Skip to main content
Log in

Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis

  • Published:
Familial Cancer Aims and scope Submit manuscript

Abstract

The identification of Lynch syndrome has been greatly assisted by the advent of tumour immunohistochemistry (IHC) for mismatch repair (MMR) proteins, and by the recognition of the role of acquired somatic BRAF mutation in sporadic MMR-deficient colorectal cancer (CRC). However, somatic BRAF mutation may also be present in the tumours in families with a predisposition to develop serrated polyps in the colorectum. In a subgroup of affected members in these families, CRCs emerge which demonstrate clear evidence of MMR deficiency with absent MLH1 staining and high-level microsatellite instability (MSI). This may result in these families being erroneously classified as Lynch syndrome, or conversely, an individual is considered “sporadic” due to the presence of a somatic BRAF mutation in a tumour. In this report, we describe two Lynch syndrome families who demonstrated several such inconsistencies. In one family, IHC deficiency of both MSH2 and MLH1 was demonstrated in tumours from different affected family members, presenting a confusing diagnostic picture. In the second family, MLH1 loss was observed in the lesions of both MLH1 mutation carriers and those who showed normal MLH1 germline sequence. Both families had Lynch syndrome complicated by an independently segregating serrated neoplasia phenotype, suggesting that in families such as these, tumour and germline studies of several key members, rather than of a single proband, are indicated to clarify the spectrum of risk.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Aaltonen L, Johns L, Jarvinen H, Mecklin JP, Houlston R (2007) Explaining the familial colorectal cancer risk associated with mismatch repair (MMR)-deficient and MMR-stable tumors. Clin Cancer Res 13(1):356–361. doi:10.1158/1078-0432.CCR-06-1256

    Article  CAS  PubMed  Google Scholar 

  2. Woods MO, Hyde AJ, Curtis FK, Stuckless S, Green JS, Pollett AF et al (2005) High frequency of hereditary colorectal cancer in Newfoundland likely involves novel susceptibility genes. Clin Cancer Res 11(19 Pt 1):6853–6861. doi:10.1158/1078-0432.CCR-05-0726

    Google Scholar 

  3. Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H et al (1997) Methylation of the hMLH1 promoter correlates with lack of expression of hMLH1 in sporadic colon tumors and mismatch repair-defective human tumor cell lines. Cancer Res 57(5):808–811

    CAS  PubMed  Google Scholar 

  4. Rahner N, Friedrichs N, Steinke V, Aretz S, Friedl W, Buettner R et al (2008) Coexisting somatic promoter hypermethylation and pathogenic MLH1 germline mutation in Lynch syndrome. J Pathol 214(1):10–16. doi:10.1002/path.2263

    Article  CAS  PubMed  Google Scholar 

  5. Kuismanen SA, Holmberg MT, Salovaara R, de la Chapelle A, Peltomaki P (2000) Genetic and epigenetic modification of MLH1 accounts for a major share of microsatellite-unstable colorectal cancers. Am J Pathol 156(5):1773–1779

    CAS  PubMed  Google Scholar 

  6. Young J, Simms LA, Biden KG, Wynter C, Whitehall V, Karamatic R et al (2001) Features of colorectal cancers with high-level microsatellite instability occurring in familial and sporadic settings: parallel pathways of tumorigenesis. Am J Pathol 159(6):2107–2116

    CAS  PubMed  Google Scholar 

  7. Goldstein NS, Bhanot P, Odish E, Hunter S (2003) Hyperplastic-like colon polyps that preceded microsatellite-unstable adenocarcinomas. Am J Clin Pathol 119(6):778–796. doi:10.1309/DRFQ0WFUF1G13CTK

    Article  PubMed  Google Scholar 

  8. Kambara T, Simms LA, Whitehall VL, Spring KJ, Wynter CV, Walsh MD et al (2004) BRAF mutation is associated with DNA methylation in serrated polyps and cancers of the colorectum. Gut 53(8):1137–1144. doi:10.1136/gut.2003.037671

    Article  CAS  PubMed  Google Scholar 

  9. McGivern A, Wynter CVA, Whitehall VLJ, Kambara T, Spring KJ, Walsh MD et al (2004) Promoter hypermethylation frequency and BRAF mutations distinguish hereditary non-polyposis colon cancer from sporadic MSI-H colon cancer. Fam Cancer 3(2):101–107

    Article  CAS  PubMed  Google Scholar 

  10. Loughrey MB, Waring PM, Tan A, Trivett M, Kovalenko S, Beshay V et al (2007) Incorporation of somatic BRAF mutation testing into an algorithm for the investigation of hereditary non-polyposis colorectal cancer. Fam Cancer 6(3):301–310. doi:10.1007/s10689-007-9124-1

    Article  CAS  PubMed  Google Scholar 

  11. Jass JR (2005) Serrated adenoma of the colorectum and the DNA-methylator phenotype. Nat Clin Pract 2(8):398–405

    CAS  Google Scholar 

  12. O’Brien MJ, Yang S, Mack C, Xu H, Huang CS, Mulcahy E et al (2006) Comparison of microsatellite instability, CpG island methylation phenotype, BRAF and KRAS status in serrated polyps and traditional adenomas indicates separate pathways to distinct colorectal carcinoma end points. Am J Surg Pathol 30(12):1491–1501. doi:10.1097/01.pas.0000213313.36306.85

    Article  PubMed  Google Scholar 

  13. Young J, Barker MA, Simms LA, Walsh MD, Biden KG, Buchanan D et al (2005) Evidence for BRAF mutation and variable levels of microsatellite instability in a syndrome of familial colorectal cancer. Clin Gastroenterol Hepatol 3(3):254–263. doi:10.1016/S1542-3565(04)00673-1

    Article  CAS  PubMed  Google Scholar 

  14. Lagerstedt Robinson K, Liu T, Vandrovcova J, Halvarsson B, Clendenning M, Frebourg T et al (2007) Lynch syndrome (hereditary nonpolyposis colorectal cancer) diagnostics. J Natl Cancer Inst 99(4):291–299. doi:10.1093/jnci/djk051

    Article  PubMed  Google Scholar 

  15. Vandrovcova J, Lagerstedt-Robinsson K, Pahlman L, Lindblom A (2006) Somatic BRAF-V600E mutations in familial colorectal cancer. Cancer Epidemiol Biomarkers Prev 15(11):2270–2273. doi:10.1158/1055-9965.EPI-06-0359

    Article  CAS  PubMed  Google Scholar 

  16. Newcomb PA, Baron J, Cotterchio M, Gallinger S, Grove J, Haile R et al (2007) Colon cancer family registry: an international resource for studies of the genetic epidemiology of colon cancer. Cancer Epidemiol Biomarkers Prev 16(11):2331–2343. doi:10.1158/1055-9965.EPI-07-0648

    Article  PubMed  Google Scholar 

  17. Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW et al (1998) 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 58(22):5248–5257

    CAS  PubMed  Google Scholar 

  18. Walsh MD, Cummings MC, Buchanan DD, Dambacher WM, Arnold S, McKeone D et al (2008) Molecular, pathologic, and clinical features of early-onset endometrial cancer: identifying presumptive Lynch syndrome patients. Clin Cancer Res 14(6):1692–1700. doi:10.1158/1078-0432.CCR-07-1849

    Article  CAS  PubMed  Google Scholar 

  19. Jenkins MA, Hayashi S, O’Shea AM, Burgart LJ, Smyrk TC, Shimizu D et al (2007) Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: a population-based study. Gastroenterology 133(1):48–56. doi:10.1053/j.gastro.2007.04.044

    Article  CAS  PubMed  Google Scholar 

  20. Leggett BA, Devereaux B, Biden K, Searle J, Young J, Jass J (2001) Hyperplastic polyposis: association with colorectal cancer. Am J Surg Pathol 25(2):177–184. doi:10.1097/00000478-200102000-00005

    Article  CAS  PubMed  Google Scholar 

  21. Yeoman A, Young J, Arnold J, Jass J, Parry S (2007) Hyperplastic polyposis in the New Zealand population: a condition associated with increased colorectal cancer risk and European ancestory. NZMJ 120:31–39

    Google Scholar 

  22. Takahashi M, Shimodaira H, Andreutti-Zaugg C, Iggo R, Kolodner R, Ishioka C (2007) Functional analysis of human MLH1 variants using yeast and in vitro mismatch repair assays. Cancer Res 67(10):4595–4604. doi:10.1158/0008-5472.CAN-06-3509

    Article  CAS  PubMed  Google Scholar 

  23. Trojan J, Zeuzem S, Randolph A, Hemmerle C, Brieger A, Raedle J et al (2002) Functional analysis of hMLH1 variants and HNPCC-related mutations using a human expression system. Gastroenterology 122(1):211–219. doi:10.1053/gast.2002.30296

    Article  CAS  PubMed  Google Scholar 

  24. Wynter CV, Walsh MD, Higuchi T, Leggett BA, Young J, Jass JR (2004) Methylation patterns define two types of hyperplastic polyp associated with colorectal cancer. Gut 53(4):573–580. doi:10.1136/gut.2003.030841

    Article  CAS  PubMed  Google Scholar 

  25. Skoglund J, Djureinovic T, Zhou XL, Vandrovcova J, Renkonen E, Iselius L et al (2006) Linkage analysis in a large Swedish family supports the presence of a susceptibility locus for adenoma and colorectal cancer on chromosome 9q22.32–31.1. J Med Genet 43(2):e7. doi:10.1136/jmg.2005.033928

  26. Wiesner GL, Daley D, Lewis S, Ticknor C, Platzer P, Lutterbaugh J (2003) A subset of familial colorectal neoplasia kindreds linked to chromosome 9q22.2–31.2. Proc Natl Acad Sci USA 100(22):12961–12965. doi:10.1073/pnas.2132286100

    Article  CAS  PubMed  Google Scholar 

  27. Kemp ZE, Carvajal-Carmona LG, Barclay E, Gorman M, Martin L, Wood W (2006) Evidence of linkage to chromosome 9q22.33 in colorectal cancer kindreds from the United Kingdom. Cancer Res 66(10):5003–5006. doi:10.1158/0008-5472.CAN-05-4074

    Article  CAS  PubMed  Google Scholar 

  28. Jasperson KW, Blazer KR, Lowstuter K, Weitzel JN (2008) Working through a diagnostic challenge: colonic polyposis, Amsterdam criteria, and a mismatch repair mutation. Fam Cancer 7(4):281–285

    Article  PubMed  Google Scholar 

  29. van Puijenbroek M, Nielsen M, Reinards TH, Weiss MM, Wagner A, Hendriks YM et al (2007) The natural history of a combined defect in MSH6 and MUTYH in a HNPCC family. Fam Cancer 6(1):43–51. doi:10.1007/s10689-006-9103-y

    Article  CAS  PubMed  Google Scholar 

  30. Boparai KS, Dekker E, Van Eeden S, Polak MM, Bartelsman JF, Mathus-Vliegen EM et al (2008) Hyperplastic polyps and sessile serrated adenomas as a phenotypic expression of MYH-associated polyposis. Gastroenterology 135(6):2014–2018. doi:10.1053/j.gastro.2008.09.020

    Article  CAS  PubMed  Google Scholar 

  31. Al-Tassan N, Chmiel NH, Maynard J, Fleming N, Livingston AL, Williams GT et al (2002) Inherited variants of MYH associated with somatic G:C→T:A mutations in colorectal tumors. Nat Genet 30(2):227–232. doi:10.1038/ng828

    Article  CAS  PubMed  Google Scholar 

  32. Young J, Jass JR (2006) The case for a genetic predisposition to serrated neoplasia in the colorectum: hypothesis and review of the literature. Cancer Epidemiol Biomarkers Prev 15(10):1778–1784. doi:10.1158/1055-9965.EPI-06-0164

    Article  CAS  PubMed  Google Scholar 

  33. Samowitz WS, Sweeney C, Herrick J, Albertsen H, Levin TR, Murtaugh MA et al (2005) Poor survival associated with the BRAF V600E mutation in microsatellite-stable colon cancers. Cancer Res 65(14):6063–6069. doi:10.1158/0008-5472.CAN-05-0404

    Article  CAS  PubMed  Google Scholar 

  34. English DR, Young JP, Simpson JA, Jenkins MA, Southey MC, Walsh MD et al (2008) Ethnicity and risk for colorectal cancers showing somatic BRAF V600E mutation or CpG Island Methylator Phenotype. Cancer Epidemiol Biomarkers Prev 17:1774–1780. doi:10.1158/1055-9965.EPI-08-0091

    Article  CAS  PubMed  Google Scholar 

  35. East JE, Saunders BP, Jass JR (2008) Sporadic and syndromic hyperplastic polyps and serrated adenomas of the colon: classification, molecular genetics, natural history, and clinical management. Gastroenterol Clin North Am 37(1):25–46. doi:10.1016/j.gtc.2007.12.014

    Article  PubMed  Google Scholar 

  36. Rijcken FE, van der Sluis T, Hollema H, Kleibeuker JH (2003) Hyperplastic polyps in hereditary nonpolyposis colorectal cancer. Am J Gastroenterol 98(10):2306–2311. doi:10.1111/j.1572-0241.2003.07629.x

    Article  PubMed  Google Scholar 

  37. Iino H, Simms L, Young J, Arnold J, Winship IM, Webb SI et al (2000) DNA microsatellite instability and mismatch repair protein loss in adenomas presenting in hereditary non-polyposis colorectal cancer. Gut 47(1):37–42. doi:10.1136/gut.47.1.37

    Article  CAS  PubMed  Google Scholar 

  38. Deng G, Bell I, Crawley S, Gum J, Terdiman J, Allen B et al (2004) BRAF mutation is frequently present in sporadic colorectal cancer with methylated hMLH1 but not in hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10(1):191–195. doi:10.1158/1078-0432.CCR-1118-3

    Article  CAS  PubMed  Google Scholar 

  39. Koinuma K, Shitoh K, Miyakura Y, Furukawa T, Yamashita Y, Ota J et al (2004) Mutations of BRAF are associated with extensive hMLH1 promoter methylation in sporadic colorectal carcinomas. Int J Cancer 108(2):237–242. doi:10.1002/ijc.11523

    Article  CAS  PubMed  Google Scholar 

  40. Wang L, Cunningham JM, Winters JL, Guenther JC, French AJ, Boardman LA et al (2003) BRAF mutations in colon cancer are not likely attributable to defective DNA mismatch repair. Cancer Res 63(17):5209–5212

    CAS  PubMed  Google Scholar 

  41. Lubomierski N, Plotz G, Wormek M, Engels K, Kriener S, Trojan J et al (2005) BRAF mutations in colorectal carcinoma suggest two entities of microsatellite-unstable tumors. Cancer 104(5):952–961. doi:10.1002/cncr.21266

    Article  CAS  PubMed  Google Scholar 

  42. Jass JR (2004) HNPCC and sporadic MSI-H colorectal cancer: a review of the morphological similarities and differences. Fam Cancer 3(2):93–100. doi:10.1023/B:FAME.0000039849.86008.b7

    Article  CAS  PubMed  Google Scholar 

  43. Andersen SH, Lykke E, Folker MB, Bernstein I, Holck S (2007) Sessile serrated polyps of the colorectum are rare in patients with Lynch syndrome and in familial colorectal cancer families. Fam Cancer 7(2):157–162

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Cancer Council Queensland, the Hicks Foundation in Victoria, and the National Cancer Institute under RFA CA-95-011 (Australasian Colorectal Cancer Family Registry Centre UO1 CA097735), and through cooperative agreements with members of the Colon Cancer Family Registry and P·I.s. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the CFRs, nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the CFR. The authors are grateful to members of the two families who have given significant time and effort to the contribution of data, for the assistance of Maggie Angelakos in the retrieval and preparation of pedigrees for this manuscript, Lesley Jaskowski for data retrieval, and to the many pathology laboratories involved for supply of archived tissue for analysis.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Joanne P. Young.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Walsh, M.D., Buchanan, D.D., Walters, R. et al. Analysis of families with Lynch syndrome complicated by advanced serrated neoplasia: the importance of pathology review and pedigree analysis. Familial Cancer 8, 313–323 (2009). https://doi.org/10.1007/s10689-009-9238-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10689-009-9238-8

Keywords

Navigation