 39371029
Maratt JK, Stoffel E
Gastrointest Endosc Clin N Am 2022 Jan;32(1):45-58. doi: 10.1016/j.giec.2021.09.002. PMID: 34798986
Wang Q, Leclerc J, Bougeard G, Olschwang S, Vasseur S, Cassinari K, Boidin D, Lefol C, Naïbo P, Frébourg T, Buisine MP, Baert-Desurmont S; French Consortium of Oncogenetic laboratories for colorectal cancers, Unicancer Cancer Genetic Group (GGC)
J Med Genet 2020 Jul;57(7):487-499. Epub 2020 Jan 28 doi: 10.1136/jmedgenet-2019-106256. PMID: 31992580
Shiraliyeva N, Friedrichs J, Buettner R, Friedrichs N
Pathol Res Pract 2017 Dec;213(12):1552-1555. Epub 2017 Sep 18 doi: 10.1016/j.prp.2017.09.012. PMID: 29033182
Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S
Gastroenterology 2015 Sep;149(3):604-13.e20. Epub 2015 May 14 doi: 10.1053/j.gastro.2015.05.006. PMID: 25980754Free PMC Article

Therapy

Crowther CA, Ashwood P, Middleton PF, McPhee A, Tran T, Harding JE; MAGENTA Study Group
JAMA 2023 Aug 15;330(7):603-614. doi: 10.1001/jama.2023.12357. PMID: 37581672Free PMC Article
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
Li SKH, Martin A
Trends Mol Med 2016 Apr;22(4):274-289. Epub 2016 Mar 9 doi: 10.1016/j.molmed.2016.02.003. PMID: 26970951
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group
JAMA 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291. PMID: 26903337
INSIGHT START Study Group, Lundgren JD, Babiker AG, Gordin F, Emery S, Grund B, Sharma S, Avihingsanon A, Cooper DA, Fätkenheuer G, Llibre JM, Molina JM, Munderi P, Schechter M, Wood R, Klingman KL, Collins S, Lane HC, Phillips AN, Neaton JD
N Engl J Med 2015 Aug 27;373(9):795-807. Epub 2015 Jul 20 doi: 10.1056/NEJMoa1506816. PMID: 26192873Free PMC Article

Prognosis

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
Maratt JK, Stoffel E
Gastrointest Endosc Clin N Am 2022 Jan;32(1):45-58. doi: 10.1016/j.giec.2021.09.002. PMID: 34798986
Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Thomas H, Evans DG, Burn J, Greenblatt M, Hovig E, de Vos Tot Nederveen Cappel WH, Sijmons RH, Bertario L, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Köstner F, Gluck N, Katz LH, Heinimann K, Vaccaro CA, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, Knebel Doeberitz MV, Loeffler M, Rahner N, Schackert HK, Steinke-Lange V, Schmiegel W, Vangala D, Pylvänäinen K, Renkonen-Sinisalo L, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Wadt K, Therkildsen C, Okkels H, Ketabi Z, Moreira L, Sánchez A, Serra-Burriel M, Pineda M, Navarro M, Blanco I, Green K, Lalloo F, Crosbie EJ, Hill J, Denton OG, Frayling IM, Rødland EA, Vasen H, Mints M, Neffa F, Esperon P, Alvarez K, Kariv R, Rosner G, Pinero TA, Gonzalez ML, Kalfayan P, Tjandra D, Winship IM, Macrae F, Möslein G, Mecklin JP, Nielsen M, Møller P
Genet Med 2020 Jan;22(1):15-25. Epub 2019 Jul 24 doi: 10.1038/s41436-019-0596-9. PMID: 31337882Free PMC Article
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, Gattinoni L, van Haren F, Larsson A, McAuley DF, Ranieri M, Rubenfeld G, Thompson BT, Wrigge H, Slutsky AS, Pesenti A; LUNG SAFE Investigators; ESICM Trials Group
JAMA 2016 Feb 23;315(8):788-800. doi: 10.1001/jama.2016.0291. PMID: 26903337
Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S
Gastroenterology 2015 Sep;149(3):604-13.e20. Epub 2015 May 14 doi: 10.1053/j.gastro.2015.05.006. PMID: 25980754Free PMC Article

Clinical prediction guides

Maratt JK, Stoffel E
Gastrointest Endosc Clin N Am 2022 Jan;32(1):45-58. doi: 10.1016/j.giec.2021.09.002. PMID: 34798986
Dominguez-Valentin M, Sampson JR, Seppälä TT, Ten Broeke SW, Plazzer JP, Nakken S, Engel C, Aretz S, Jenkins MA, Sunde L, Bernstein I, Capella G, Balaguer F, Thomas H, Evans DG, Burn J, Greenblatt M, Hovig E, de Vos Tot Nederveen Cappel WH, Sijmons RH, Bertario L, Tibiletti MG, Cavestro GM, Lindblom A, Della Valle A, Lopez-Köstner F, Gluck N, Katz LH, Heinimann K, Vaccaro CA, Büttner R, Görgens H, Holinski-Feder E, Morak M, Holzapfel S, Hüneburg R, Knebel Doeberitz MV, Loeffler M, Rahner N, Schackert HK, Steinke-Lange V, Schmiegel W, Vangala D, Pylvänäinen K, Renkonen-Sinisalo L, Hopper JL, Win AK, Haile RW, Lindor NM, Gallinger S, Le Marchand L, Newcomb PA, Figueiredo JC, Thibodeau SN, Wadt K, Therkildsen C, Okkels H, Ketabi Z, Moreira L, Sánchez A, Serra-Burriel M, Pineda M, Navarro M, Blanco I, Green K, Lalloo F, Crosbie EJ, Hill J, Denton OG, Frayling IM, Rødland EA, Vasen H, Mints M, Neffa F, Esperon P, Alvarez K, Kariv R, Rosner G, Pinero TA, Gonzalez ML, Kalfayan P, Tjandra D, Winship IM, Macrae F, Möslein G, Mecklin JP, Nielsen M, Møller P
Genet Med 2020 Jan;22(1):15-25. Epub 2019 Jul 24 doi: 10.1038/s41436-019-0596-9. PMID: 31337882Free PMC Article
Latham A, Srinivasan P, Kemel Y, Shia J, Bandlamudi C, Mandelker D, Middha S, Hechtman J, Zehir A, Dubard-Gault M, Tran C, Stewart C, Sheehan M, Penson A, DeLair D, Yaeger R, Vijai J, Mukherjee S, Galle J, Dickson MA, Janjigian Y, O'Reilly EM, Segal N, Saltz LB, Reidy-Lagunes D, Varghese AM, Bajorin D, Carlo MI, Cadoo K, Walsh MF, Weiser M, Aguilar JG, Klimstra DS, Diaz LA Jr, Baselga J, Zhang L, Ladanyi M, Hyman DM, Solit DB, Robson ME, Taylor BS, Offit K, Berger MF, Stadler ZK
J Clin Oncol 2019 Feb 1;37(4):286-295. Epub 2018 Oct 30 doi: 10.1200/JCO.18.00283. PMID: 30376427Free PMC Article
Shiraliyeva N, Friedrichs J, Buettner R, Friedrichs N
Pathol Res Pract 2017 Dec;213(12):1552-1555. Epub 2017 Sep 18 doi: 10.1016/j.prp.2017.09.012. PMID: 29033182
Yurgelun MB, Allen B, Kaldate RR, Bowles KR, Judkins T, Kaushik P, Roa BB, Wenstrup RJ, Hartman AR, Syngal S
Gastroenterology 2015 Sep;149(3):604-13.e20. Epub 2015 May 14 doi: 10.1053/j.gastro.2015.05.006. PMID: 25980754Free PMC Article

Recent systematic reviews

Lyons S, Trépel D, Lynch T, Walsh R, O'Dowd S
J Neurol 2023 Sep;270(9):4451-4465. Epub 2023 Jun 8 doi: 10.1007/s00415-023-11791-2. PMID: 37289323Free PMC Article
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
Rasmussen M, Madsen MG, Therkildsen C
Urology 2022 Jul;165:44-53. Epub 2022 Feb 22 doi: 10.1016/j.urology.2022.02.006. PMID: 35217028
Anele CC, Adegbola SO, Askari A, Rajendran A, Clark SK, Latchford A, Faiz OD
Colorectal Dis 2017 Jun;19(6):528-536. doi: 10.1111/codi.13679. PMID: 28407411
Sharaf RN, Myer P, Stave CD, Diamond LC, Ladabaum U
Clin Gastroenterol Hepatol 2013 Sep;11(9):1093-100. Epub 2013 May 10 doi: 10.1016/j.cgh.2013.04.044. PMID: 23669308

Supplemental Content

Table of contents

    Clinical resources

    Practice guidelines

    • PubMed
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    • Bookshelf
      See practice and clinical guidelines in NCBI Bookshelf. The search results may include broader topics and may not capture all published guidelines. See the FAQ for details.

    Curated

    • NICE, 2021
      UK NICE Guideline NG151, Colorectal cancer, 2021
    • NICE, 2020
      UK NICE Diagnostics Guidance DG42, Testing strategies for Lynch syndrome in people with endometrial cancer, 2020
    • ACMG ACT, 2019
      American College of Medical Genetics and Genomics, Genomic Testing (Secondary Findings) ACT Sheet, MLH1, MSH2, MSH6, PMS2, EPCAM Pathogenic Variants, Lynch Syndrome (Hereditary Non-polyposis Colon Cancer [HNPCC]), 2019

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