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familial nonpolyposis colon cancer; hereditary nonpolyposis colorectal cancer (HNPCC); Lynch syndrome; cancer family syndrome

Hereditary nonpolyposis colon cancer (HNPCC) is one of the most common inherited cancer susceptibility syndromes. Diagnostic criteria: 3-2-1 rule 3) three or more relatives with colorectal carcinoma; one affected patient is 1st degree relative of another affected patient 2) two generations of the family with colorectal carcinoma 1) one case of colorectal carcinoma diagnosed in a patient < 50 years of age 5) familial adenomatous polyposis excluded 6) tumors verified by histopathology Epidemiology: 1) from 3-15% of sporadic colon cancers in western nations have been attributed to HNPCC 2) the exact frequency of HPNCC mutations is not known 3) most common hereditary colorectal cancer syndrome - prevalence is 1 in 440 [2] 4) of 65 cases of Lynch syndrome, 58 identified < 70 years old [17] Pathology: 1) colon tumors are the most common types of tumors seen in HNPCC families - colon cancer occurs in 50-80% of patients with Lynch syndrome by age 44 [2] - colon cancer occurs at unusually high frequency in the proximal colon (predominance of right-sided colon cancer) [15] - generally larger but less aggressive cancers than seen in adenomatous polyposis coli 2) poor differentiation, may include mucinous features, infiltrating lymphocytes 3) 35-40% of family members develop other types of tumors; - endometrial cancer & ovarian camcer are the most common - lifetime risk of endometrial cancer is 40-60%, with a median age at onset of 48 years - also gastric cancer, small intestinal cancer, pancreatic cancer, liver cancer, biliary cancer, brain tumor, & upper urinary tract cancer (urothelial carcinoma) 4) tumors from patients with HNPCC show microsatellite instability which results from a failure to repair insertion/deletion mispairs - response to neoantigens generated by a high mutational burden 5) colon polyps much less common than in familial adenomatous polyposis Genetics: 1) autosomal dominant with high penetrance 2) four different genes have been identified (including genes on chromosomes 2 & 3; all participate in mismatch DNA repair a) MSH2 (31%) (type 1) b) MLH1 (33%) (type 2) c) PMS1 (2%) (type 3) d) PMS2 (4%) (type 4) e) MSH6 (type 5) f) TGFBR2 (type 6) g) MLH3 (type 7) 3) germline deletion in EpCAM leading to epigenetic inactivation of MSH2 [15] History: - family history of colon cancer (3-2-1 rule) [2] - 3 affected family members - 2 generations affected - 1 under age 50 years Laboratory: 1) HNPCC gene mutations after genetic counseling - genotyping is NOT yet clinically useful 2) urine cytology 3) see ARUP consult [5] Special laboratory: 1) surveillance colonoscopy every 1-3 years (1-2 years) [9] a) begin at age 25 or 2-5 years prior to the earliest age of colon cancer diagnosis in the family b) for carriers of MSH6, surveillance colonoscopy every 1-2 years beginning at age 30 [15] c) for carriers of PSM2, surveillance colonoscopy every 1-2 years beginning at age 35 [15] d) tumors frequently occur in the proximal colon making sigmoidoscopy of limited usefulness 2) upper GI endoscopy (genetically-confirmed Lynch syndrome) [2] 3) capsule endoscopy not recommended [2] 4) transvasginal ultrasound Radiology: - CT urography for post-glomerular hematuria (without pyuria, bacteriuria) Differential diagnosis: - adenomatous polyposis coli Management: 1) genetic counseling [20] (NEJM) 2) aspirin 600 mg QD - lifelong therapy [9] - for at least 2 years decreases the incidence of colorectal cancer after 4 years in carriers of Lynch syndrome [4,18] 3) exercise reduces cancer risk [21] - decreases inflammatory markers (prostaglandin E2) in colon & blood - increases colonic mucosa natural killer cells & CD8+ T cells [21]

Related

DNA mismatch repair; post-replication repair; DNA loop repair HNPCC gene mutations; mismatch repair mutations intestinal polyposis syndrome microsatellite or variable number of tandem repeat (VNTR) MLH1 gene MSH2 gene PMS1 gene PMS2 gene

Specific

familial nonpolyposis colon cancer type 1 (Lynch-1 syndrome) familial nonpolyposis colon cancer type 2 (Lynch-2 syndrome) familial nonpolyposis colon cancer type 3 familial nonpolyposis colon cancer type 4 familial nonpolyposis colon cancer type 5 familial nonpolyposis colon cancer type 6 familial nonpolyposis colon cancer type 7 hereditary ovarian cancer syndrome Muir-Torre syndrome

General

hereditary colon cancer syndrome

Figures/Diagrams

Human Disorders of DNA Repair

Properties

ASSOCIATED-NEOPLASM[S]: adenocarcinoma of the colon

References

  1. Kolodner RD. Mismatch repair: mechanisms and relationship to cancer susceptibility. Trends Biochem Sci. 1995 Oct;20(10):397-401. Review. PMID: 8533151
  2. Medical Knowledge Self Assessment Program (MKSAP) 11, 15, 16, 17, 18. American College of Physicians, Philadelphia 1998, 2009, 2012, 2015, 2018.
  3. Harrison's Principles of Internal Medicine, 14th ed. Fauci et al (eds), McGraw-Hill Inc. NY, 1998, pg 514
  4. Burn J et al Long-term effect of aspirin on cancer risk in carriers of hereditary colorectal cancer: an analysis from the CAPP2 randomised controlled trial. Lancet. 2011 Oct 27 PMID: 22036019
  5. ARUP Consult: Lynch Syndrome - Hereditary Nonpolyposis Colorectal Cancer (HNPCC) The Physician's Guide to Laboratory Test Selection & Interpretation https://www.arupconsult.com/content/lynch-syndrome - ARUP Consult (Algorithm) Lynch Syndrome (HNPCC) Testing Algorithm https://arupconsult.com/algorithm/lynch-syndrome-hnpcc-testing-algorithm - ARUP Consult: Lynch Syndrome/Hereditary Nonpolyposis Colorectal Cancer https://arupconsult.com/ati/lynch-syndrome - ARUP consult: Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome. https://arupconsult.com/ati/Hereditary-Gastrointestinal-Cancer-Panel
  6. Goodenberger M, Lindor NM. Lynch syndrome and MYH-associated polyposis: review and testing strategy. J Clin Gastroenterol. 2011 Jul;45(6):488-500 PMID: 21325953
  7. Umar A, Boland CR, Terdiman JP et al Revised Bethesda Guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004 Feb 18;96(4):261-8. PMID: 14970275
  8. Vasen HF, Watson P, Mecklin JP, Lynch HT. New clinical criteria for hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome) proposed by the International Collaborative group on HNPCC. Gastroenterology. 1999 Jun;116(6):1453-6. PMID: 10348829
  9. Rubenstein JH et al American Gastroenterological Association Institute Guideline on the Diagnosis and Management of Lynch Syndrome. Gastroenterology. July 28, 2015 PMID: 26226577 http://www.gastrojournal.org/article/S0016-5085%2815%2901031-8/fulltext
  10. Koornstra JJ, Mourits MJ, Sijmons RH et al Management of extracolonic tumours in patients with Lynch syndrome. Lancet Oncol. 2009 Apr;10(4):400-8 PMID: 19341971
  11. Dana-Farber Cancer Institute Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) PREMM1,2,6 Model: Prediction Model for MLH1, MSH2, and MSH6 Gene Mutations. http://premm.dfci.harvard.edu
  12. Giardiello FM, Allen JI, Axilbund JE et al Guidelines on genetic evaluation and management of Lynch syndrome: a consensus statement by the US Multi- Society Task Force on colorectal cancer. Gastroenterology. 2014 Aug;147(2):502-26. PMID: 25043945
  13. Hegde M, Ferber M, Mao R et al ACMG technical standards and guidelines for genetic testing for inherited colorectal cancer (Lynch syndrome, familial adenomatous polyposis, and MYH-associated polyposis). Genet Med. 2014 Jan;16(1):101-16. PMID: 24310308
  14. Lynch HT, de la Chapelle A Hereditary Colorectal Cancer. N Engl J Med 2003; 348:919-932. March 6, 2003 PMID: 12621137 http://www.nejm.org/doi/full/10.1056/NEJMra012242
  15. Rothaus C Lynch Syndrome-Associated Colorectal Cancer. NEJM Resident 360. Aug 22, 2018 https://resident360.nejm.org/content_items/lynch-syndrome-associated-colorectal-cancer
  16. Silva FC, Valentin MD, Ferreira Fde O, Carraro DM, Rossi BM. Mismatch repair genes in Lynch syndrome: a review. Sao Paulo Med J. 2009 Jan;127(1):46-51. Review. PMID: 19466295 Free Article
  17. Li D, Hoodfar E, Jiang SF et al. Comparison of universal versus age-restricted screening of colorectal tumors for Lynch syndrome using mismatch repair immunohistochemistry: A cohort study. Ann Intern Med 2019 Jun 11; PMID: 31181578
  18. Burn J et al. Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study: A double-blind, randomised, placebo-controlled trial. Lancet 2020 Jun 13; 395:1855. PMID: 32534647 PMCID: PMC7294238 Free PMC article https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)30366-4/fulltext
  19. NEJM Knowledge+ Nephrology/Urology
  20. Sinicrope FA. Lynch syndrome-associated colorectal cancer. N Engl J Med. 2018;379:764-773. PMID: 30134129
  21. Deng N, Reyes-Uribe L, Fahrmann JF et al Exercise Training Reduces the Inflammatory Response and Promotes Intestinal Mucosa-Associated Immunity in Lynch Syndrome. Clin Cancer Res 2023 Sep 19. PMID: 37724990