Lynch Syndrome Presenting as Endometrial Cancer

Tafe, Laura J.; Riggs, Eleanor R.; Tsongalis, Gregory J.

doi:10.1373/clinchem.2013.206888

Cited by 35 publications

(23 citation statements)

References 62 publications

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“…Most inherited ECs occur within the context of hereditary nonpolyposis colorectal cancer (HNPCC), a highly penetrant cancer syndrome in which carriers of mutations in mismatch repair genes are at increased risk of developing specific cancers including colorectal and endometrial cancer (Reviewed in [31]). An increased incidence of endometrial cancer has also been noted in Cowdens syndrome, which is linked to germline mutations in PTEN , but the risk of EC in this clinical context is still under debate [32–34].…”

Section: Germline Susceptibility To Endometrial Cancermentioning

confidence: 99%

The mutational landscape of endometrial cancer

Hong

Gallo

Bell

2015

Current Opinion in Genetics & Development

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Globally, endometrial carcinoma causes about 74,000 deaths annually. Endometrial carcinomas can be classified into several histological subtypes including endometrioid and serous histologies. Over the course of the past two years, a number of studies have decoded the exomes of endometrioid and serous endometrial carcinomas revealing novel somatically mutated genes that are likely to drive their development. Moreover, an integrated genomic analysis of these two histological subtypes by The Cancer Genome Atlas has led to their molecular reclassification into four discrete molecular subgroups. Collectively, these genomic advances set the stage for future biological and clinical studies to determine their relevance for patient care.

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Section: Germline Susceptibility To Endometrial Cancermentioning

confidence: 99%

The mutational landscape of endometrial cancer

Hong

Gallo

Bell

2015

Current Opinion in Genetics & Development

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“…3 LS is a heterogeneous disorder exhibiting reduced penetrance, differences in age of onset, and variability in expression.…”

mentioning

confidence: 99%

“…9 Both assays have a reported sensitivity of 92% to 93%. 3 Initially, MSI testing was performed using two mono-and three dinucleotide polymorphic DNA markers, as presented at a National Cancer Institute 1998 workshop. 10 Currently, however, the majority of diagnostic laboratories use a commercial kit containing five mononucleotide markers (see Materials and Methods for details).…”

mentioning

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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“…Lynch Syndrome (LS) is a hereditary cancer syndrome caused by germline alterations in the DNA mismatch repair (MMR) genes (Tafe et al, 2014). Those with LS will have an increased risk of colon cancer.…”

Section: Overview Of Endometrial Cancermentioning

confidence: 99%

“…Those with LS will have an increased risk of colon cancer. Despite being overlooked in association with LS, individuals with this syndrome also has 20–60% risk of developing EC (Tafe et al, 2014). The mutation frequencies of MMR genes are: 50–66% in MSH2 , 24–40% in MLH1 , 10–13% in MSH6 and <5% in PMS2 (Wang et al, 2013).…”

Section: Overview Of Endometrial Cancermentioning

confidence: 99%

Understanding Molecular Landscape of Endometrial Cancer through Next Generation Sequencing: What We Have Learned so Far?

2016

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Endometrial cancer (EC) is among the most common gynecological cancers affecting women worldwide. Despite the early detection and rather high overall survival rate, around 20% of the cases recur with poor prognosis. The Next Generation Sequencing (NGS) technology, also known as massively parallel sequencing, symbolizes a high-throughput, fast, sensitive and accurate way to study the molecular landscape of a cancer and this has indeed revolutionized endometrial cancer research. Understanding the potential, advantages, and limitations of NGS will be crucial for the healthcare providers and scientists in providing the genome-driven care in this era of precision medicine and pharmacogenomics. This mini review aimed to compile and critically summarize the recent findings contributed by NGS technology pertaining to EC. Importantly, we also discussed the potential of this technology for fundamental discovery research, individualized therapy, screening of at-risk individual and early diagnosis.

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Lynch Syndrome Presenting as Endometrial Cancer

Cited by 35 publications

References 62 publications

The mutational landscape of endometrial cancer

The mutational landscape of endometrial cancer

Differences in Microsatellite Instability Profiles between Endometrioid and Colorectal Cancers

Understanding Molecular Landscape of Endometrial Cancer through Next Generation Sequencing: What We Have Learned so Far?

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