Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Engel, Christoph; Forberg, Jochen; Holinski‐Feder, Elke; Pagenstecher, Constanze; Plaschke, Jens; Kloor, Matthias; Poremba, Christopher; Pox, Christian; Rüschoff, Josef; Keller, Gisela; Dietmaier, Wolfgang; Rümmele, Petra; Friedrichs, Nicolaus; Mangold, Elisabeth; Buettner, Reinhard; Schackert, Hans K.; Kienle, Peter; Stemmler, Susanne; Möeslein, Gabriela; Loeffler, Markus

doi:10.1002/ijc.21313

Cited by 93 publications

(83 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Immunohistochemistry with monoclonal antibodies specific for MLH1 and MSH2 is commonly accepted as a useful lower-cost tool to identify MSI-H colorectal cancers; however, about 10% of MSI-H tumors are missed if immunohistochemistry is used alone (12). Hence, we believe that PCR-based MSI testing is indispensable for correct MSI classification at present, at least in tumors without abnormal immunohistochemical staining results (13).…”

Section: Discussionmentioning

confidence: 98%

T25 Repeat in the 3′ Untranslated Region of the CASP2 Gene: A Sensitive and Specific Marker for Microsatellite Instability in Colorectal Cancer

et al. 2005

Self Cite

View full text Add to dashboard Cite

DNA mismatch repair deficiency is observed in about 10% to 15% of all colorectal carcinomas and in up to 90% of hereditary nonpolyposis colorectal cancer (HNPCC) patients. Tumors with mismatch repair defects acquire mutations in short repetitive DNA sequences, a phenomenon termed high-level microsatellite instability (MSI-H). The diagnosis of MSI-H in colon cancer is of increasing relevance, because MSI-H is an independent prognostic factor in colorectal cancer, seems to influence the efficacy of adjuvant chemotherapy, and is the most important molecular screening tool to identify HNPCC patients. To make MSI typing feasible for the routine pathology laboratory, highly reproducible and cost effective laboratory tests are required. Here, we describe a novel T 25 mononucleotide marker in the 3Vuntranslated region of the CASP2 gene (CAT25) that displayed a quasimonomorphic repeat pattern in normal tissue of 200 unrelated individuals of Caucasian origin. In addition, CAT25 was monomorphic also in all tested donors of African and Asian origin (n = 102 and n = 79, respectively) and thus differs from the most commonly used markers BAT25 and BAT26. Without the analysis of corresponding normal tissue, CAT25 correctly detected 56 of 57 colorectal cancer specimens classified as MSI-H by using the standard National Cancer Institute/International Collaborative Group-HNPCC marker panel. Combined with the standard markers BAT25 and BAT26 in a multiplex PCR, all MSI-H colorectal cancer samples were typed correctly. No falsepositive results were obtained in 60 non-MSI-H control colorectal cancer specimens. These data suggest that CAT25 should be included into novel marker panels for microsatellite testing thus allowing for a significant reduction of the complexity and costs of MSI typing. Moreover, CAT25 represents a highly promising marker for early detection of colorectal cancer in HNPCC germ line mutation carriers. (Cancer Res 2005; 65(18): 8072-8)

show abstract

Section: Discussionmentioning

confidence: 98%

T25 Repeat in the 3′ Untranslated Region of the CASP2 Gene: A Sensitive and Specific Marker for Microsatellite Instability in Colorectal Cancer

et al. 2005

Self Cite

View full text Add to dashboard Cite

show abstract

“…34 Furthermore, IHC triage of women with endometrial cancer having at least one affected first-degree relative was reported to be the most cost-effective strategy to identify mutation carriers and to prevent colorectal cancer. 35 Because some highly penetrant MMR missense mutations are reported to present with immunonormal tumor profiles, [36][37][38][39][40][41] we believe that IHC testing should support but not supplant the role of family history records in the detection of Lynch syndrome patients.…”

Section: Early Detection and Diagnosismentioning

confidence: 99%

Improving identification of lynch syndrome patients: A comparison of research data with clinical records

Tan

McGaughran

Ferguson

et al. 2013

Intl Journal of Cancer

View full text Add to dashboard Cite

Current evidence suggests poor identification and referral of Lynch syndrome patients. This study evaluated the strategies by which patients with endometrial cancer were referred to genetics services. Data from clinic-based patients with endometrial cancer enrolled through the Australian National Endometrial Cancer population-based research study with detailed family history information were analyzed. The Amsterdam II criteria, the revised Bethesda guidelines, and criteria adapted for this study was assessed using personal/family history information. The percentages of patients referred and who could have been referred to genetics services, and the performance of each criterion for identifying possible mismatch-repair (MMR) gene mutation carriers, based on tumor MMR immunohistochemistry (IHC), were determined. Research data indicated that 236/397(59%) of patients with endometrial cancer had family/personal history of cancer, including 14 (4%) who fulfilled Amsterdam II criteria. Family history information was noted in the hospital records for only 61(15%) patients, including 7/14 (50%) of patients meeting Amsterdam criteria, and always less extensively than that recorded in the research setting. Only 13 patients (two meeting Amsterdam criteria) were referred for genetic assessment. Of 58 patients with tumor MMR protein-IHC loss, the Amsterdam criteria and Bethesda guidelines identified only three and 34% of these possible germline mutation carriers, respectively. Greater sensitivity (60%) was obtained using a single criterion proposed by our study, 2 first-degree or second-degree relatives reporting Lynch cancers. Hospital records indicate poor recognition of family history. Application of research methods show improved identification and may facilitate appropriate referrals of endometrial cancer patients with possible Lynch syndrome.

show abstract

“…11,12 In such a scenario, it may seem attractive to include VE1 into the antibody panel. Although this will not increase the overall sensitivity, it will immediately indicate patients who do most likely not carry Lynch syndrome germline mutations, but are affected by sporadic tumors.…”

Section: Cancer Geneticsmentioning

confidence: 99%

“…In >90% of MSI-H colorectal cancers, expression loss of one or more MMR protein is detected. 11,12 One important shortcoming of current procedures is the fact that selection of tumors for microsatellite instability analysis by using clinical criteria bears a high risk of missing Lynch syndrome patients who do not fulfill the clinical criteria and who are therefore excluded from further germline mutation analysis. 13,14 To avoid underdiagnosis of Lynch syndrome among colorectal cancer patients, it has been proposed to perform microsatellite instability testing in all colorectal cancers; however, this approach will increase the number of sporadic MSI-H tumors that can only be differentiated from Lynch syndrome by laborious and cost-intensive germline mutation analysis.…”

mentioning

confidence: 99%

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Capper

Voigt

Bozukova

et al. 2013

Intl Journal of Cancer

Self Cite

View full text Add to dashboard Cite

The differentiation between hereditary and sporadic microsatellite-unstable (MSI-H) colorectal cancer is a crucial step in Lynch syndrome diagnostics. Within MSI-H colorectal cancers, the BRAF V600E mutation is strongly associated with sporadic origin. Here, we asked whether BRAF V600E-specific immunohistochemistry (clone VE1) is helpful in separating sporadic from Lynch syndrome-associated MSI-H colorectal cancers. To that end, we performed VE1 immunohistochemistry and BRAF sequencing in a series of 91 MSI-H colorectal cancer specimens from patients tested for Lynch syndrome. Concordance of VE1 immunohistochemistry and molecular BRAF mutation status was observed in 90 of 91 (98.9%) MSI-H samples. All 11 tumors classified as BRAF V600E mutation-positive by Sanger sequencing were immunopositive, and 79 (98.8%) of 80 tumors classified as BRAF wild type showed negative staining. All VE1-positive tumors were MLH1-and PMS2-negative by immunohistochemistry. None of the tumors from mismatch repair (MMR) gene germline mutation carriers (n 5 28) displayed positive VE1 staining, indicating that BRAF V600E mutation-specific immunostaining has a low risk of excluding Lynch syndrome patients from germline mutation analysis. In conclusion, implementation of VE1 immunohistochemistry was able to detect BRAF-mutated MSI-H colorectal cancers with a sensitivity of 100% and a specificity of 98.8%. Among MLH1-negative colorectal cancers, the rate of VE1-positive lesions was 21%, offering the exclusion of these patients from MMR germline testing. Therefore, we suggest the integration of VE1 immunohistochemistry into the diagnostic panel of Lynch syndrome.Lynch syndrome, which represents one of the most frequent autosomal dominantly inherited cancer syndromes, is caused by germline mutations affecting DNA mismatch repair (MMR) genes, most frequently MLH1 and MSH2, followed by MSH6 and PMS2.

show abstract

Novel strategy for optimal sequential application of clinical criteria, immunohistochemistry and microsatellite analysis in the diagnosis of hereditary nonpolyposis colorectal cancer

Cited by 93 publications

References 38 publications

T25 Repeat in the 3′ Untranslated Region of the CASP2 Gene: A Sensitive and Specific Marker for Microsatellite Instability in Colorectal Cancer

T25 Repeat in the 3′ Untranslated Region of the CASP2 Gene: A Sensitive and Specific Marker for Microsatellite Instability in Colorectal Cancer

Improving identification of lynch syndrome patients: A comparison of research data with clinical records

BRAF V600E‐specific immunohistochemistry for the exclusion of Lynch syndrome in MSI‐H colorectal cancer

Contact Info

Product

Resources

About