Lynch syndrome in the hands of pathologists
Authors:
Ondřej Daum 1; Zdeněk Beneš 2; Ladislav Hadravský 1; Jan Stehlík 3; Kateřina Černá 3; Martin Dušek 1,3; Bohuslava Kokošková 1; Michal Michal 1,3
Authors‘ workplace:
Šiklův ústav patologie LF UK a FN Plzeň
1; Interní oddělení Fakultní Thomayerovy nemocnice, Praha
2; Bioptická laboratoř, s. r. o., Plzeň
3
Published in:
Čes.-slov. Patol., 50, 2014, No. 1, p. 18-24
Category:
Reviews Article
Overview
Lynch syndrome (formerly hereditary non-polyposis colorectal cancer) is the most common familial colorectal cancer syndrome with a known molecular genetic background. The syndrome is caused by a germline mutation of one of the genes encoding mismatch repair (MMR) proteins that are responsible for DNA replication errors repair. Impaired function of these proteins leads to microsatellite instability (MSI) and forms a suitable background for the development and progression of tumors, mainly colorectal cancer. Traditionally, Lynch syndrome was regarded to be responsible for 2 % of all cases of colorectal cancer, however recent estimates reach even 5 %. Due to this relatively high frequency, familial occurence, the absence of the premorbid phenotype and the development of malignant tumors during the productive years of life, the correct diagnosis becomes not only a medical, but also a socioeconomical problem. Unfortunately, clinical means of diagnostics of Lynch syndrome (like the Amsterdam criteria and Bethesda guidelines) lack sensitivity. It was shown that predictive models based on histological signs of MSI are more sensitive than the clinical criteria used to detect patients suspicious of Lynch syndrome. Of all MSI-H colorectal cancers, 1/5 is caused by Lynch syndrome, the rest being only sporadic cancers caused by epigenetic inactivation of a MMR protein. To rule out the sporadic cases, molecular genetic investigation of the BRAF gene and methylation analysis of MLH1 is used in the diagnostic workup of Lynch syndrome. The suspicion of Lynch syndrome, based on the results of the assortment of diagnostic methods mentioned above, should be proven by detection of a germline mutation of an MMR gene in peripheral blood, and followed by screening of family members, which is a necessary condition for efficient prevention.
Keywords:
colorectal cancer – Lynch syndrome – HNPCC – MSI – microsatellite instability
Sources
1. Kacerovská D, Kazakov DV, Černá K, et al. Muir-Torre syndrom - fenotypická varianta Lynchova syndromu. Cesk Patol 2010; 46(4): 86-94.
2. Warthin AS. Heredity with reference to carcinoma: as shown by the study of the cases examined in the pathological laboratory of the University of Michigan, 1895-1913. Arch Intern Med 1913; 12(5): 546-555.
3. Lynch HT, Shaw MW, Magnuson CW, Larsen AL, Krush AJ. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch Intern Med 1966; 117(2): 206-212.
4. Lynch HT, Krush AJ. Cancer family “G” revisited: 1895-1970. Cancer 1971; 27(6): 1505-1511.
5. Lynch HT, Drouhard TJ, Schuelke GS, et al. Hereditary nonpolyposis colorectal cancer in a Navajo Indian family. Cancer Genet Cytogenet 1985; 15(3-4): 209-213.
6. Boland CR, Troncale FJ. Familial colonic cancer without antecedent polyposis. Ann Intern Med 1984; 100(5): 700-701.
7. Lindor NM, Rabe K, Petersen GM, et al. Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency: familial colorectal cancer type X. JAMA 2005; 293(16): 1979-1985.
8. Fishel R, Lescoe MK, Rao MR, et al. The human mutator gene homolog MSH2 and its association with hereditary nonpolyposis colon cancer. Cell 1993; 75(5): 1027-1038.
9. Leach FS, Nicolaides NC, Papadopoulos N, et al. Mutations of a mutS homolog in hereditary nonpolyposis colorectal cancer. Cell 1993; 75(6): 1215-1225.
10. Peltomaki P, Lothe RA, Aaltonen LA, et al. Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 1993; 53(24): 5853-5855.
11. Thibodeau SN, Bren G, Schaid D. Microsatellite instability in cancer of the proximal colon. Science 1993; 260(5109): 816-819.
12. Boland CR, Thibodeau SN, Hamilton SR, et al. A National Cancer Institute Workshop on Microsatellite Instability for cancer detection and familial predisposition: development of international criteria for the determination of microsatellite instability in colorectal cancer. Cancer Res 1998; 58(22): 5248-5257.
13. Yuen ST, Chan TL, Ho JW, et al. Germline, somatic and epigenetic events underlying mismatch repair deficiency in colorectal and HNPCC-related cancers. Oncogene 2002; 21(49): 7585-7592.
14. Nystrom-Lahti M, Wu Y, Moisio AL, et al. DNA mismatch repair gene mutations in 55 kindreds with verified or putative hereditary non-polyposis colorectal cancer. Hum Mol Genet 1996; 5(6): 763-769.
15. Wijnen J, van der Klift H, Vasen H, et al. MSH2 genomic deletions are a frequent cause of HNPCC. Nat Genet 1998; 20(4): 326-328.
16. Gazzoli I, Loda M, Garber J, Syngal S, Kolodner RD. A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor. Cancer Res 2002; 62(14): 3925-3928.
17. Hitchins MP, Wong JJ, Suthers G, et al. Inheritance of a cancer-associated MLH1 germ-line epimutation. N Engl J Med 2007; 356(7): 697-705.
18. Ligtenberg MJ, Kuiper RP, Chan TL, et al. Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3’ exons of TACSTD1. Nat Genet 2009; 41(1): 112-117.
19. Kovacs ME, Papp J, Szentirmay Z, Otto S, Olah E. Deletions removing the last exon of TACSTD1 constitute a distinct class of mutations predisposing to Lynch syndrome. Hum Mutat 2009; 30(2): 197-203.
20. Kruse R, Rutten A, Hosseiny-Malayeri HR, et al. “Second hit” in sebaceous tumors from Muir-Torre patients with germline mutations in MSH2: allele loss is not the preferred mode of inactivation. J Invest Dermatol 2001; 116(3): 463-465.
21. Gallinger S, Aronson M, Shayan K, et al. Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation. Gastroenterology 2004; 126(2): 576-585.
22. Bandipalliam P. Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam Cancer 2005; 4(4): 323-333.
23. Kastrinos F, Stoffel EM, Balmana J, et al. Phenotype comparison of MLH1 and MSH2 mutation carriers in a cohort of 1,914 individuals undergoing clinical genetic testing in the United States. Cancer Epidemiol Biomarkers Prev 2008; 17(8): 2044-2051.
24. Hampel H, Frankel W, Panescu J, et al. Screening for Lynch syndrome (hereditary nonpolyposis colorectal cancer) among endometrial cancer patients. Cancer Res 2006; 66(15): 7810-7817.
25. Berends MJ, Wu Y, Sijmons RH, et al. Molecular and clinical characteristics of MSH6 variants: an analysis of 25 index carriers of a germline variant. Am J Hum Genet 2002; 70(1): 26-37.
26. Nakagawa H, Lockman JC, Frankel WL, et al. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res 2004; 64(14): 4721-4727.
27. Hendriks YM, Jagmohan-Changur S, van der Klift HM, et al. Heterozygous mutations in PMS2 cause hereditary nonpolyposis colorectal carcinoma (Lynch syndrome). Gastroenterology 2006; 130(2): 312-322.
28. Truninger K, Menigatti M, Luz J, et al. Immunohistochemical analysis reveals high frequency of PMS2 defects in colorectal cancer. Gastroenterology 2005; 128(5): 1160-1171.
29. Mathiak M, Rutten A, Mangold E, et al. Loss of DNA mismatch repair proteins in skin tumors from patients with Muir-Torre syndrome and MSH2 or MLH1 germline mutations: establishment of immunohistochemical analysis as a screening test. Am J Surg Pathol 2002; 26(3): 338-343.
30. Mangold E, Pagenstecher C, Leister M, et al. A genotype-phenotype correlation in HNPCC: strong predominance of msh2 mutations in 41 patients with Muir-Torre syndrome. J Med Genet 2004; 41(7): 567-572.
31. De Rosa M, Fasano C, Panariello L, et al. Evidence for a recessive inheritance of Turcot’s syndrome caused by compound heterozygous mutations within the PMS2 gene. Oncogene 2000; 19(13): 1719-1723.
32. Kamory E, Kolacsek O, Otto S, Csuka O. hMLH1 and hMSH2 somatic inactivation mechanisms in sporadic colorectal cancer patients. Pathol Oncol Res 2003; 9(4): 236-241.
33. Entius MM, Keller JJ, Drillenburg P, et al. Microsatellite instability and expression of hMLH-1 and hMSH-2 in sebaceous gland carcinomas as markers for Muir-Torre syndrome. Clin Cancer Res 2000; 6(5): 1784-1789.
34. Vasen HF, Mecklin JP, Khan PM, Lynch HT. The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC). Dis Colon Rectum 1991; 34(5): 424-425.
35. 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; 116(6): 1453-1456.
36. 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; 96(4): 261-268.
37. Hampel H, Frankel WL, Martin E, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med 2005; 352(18): 1851-1860.
38. Liu T, Yan H, Kuismanen S, et al. The role of hPMS1 and hPMS2 in predisposing to colorectal cancer. Cancer Res 2001; 61(21): 7798-7802.
39. van der Klift H, Wijnen J, Wagner A, et al. Molecular characterization of the spectrum of genomic deletions in the mismatch repair genes MSH2, MLH1, MSH6, and PMS2 responsible for hereditary nonpolyposis colorectal cancer (HNPCC). Genes Chromosomes Cancer 2005; 44(2): 123-138.
40. Dovrat S, Figer A, Fidder HH, et al. Mutational analysis of hMsh6 in Israeli HNPCC and HNPCC-like families. Fam Cancer 2005; 4(4): 291-294.
41. Hegde MR, Chong B, Blazo ME, et al. A homozygous mutation in MSH6 causes Turcot syndrome. Clin Cancer Res 2005; 11(13): 4689-4693.
42. de la Chapelle A. The incidence of Lynch syndrome. Fam Cancer 2005; 4(3): 233-237.
43. Jenkins MA, Baglietto L, Dowty JG, et al. Cancer risks for mismatch repair gene mutation carriers: a population-based early onset case-family study. Clin Gastroenterol Hepatol 2006; 4(4): 489-498.
44. Quehenberger F, Vasen HF, van Houwelingen HC. Risk of colorectal and endometrial cancer for carriers of mutations of the hMLH1 and hMSH2 gene: correction for ascertainment. J Med Genet 2005; 42(6): 491-496.
45. Lynch HT, de la Chapelle A. Genetic susceptibility to non-polyposis colorectal cancer. J Med Genet 1999; 36(11): 801-818.
46. Jass JR, Stewart SM. Evolution of hereditary non-polyposis colorectal cancer. Gut 1992; 33(6): 783-786.
47. Hyde A, Fontaine D, Stuckless S, et al. A histology-based model for predicting microsatellite instability in colorectal cancers. Am J Surg Pathol 2010; 34(12): 1820-1829.
48. Jenkins MA, Hayashi S, O’Shea AM, et al. Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 2007; 133(1): 48-56.
49. Roman R, Verdu M, Calvo M, et al. Microsatellite instability of the colorectal carcinoma can be predicted in the conventional pathologic examination. A prospective multicentric study and the statistical analysis of 615 cases consolidate our previously proposed logistic regression model. Virchows Arch 2010; 456(5): 533-541.
50. Shia J. Immunohistochemistry versus microsatellite instability testing for screening colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome. Part I. The utility of immunohistochemistry. J Mol Diagn 2008; 10(4): 293-300.
51. Shia J, Tang LH, Vakiani E, et al. Immunohistochemistry as first-line screening for detecting colorectal cancer patients at risk for hereditary nonpolyposis colorectal cancer syndrome: a 2-antibody panel may be as predictive as a 4-antibody panel. Am J Surg Pathol 2009; 33(11): 1639-1645.
52. Barrow E, Jagger E, Brierley J, et al. Semiquantitative assessment of immunohistochemistry for mismatch repair proteins in Lynch syndrome. Histopathology 2010; 56(3): 331-344.
53. Funkhouser WK, Jr., Lubin IM, Monzon FA, et al. Relevance, pathogenesis, and testing algorithm for mismatch repair-defective colorectal carcinomas: a report of the association for molecular pathology. J Mol Diagn 2012; 14(2): 91-103.
54. Halvarsson B, Lindblom A, Rambech E, Lagerstedt K, Nilbert M. Microsatellite instability analysis and/or immunostaining for the diagnosis of hereditary nonpolyposis colorectal cancer? Virchows Arch 2004; 444(2): 135-141.
55. Boland CR, Koi M, Chang DK, Carethers JM. The biochemical basis of microsatellite instability and abnormal immunohistochemistry and clinical behavior in Lynch syndrome: from bench to bedside. Fam Cancer 2008; 7(1): 41-52.
56. Jass JR. Classification of colorectal cancer based on correlation of clinical, morphological and molecular features. Histopathology 2007; 50(1): 113-130.
57. Domingo E, Laiho P, Ollikainen M, et al. BRAF screening as a low-cost effective strategy for simplifying HNPCC genetic testing. J Med Genet 2004; 41(9): 664-668.
58. Dunlop MG, Farrington SM, Carothers AD, et al. Cancer risk associated with germline DNA mismatch repair gene mutations. Hum Mol Genet 1997; 6(1): 105-110.
59. Aarnio M, Sankila R, Pukkala E, et al. Cancer risk in mutation carriers of DNA-mismatch-repair genes. Int J Cancer 1999; 81(2): 214-218.
60. Clarke BA, Cooper K. Identifying Lynch syndrome in patients with endometrial carcinoma: shortcomings of morphologic and clinical schemas. Adv Anat Pathol 2012; 19(4): 231-238.
Labels
Anatomical pathology Forensic medical examiner ToxicologyArticle was published in
Czecho-Slovak Pathology
2014 Issue 1
Most read in this issue
- Cell cultures
- Lynch syndrome in the hands of pathologists
- Detection of chromosome changes by CGH, array-CGH and SNP array techniques in tumours
- Uterine tumors resembling ovarian sex cord tumors (UTROSCT). Report of a case with lymph node metastasis