Molecular Analysis of Familial Endometrial Carcinoma: A Manifestation of Hereditary Nonpolyposis Colorectal Cancer or a Separate Syndrome?

Ollikainen, Miina; Abdel‐Rahman, Wael M.; Moisio, Anu-Liisa; Lindroos, Annette; Kariola, Reetta; Järvelä, Irma; Pöyhönen, Minna; Bützow, Ralf; Peltomäki, Païvi

doi:10.1200/jco.2005.06.055

Cited by 123 publications

(110 citation statements)

References 36 publications

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“…Factors that have delayed the elucidation of an exact frequency have primarily arisen from the diversity of study designs, including positive family history-only case designs (32 -35), MSI-type EC studies (36,37), and groups without definitive MMR mutation results, a limitation also associated with our current study. The largest study thus far of unselected EC patients (n = 543) concluded, after comprehensive mutation testing and consistent with two previous reports (11,35), that at least 1.8% of all EC could be attributed to Lynch syndrome (14). In that report, immunohistochemistry for MMR was used post hoc essentially to confirm MSI results, and investigations were not confined to the young-onset patient as is the case here.…”

Section: Discussionsupporting

confidence: 62%

“…We also examined the family history of a first-degree relative with any type of cancer and found no significant difference between our two groups. In a previous study, Suomi et al (35) investigated the family history of 291 EC patients ages V60 years. They found that 45% (130 of 291) of patients in their study had at least one first-degree family member with cancer.…”

Section: Discussionmentioning

confidence: 99%

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Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Walsh¹,

Cummings²,

Buchanan³

et al. 2008

Clinical Cancer Research

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Purpose: A woman with early-onset endometrial cancer (EC) may represent the ''sentinel''cancer event in a Lynch syndrome kindred.The aim of this study was to determine the incidence of Lynch syndrome in a series of young-onset EC, and to identify molecular, clinical, and pathologic features that may alert clinicians to the presence of this disorder. Experimental Design: Patients with EC, ages V50 years, were identified from the Queensland Centre for Gynaecological Cancer. Tumor sections underwent histopathology review and were immunostained for mismatch repair proteins. Tumor DNA was tested for microsatellite instability and methylation of MLH1. Patients were conservatively classified as presumptive Lynch syndrome if their tumors showed loss of at least one mismatch repair protein and were negative for methylation of MLH1. Personal and family history of cancer was reviewed where available. Results: Presumptive Lynch syndrome was seen in 26 of 146 (18%) tumors. These tumors were more likely to be poorly differentiated, International Federation of Gynecology and Obstetrics stage II and above, have tumor-infiltrating lymphocytes, have higher mitotic rate, and have deeper myometrial invasion (P < 0.05). Lynch syndrome cases were more likely to be associated with a positive family history when analyzed for Amsterdam criteria II, diagnosis of a Lynch syndrome spectrum cancer in at least one first-degree relative, and family history of any cancer (P < 0.05).Conclusion: Presumptive Lynch syndrome was identified in 18% of early-onset EC. A risk of this magnitude would argue for routine immunohistochemical testing of tumors in patients diagnosed with EC at or before the age of 50 years.

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Section: Discussionsupporting

confidence: 62%

Section: Discussionmentioning

confidence: 99%

Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Walsh¹,

Cummings²,

Buchanan³

et al. 2008

Clinical Cancer Research

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“…Analysis of all 24 tumor suppressor loci included in the assay All tumors displaying a reduction over 21% for one allele (i.e. having ratios below 0.8 or above 1.25) were regarded as having LOH, including 21 with 'strict LOH' (X40% reduction) and nine with 'putative LOH' (21-39% reduction; Ollikainen et al (2005)). ND, not determined.…”

Section: Resultsmentioning

confidence: 99%

“…The allele frequency ratios for tumor samples were divided by the allele frequency ratio of the corresponding normal sample. The thresholds for LOH were defined according to Ollikainen et al (2005).…”

Section: Methodsmentioning

confidence: 99%

“…Considerably less data are available on the mechanisms of inactivation of the wt allele in HNPCC spectrum tumors other than CRC, notably endometrial cancer (EC) that is the most common extracolonic malignancy in HNPCC. In occasional EC tumors studied from HNPCC patients, LOH (for MSH2 and MSH6; Ollikainen et al, 2005) and somatic frameshift mutations (for MSH6; Wijnen et al, 1999) have been implicated. Sporadic EC resembles sporadic CRC, in that MLH1 promoter methylation appears to be the primary mechanism of MSI (Esteller et al, 1998;Simpkins et al, 1999).…”

Section: Introductionmentioning

confidence: 99%

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Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

et al. 2007

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Mutations in the DNA mismatch repair gene MLH1 are a major cause of hereditary nonpolyposis colorectal cancer (HNPCC). No mutant phenotype is observed before the wild-type (wt) allele is somatically inactivated in target tissue. We addressed the mechanisms of MLH1 inactivation in 25 colorectal (CRC) and 32 endometrial cancers (ECs) from MLH1 mutation carriers (Mut1, in-frame genomic deletion; Mut2, out-of-frame splice site mutation; Mut3, missense mutation). By a quantitative method, matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF), utilizing four intragenic single nucleotide polymorphisms and mutations, loss of heterozygosity (LOH) was present in 31/57 (54.4%) of tumors. The wt allele displayed LOH more often than the mutant allele (23/57 vs 8/57, P ¼ 0.006). For Mut1, LOH was more frequent in CRC than EC (10/11 vs 1/13, Po0.0001), whereas Mut2 and Mut3 displayed opposite LOH pattern. Moreover, although wt LOH predominated in CRC irrespective of the predisposing mutation, LOH often affected the mutant allele in EC from Mut2 and Mut3 carriers (6/19, 31.6%). MLH1 promoter methylation, which reflected a more widespread hypermethylation tendency, occurred in 4/55 (7.3%) of tumors and was inversely associated with LOH. In conclusion, the patterns of somatic events (LOH and promoter methylation) differ depending on the tissue and germline mutation, which may in part explain the differential tumor susceptibility of different organs in HNPCC. MALDI-TOF provides a novel approach for the detection and quantification of LOH.

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Targeted next‐generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families

et al. 2016

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Causative germline mutations in mismatch repair (MMR) genes can only be identified in ~50% of families with a clinical diagnosis of the inherited colorectal cancer (CRC) syndrome hereditary nonpolyposis colorectal cancer (HNPCC)/Lynch syndrome (LS). Identification of these patients are critical as they are at substantially increased risk of developing multiple primary tumors, mainly colorectal and endometrial cancer (EC), occurring at a young age. This demonstrates the need to develop new and/or more thorough mutation detection approaches. Next‐generation sequencing (NGS) was used to screen 22 genes involved in the DNA MMR pathway in constitutional DNA from 14 HNPCC and 12 sporadic EC patients, plus 2 positive controls. Several softwares were used for analysis and functional annotation. We identified 5 exonic indel variants, 42 exonic nonsynonymous single‐nucleotide variants (SNVs) and 1 intronic variant of significance. Three of these variants were class 5 (pathogenic) or class 4 (likely pathogenic), 5 were class 3 (uncertain clinical relevance) and 40 were classified as variants of unknown clinical significance. In conclusion, we have identified two LS families from the sporadic EC patients, one without a family history of cancer, supporting the notion for universal MMR screening of EC patients. In addition, we have detected three novel class 3 variants in EC cases. We have, in addition discovered a polygenic interaction which is the most likely cause of cancer development in a HNPCC patient that could explain previous inconsistent results reported on an intronic EXO1 variant.

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Molecular Analysis of Familial Endometrial Carcinoma: A Manifestation of Hereditary Nonpolyposis Colorectal Cancer or a Separate Syndrome?

Cited by 123 publications

References 36 publications

Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Molecular, Pathologic, and Clinical Features of Early-Onset Endometrial Cancer: Identifying Presumptive Lynch Syndrome Patients

Mechanisms of inactivation of MLH1 in hereditary nonpolyposis colorectal carcinoma: a novel approach

Targeted next‐generation sequencing of 22 mismatch repair genes identifies Lynch syndrome families

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