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Annals of Surgical Oncology
Published in: Annals of Surgical Oncology 3/2012

01-03-2012 | Colorectal Cancer

Screening for Lynch Syndrome in Colorectal Cancer: Are We Doing Enough?

Authors: Guillaume Canard, MD, Jeremie H. Lefevre, MD, Chrystelle Colas, MD, Florence Coulet, PharmD, PhD, Magali Svrcek, MD, PhD, Olivier Lascols, MD, Richard Hamelin, PhD, Conor Shields, MD, Alex Duval, MD, PhD, Jean-Francois Fléjou, MD, PhD, Florent Soubrier, MD, PhD, Emmanuel Tiret, MD, Yann Parc, MD, PhD

Published in: Annals of Surgical Oncology | Issue 3/2012

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Abstract

Purpose

The purpose of this study was to assess the efficacy of screening for the detection of Lynch syndrome (LS) in an unselected population undergoing surgery for a colorectal cancer.

Methods

A total of 1,040 patients were prospectively included between 2005 and 2009. LS screening modalities included the Bethesda criteria, immunochemistry (IHC) for MLH1, MSH2, and MSH6, and microsatellite instability (MSI) by using pentaplex markers. Promoter methylation was assessed in tumors with a loss of MLH1 expression. Gene sequencing was offered to patients with abnormal IHC or MSI status without promoter methylation.

Results

A total of 105 patients had an abnormal result: 102 (9.8%) exhibited a loss of protein on IHC and 98 (9.4%) had MSI. A discordant result was observed in 10 patients with eventual proven LS in 6 patients. Loss of MLH1 (n = 64) was due to promoter methylation in 43 patients (67.2%). Overall, of 62 patients with an abnormal result, 38 had genetic sequencing leading to 25 (65.8%) identified with a germ-line mutation. Loss of MSH2 on IHC was associated with a mutation in 78.3% (18 of 23) of cases. Among the 62 patients with abnormal results, 23 (37.1%) did not meet the Bethesda criteria.

Conclusions

Strict application of the Bethesda criteria does not lead to identification of all patients with LS. IHC and MSI testing are complementary methods and should be used in association to identify potential LS patients.
Literature
1.
Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Screening for the Lynch syndrome (hereditary nonpolyposis colorectal cancer). N Engl J Med. 2005;352:1851–60.PubMedCrossRef
2.
Cunningham JM, Kim CY, Christensen ER, Tester DJ, Parc Y, Burgart LJ, et al. The frequency of hereditary defective mismatch repair in a prospective series of unselected colorectal carcinomas. Am J Hum Genet. 2001;69:780–90.PubMedCrossRef
3.
4.
Rodriguez-Bigas MA, Boland CR, Hamilton SR, Henson DE, Jass JR, Khan PM, et al. A National Cancer Institute workshop on hereditary nonpolyposis colorectal cancer syndrome: meeting highlights and Bethesda guidelines. J Natl Cancer Inst. 1997;89:1758–62.PubMedCrossRef
5.
6.
Renkonen E, Zhang Y, Lohi H, Salovaara R, Abdel-Rahman WM, Nilbert M, et al. Altered expression of MLH1, MSH2, and MSH6 in predisposition to hereditary nonpolyposis colorectal cancer. J Clin Oncol. 2003;21:3629–37.PubMedCrossRef
7.
Vasen HF, Moslein G, Alonso A, Bernstein I, Bertario L, Blanco I, et al. Guidelines for the clinical management of Lynch syndrome (hereditary non-polyposis cancer). J Med Genet. 2007;44:353–62.PubMedCrossRef
8.
Boland CR, Thibodeau SN, Hamilton SR, Sidransky D, Eshleman JR, Burt RW, 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;58:5248–57.PubMed
9.
Umar A, Boland CR, Terdiman JP, Syngal S, de la Chapelle A, Ruschoff J, et al. Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst. 2004;96:261–8.PubMedCrossRef
10.
Julie C, Tresallet C, Brouquet A, Vallot C, Zimmermann U, Mitry E, et al. Identification in daily practice of patients with Lynch syndrome (hereditary nonpolyposis colorectal cancer): revised Bethesda guidelines–based approach versus molecular screening. Am J Gastroenterol. 2008;103:2825–35.PubMedCrossRef
11.
Pinol V, Castells A, Andreu M, Castellvi-Bel S, Alenda C, Llor X, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005;293:1986–94.PubMedCrossRef
12.
Barnetson RA, Tenesa A, Farrington SM, Nicholl ID, Cetnarskyj R, Porteous ME, et al. Identification and survival of carriers of mutations in DNA mismatch-repair genes in colon cancer. N Engl J Med. 2006;354:2751–63.PubMedCrossRef
13.
Kane MF, Loda M, Gaida GM, Lipman J, Mishra R, Goldman H, et al. 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. 1997;57:808–11.PubMed
14.
Rigau V, Sebbagh N, Olschwang S, Paraf F, Mourra N, Parc Y, et al. Microsatellite instability in colorectal carcinoma. The comparison of immunohistochemistry and molecular biology suggests a role for hMSH6 [correction of hMLH6] immunostaining. Arch Pathol Lab Med. 2003;127:694–700.PubMed
15.
Ewald J, Rodrigue CM, Mourra N, Lefevre JH, Flejou JF, Tiret E, et al. Immunohistochemical staining for mismatch repair proteins, and its relevance in the diagnosis of hereditary non-polyposis colorectal cancer. Br J Surg. 2007;94:1020–7.PubMedCrossRef
16.
Suraweera N, Duval A, Reperant M, Vaury C, Furlan D, Leroy K, et al. Evaluation of tumor microsatellite instability using five quasimonomorphic mononucleotide repeats and pentaplex PCR. Gastroenterology. 2002;123:1804–11.PubMedCrossRef
17.
Buhard O, Cattaneo F, Wong YF, Yim SF, Friedman E, Flejou JF, et al. Multipopulation analysis of polymorphisms in five mononucleotide repeats used to determine the microsatellite instability status of human tumors. J Clin Oncol. 2006;24:241–51.PubMedCrossRef
18.
Capel E, Flejou JF, Hamelin R. Assessment of MLH1 promoter methylation in relation to gene expression requires specific analysis. Oncogene. 2007;26:7596–600.PubMedCrossRef
19.
de la Chapelle A, Hampel H. Clinical relevance of microsatellite instability in colorectal cancer. J Clin Oncol. 2010;28:3380–7.CrossRef
20.
Parc Y, Gueroult S, Mourra N, Serfaty L, Flejou JF, Tiret E, et al. Prognostic significance of microsatellite instability determined by immunohistochemical staining of MSH2 and MLH1 in sporadic T3N0M0 colon cancer. Gut. 2004;53:371–5.PubMedCrossRef
21.
Baudhuin LM, Burgart LJ, Leontovich O, Thibodeau SN. Use of microsatellite instability and immunohistochemistry testing for the identification of individuals at risk for Lynch syndrome. Fam Cancer. 2005;4:255–65.PubMedCrossRef
22.
Palomaki GE, McClain MR, Melillo S, Hampel HL, Thibodeau SN. EGAPP supplementary evidence review: DNA testing strategies aimed at reducing morbidity and mortality from Lynch syndrome. Genet Med. 2009;11:42–65.PubMedCrossRef
23.
Hampel H, Frankel WL, Martin E, Arnold M, Khanduja K, Kuebler P, et al. Feasibility of screening for Lynch syndrome among patients with colorectal cancer. J Clin Oncol. 2008;26:5783–8.PubMedCrossRef
24.
Mitchell RJ, Brewster D, Campbell H, Porteous ME, Wyllie AH, Bird CC, et al. Accuracy of reporting of family history of colorectal cancer. Gut. 2004;53:291–5.PubMedCrossRef
25.
Vasen HF, Moslein G, Alonso A, Aretz S, Bernstein I, Bertario L, et al. Recommendations to improve identification of hereditary and familial colorectal cancer in Europe. Fam Cancer. 2010;9:109–15.PubMedCrossRef
26.
Jarvinen HJ, Aarnio M, Mustonen H, Aktan-Collan K, Aaltonen LA, Peltomaki P, et al. Controlled 15-year trial on screening for colorectal cancer in families with hereditary nonpolyposis colorectal cancer. Gastroenterology. 2000;118:829–34.PubMedCrossRef
27.
Ligtenberg MJ, Kuiper RP, Chan TL, Goossens M, Hebeda KM, Voorendt M, 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;41:112–7.PubMedCrossRef
Metadata
Title
Screening for Lynch Syndrome in Colorectal Cancer: Are We Doing Enough?
Authors
Guillaume Canard, MD
Jeremie H. Lefevre, MD
Chrystelle Colas, MD
Florence Coulet, PharmD, PhD
Magali Svrcek, MD, PhD
Olivier Lascols, MD
Richard Hamelin, PhD
Conor Shields, MD
Alex Duval, MD, PhD
Jean-Francois Fléjou, MD, PhD
Florent Soubrier, MD, PhD
Emmanuel Tiret, MD
Yann Parc, MD, PhD
Publication date
01-03-2012
Publisher
Springer-Verlag
Published in
Annals of Surgical Oncology / Issue 3/2012
Print ISSN: 1068-9265
Electronic ISSN: 1534-4681
DOI
https://doi.org/10.1245/s10434-011-2014-7

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