|
Advertisement |
|
|
||
 |
|
|||||
|
|||||
|
 |
||||||
|
||||||
|
||||||
|
Originally published as JCO Early Release 10.1200/JCO.2004.06.940 on October 13 2004 © 2004 American Society of Clinical Oncology.
MSH6 Mutations in Hereditary Nonpolyposis Colon Cancer: Another Slice of the PieMemorial Sloan-Kettering Cancer Center, New York, NY The identification of individuals at hereditary risk for cancer is now an established aspect of the practice of clinical oncology.1 Documentation of a family history of cancer offers a critical opportunity for the prevention or early detection of hereditary malignancies. One such preventive strategy is endoscopic and extracolonic surveillance in kindreds with hereditary nonpolyposis colon cancer (HNPCC)2 (Table 1). In HNPCC, also known as Lynch syndrome, cancers of the colon and other sites (endometrium, ovary, stomach, genitourinary tract, and skin) occur and appear at an early age (average age, < 45 years).
Approximately 3% to 5% of all patients with colon cancer can be diagnosed as HNPCC by the clinician who is aware of this syndrome. Just as oncologists have finally memorized the "3 to 2-1" Amsterdam rule for the diagnosis of HNPCC (three cases of colon cancer in two successive generations with at least one diagnosed before age 50 years), revisions to testing guidelines throughout the years have sought to broaden clinical criteria to capture a greater number of families carrying the genetic hallmarks of HNPCC. The latest revision, published earlier this year, is presented in Table 2. 3 Central to the diagnosis of HNPCC is the identification of mutations in one of a class of genes whose products are involved in the fundamental biologic process of DNA mismatch repair (MMR). Defects of one of these MMR genes (MSH2, MLH1, and MSH6) underlie most cases of HNPCC. As detailed in the article by Plaschke et al in this issue of the Journal of Clinical Oncology,4 the "slice" of the "HNPCC pie" associated with MSH6 mutations in families with colon cancer is somewhat larger than previously believed. Moreover, these authors show that MSH6 mutations require the same stringent level of surveillance as for any other HNPCC kindred.
In the recently released American Society of Clinical Oncology curriculum on cancer genetics,5 we depict MMR gene mutations in HNPCC as a pie chart, with the MSH6 fraction shown as a very small slice. The 15% frequency of MSH6 mutations among all mutations of MMR genes in the report by Plaschke et al is the highest yet reported. Can we assume that this frequency of MSH6 mutations observed in a German consortium will be relevant to other geographical settings? While a 12% frequency of MSH6 mutations (among all MMR mutations noted) was initially reported by the Dutch consortium,6 we recently observed a 7% frequency in a single center in North America.7 However, as emphasized in a recent review,2 data on MSH6 mutations in families remain relatively sparse; therefore, MSH6 sequence analysis should be performed in HNPCC families when other MMR genes are not mutated. The report by Plaschke et al4 also reinforces the limitations of the classical criteria for HNPCC. Almost two-thirds of families carrying MSH6 mutations in this report would have been missed by the "Amsterdam" criteria. Recent reports have confirmed a high risk of cancer (60% lifetime risk8) and altered tumor spectrum in MSH6 mutation carriers. In seven families with MSH6 mutations, the proband was identified solely on the basis of endometrial cancers demonstrating a high pattern of microsatellite instability (MSI)—the hallmark of mutations in MMR genes.9 In four of the seven families in that report, the tumor spectrum and age of diagnosis fell outside even the broadest definitions of the revised Bethesda criteria. The high rate of endometrial cancer in these reports4,6,9 seems to be a hallmark of MSH6 mutation carriers. A prior study in the Journal found no MMR gene mutations in 35 patients with early onset (younger than 50 years) endometrial cancer and no family history of HNPCC,10 but did note mutations in five of 22 cases of endometrial cancer with a family history of HNPCC. In another report, MSH6 mutations were actually more common that MLH1 or MSH2 mutations in patients with primary cancers of both the colon and the endometrium.11 The report by Plaschke et al4 also supports the role of immunohistochemical (IHC) screening in pinpointing particular MMR genes for sequence analysis. In 20 of 23 cases in which IHC was successful, loss of MSH6 antibody expression predicted the underlying MSH6 mutation. While IHC was not completely predictive, neither was MSI testing. Consistent with prior reports, five of 26 MSH6-mutated cases analyzed were either MSI-stable or -low. The finding of lack of MSI in some patients with MSH6 mutations suggests that a combination of MSI analysis and MSH6 immunostaining would be optimal. Such an approach would have led the oncologist to order MSH6 sequence analysis in all but one of the 27 cases in the current series. These findings support an algorithm in which the clinician has the option of proceeding directly to IHC and sequence analysis for "classical Amsterdam" families, while "expanded Bethesda" families that are MSI negative can proceed to MSH6 IHC and "targeted" MSH6 sequencing. Such an algorithm bears with it important caveats previously outlined in these editorial pages,12 including the possibility of missense or C-terminal MMR gene mutations compatible with normal translation and normal IHC staining.12 Recently, PMS2 IHC testing has been shown to improve the sensitivity of MLH1 immunostaining,13 and the utility of MSH6 immunostaining has also emerged.14 Importantly, an additional advantage of MMR genotyping is its emerging role as a prognostic indicator.15 Despite its prognostic and hereditary risk-assessment roles, however, MMR testing remains underutilized in clinical practice and continues to pose issues regarding the appropriate scope of pretest counseling and informed consent.16 Given the limited uptake of MSI testing, what is the use of germ-line (sequence-based) genetic testing for HNPCC? The report by Plaschke et al serves as a testimony to the rigorous assembly of HNPCC kindreds and the accessibility of sequence-based genetic testing in clinics in Germany. This is also the case in the Netherlands and many countries in Europe. In North America, testing for HNPCC-associated gene mutations is widely available through a number of academic and commercial laboratories.17 However, MSH6 sequence analysis is currently not included with MSH2 and MLH1 testing in most clinical laboratories. In the largest commercial cancer genetics laboratory in the United States, market estimates based on testing volumes and the number of individuals who should be candidates for HNPCC genetic testing suggest that more than 80% of such individuals are not being identified and evaluated clinically (Greg Critchfield, Myriad Genetics, personal communication, August 1, 2004). Thus, significant underutilization of HNPCC-associated genetic evaluation may be occurring in oncologic practice, despite the fact that many HNPCC kindreds are being evaluated and tested at large academic centers. While the report of Plaschke et al4 defines the size and importance of the MSH6 slice of the HNPCC pie, the challenge remains for oncologists to use genetic information to decrease the burden of familial colorectal cancer. Oncologists should continue to increase their vigilance in documenting family histories of colon, endometrial, and other cancers, and continue to be prepared to follow-up with the increasingly available tools for the genetic diagnosis and clinical management of HNPCC. Author's Disclosures of Potential Conflicts of Interest The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Consultant/Advisory Role: Kenneth Offit, Cancer Genetics. Research Funding: Kenneth Offit, Intergenetics Inc. For a detailed description of these categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration form and the "Disclosures of Potential Conflicts of Interest" section of Information for Contributors found in the front of every issue.
REFERENCES
1. American Society of Clinical Oncology: American Society of Clinical Oncology Policy Statement Update: Genetic Testing for Cancer Susceptibility. J Clin Oncol 21:2397-2406, 2003
2. Lynch HT, de la Chapelle A: Hereditary colorectal cancer. N Engl J Med 348:919-932, 2003
3. Umar A, Boland C, Terdiman JP, et al: Revised Bethesda guidelines for hereditary nonpolyposis colorectal cancer (Lynch syndrome) and microsatellite instability. J Natl Cancer Inst 96:261-268, 2004
4. Plaschke J, Engel C, Kruger S, et al: And the German HNPCC-Consortium: Lower incidence of colorectal cancer and later age of disease onset in 27 families with pathogenic MSH6 germline mutations compared to families with MLH1 or MSH2 mutations. J Clin Oncol 22:4486-4494, 2004 5. Offit K, Garber J, Grady M, et al: ASCO Curriculum: Cancer Genetics and Cancer Predisposition Testing (ed 2). Alexandria, VA, American Society of Clinical Oncology, 2004 6. Wijnen J, de Leeuw W, Vasen H, et al: Familial endometrial cancer in female carriers of MSH6 germline mutations. Nat Genet 23:142-144, 1999[CrossRef][Medline] 7. Peterlongo P, Nafa K, Lerman GS, et al: MSH6 germline mutations are rare in colorectal cancer families. Int J Cancer 107:571-579, 2003[CrossRef][Medline] 8. Buttin BM, Powell MA, Mutch DG, et al: Penetrance and expressivity of MSH6 germline mutations in seven kindreds not ascertained by family history. Am J Hum Genet 74:262-269, 2004[CrossRef][Medline]
9. Buttin BM, Powell MA, Mutch DG, et al: Increased risk for hereditary nonpolyposis colorectal cancer-associated synchronous and metachronous malignancies in patients with microsatellite instability-positive endometrial carcinoma lacking MLH1 promoter methylation. Clin Cancer Res 10:481-490, 2004
10. Berends MJ, Wu Y, Sijmons RH, et al: Toward new strategies to select young endometrial cancer patients for mismatch repair gene mutation analysis. J Clin Oncol 21:4364-4370, 2003 11. Cederquist K, Emanuelsson M, Goransson I, et al: Mutation analysis of the MLH1, MSH2 and MSH6 genes in patients with double primary cancers of the colorectum and the endometrium: A population-based study in northern Sweden. Int J Cancer 109:370-376, 2004[Medline]
12. de la Chapelle A: Microsatellite instability phenotype of tumors: Genotyping or immunohistochemisty? The jury is still out. J Clin Oncol 20:897-899, 2002
13. De Jong AE, Puijenbrock MV, Hendriks Y, et al: Microsatellite instability, immunohistochemistry, and additional PMS2 staining in suspected hereditary nonpolyposis colorectal cancer. Clin Cancer Res 10:972-980, 2004 14. Plaschke J, Kruger S, Dietmaier W, et al: For the German HNPCC Consortium: Eight novel MSH6 germline mutations in patients with familial and nonfamilial colorectal cancer selected by loss of protein expression in tumor tissue. Hum Mutat 23:285, 2004
15. Ribic CM, Sargent DJ, Moore MJ, et al: Tumor microsatellite-instability status as a predictor of benefit from fluorouracil-based adjuvant chemotherapy for colon cancer. N Engl J Med 349:247-257, 2003
16. Offit K: Genetic prognostic markers for colorectal cancer. N Engl J Med 342:124-125, 2000 17. GeneTests Web site. http://www.genetests.org
Related Article
This article has been cited by other articles:
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
|
|||||||||||
|
|||||||||||
|
|
Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
|
Analysis for (HNPCC)
