Comment on: Screening for Lynch Syndrome (Hereditary Nonpolyposis Colorectal Cancer) among Endometrial Cancer Patients

Hampel, Heather; Panescu, Jenny; Lockman, Janet; Sotamaa, Kaisa; Fix, Daniel; Comeras, Ilene; LaJeunesse, Jennifer; Nakagawa, Hidewaki; Westman, Judith A.; Prior, Thomas W.; Clendenning, Mark; Chapelle, Albert de la; Frankel, Wendy L.; Penzone, Pamela; Cohn, David E.; Eaton, Lynne; Fowler, Jeffrey M.; Lombardi, Janet; Dunn, Patti; Bell, Jeffrey A.; Reid, Gary C.; Lewandowski, George; Vaccarello, Luis

doi:10.1158/0008-5472.can-07-2308

Cited by 91 publications

(70 citation statements)

References 2 publications

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“…[1][2][3] Mutations in one of four mismatch repair genes: MLH1, MSH2, MSH6, and PMS2 cause LS and studies suggest that there may be differences in cancer risks for mutation carriers depending on the gene that is mutated. 4,5 Most recent valid estimates of cancer risks to age 70 suggest that individuals with LS have an increased risk of colorectal cancer (22-74%), endometrial cancer (32-42%), and a number of other cancers (such as those of the stomach, ovary, small intestine, biliary tract, and urinary tract).…”

Section: Introductionmentioning

confidence: 99%

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

et al. 2008

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Background and Aims-Although the clinical phenotype of Lynch syndrome (also known as Hereditary Nonpolyposis Colorectal Cancer) has been well described, little is known about disease in PMS2 mutation carriers. Now that mutation detection methods can discern mutations in PMS2 from mutations in its pseudogenes, more mutation carriers have been identified. Information about the clinical significance of PMS2 mutations is crucial for appropriate counseling. Here, we report the clinical characteristics of a large series of PMS2 mutation carriers.

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Section: Introductionmentioning

confidence: 99%

The Clinical Phenotype of Lynch Syndrome Due to Germ-Line PMS2 Mutations

et al. 2008

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“…However, IHC is considered by some to be the preferred method of screening for EMC because of higher false-negative rates reported with MSI testing in EMC tumors. Hampel et al 11 reported that 50% of mutS homolog 6 (MSH6) mutant EMCs do not show MSI-H by MSI PCR. Another study documented that 21% of IHCdeficient EMC tumors were MSS by the MSI PCR assay.…”

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confidence: 99%

Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers

Wang

Shi

Eisenberg

et al. 2017

The Journal of Molecular Diagnostics

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The ASCP designates this journal-based CME activity ("JMD 2017 CME Program in Molecular Diagnostics") for a maximum of 36 AMA PRA Category 1 Credit(s)ä. Physicians should claim only credit commensurate with the extent of their participation in the activity. CME Disclosures: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose. Colorectal (CRCs) and endometrioid (EMCs) cancers in patients with Lynch syndrome exhibit microsatellite instability (MSI) detected by PCR or immunohistochemistry (IHC). While both assays are equally sensitive for CRCs, some suggest that PCR has a higher false-negative rate than IHC in EMCs. We assessed the MSI profiles of 91 EMC and 311 CRC specimens using five mononucleotide repeat markers: BAT25, BAT26, NR21, NR24, and MONO27. EMCs with high MSI (MSI-H) showed a mean left shift of 3 nucleotides (nt), which was significantly different from 6 nt in CRCs. A shift of 1 nt was observed in multiple markers in 76% of MSI-H EMCs, whereas only 12% of MSI-H CRCs displayed a 1-nt shift in one of five markers. IHC against four mismatch repair proteins was performed in 78 EMCs. Loss of staining in one or more proteins was detected in 18 of 19 tumors that were MSI-H by PCR. When EMC tumor cell burden was diluted to <30%, MSI-H was no longer observed in two of three EMCs with a mean nucleotide shift of 1 nt. These results indicate that EMC and CRC MSI profiles are different and that caution should be exercised when interpreting the results, as subtle, 1-nt changes may be missed. These findings provide a potential cause of previously reported discordant MSI and IHC results in EMCs. Lynch syndrome (LS) (Online Mendelian Inheritance in Man no. 120435), also referred as hereditary nonpolyposis colorectal cancer, is an autosomal dominant disorder with a relatively common disease prevalence of 1 in 440.1,2 About 2% to 3% of colorectal cancers (CRCs) and 1% to 2% of endometrioid cancers (EMCs; including endometrial cancer and endometrioid cancer of the ovary) are due to LS.3 LS is a heterogeneous disorder exhibiting reduced penetrance, differences in age of onset, and variability in expression.In LS patients, the lifetime risks are 50% to 70% for CRC and 40% to 60% for EMC in women, and the overall risk for other associated tumors is increased. 4 LS is caused by germline mutations in one of four mismatch repair (MMR) genes or by a deletion in the EPCAM locus affecting the adjacent MMR gene.5 These germline mutations result in defective MMR machinery that leads to microsatellite instability (MSI) throughout the genome and gives rise to tumors. Both Lynch-related and sporadic cancers can manifest MSI. MSI tumors are associated with a better prognosis yet a poor response to adjuvant 5-fluorouracil based chemotherapy.

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“…Specifically, MSH6 mutations have been associated with a higher cumulative risk for endometrial cancer with a later age of onset as compared to other mismatch repair gene mutations [1][2][3][4][5], and cancers other than colon and endometrial may account for as much as 50% of cancer reported with MSH6 mutations [6]. Clarifying the efficacy of MSI/IHC in other extra-colonic cancers associated with LS is important, since certain cases of LS are likely to present in a clinically atypical manner.…”

Section: Resultsmentioning

confidence: 99%