The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

Ryan, Neil; Glaire, Mark A.; Blake, Dominic; Cabrera-Dandy, Marcus; Evans, D. Gareth; Crosbie, Emma J.

doi:10.1038/s41436-019-0536-8

Cited by 168 publications

(169 citation statements)

References 81 publications

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“…Path_MMR carriers’ association with EC is well established [ 3 ]; however, the proportion of EC patients likely to test positive for LS is uncertain, with estimates spanning <1% to >10%. The variation in estimates comes from methodological heterogeneity, small sample sizes, and incomplete testing [ 13 ]. Initial tumour triage by immunohistochemistry (IHC) and/or MSI with/without MLH1 -methylation testing selects women for definitive constitutional analysis [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

et al. 2020

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Background Lynch syndrome (LS) predisposes to endometrial cancer (EC), colorectal cancer, and other cancers through inherited pathogenic variants affecting mismatch-repair (MMR) genes. Diagnosing LS in women with EC can reduce subsequent cancer mortality through colonoscopic surveillance and aspirin chemoprevention; it also enables cascade testing of relatives. A growing consensus supports LS screening in EC; however, the expected proportion of test positives, and optimal testing strategy is uncertain. Previous studies from insurance-based healthcare systems were limited by narrow selection criteria, failure to apply reference standard tests consistently, and poor conversion to definitive testing. The aim of this study was to establish the prevalence of LS and the diagnostic accuracy of LS testing strategies in an unselected EC population. Methods and findings This was a prospective cross-sectional study carried out at a large United Kingdom gynaecological cancer centre between October 2015 and January 2017. Women diagnosed with EC or atypical hyperplasia (AH) were offered LS testing. Tumours underwent MMR immunohistochemistry (IHC), microsatellite instability (MSI), and targeted MLH1 -methylation testing. Women <50 years, with strong family histories and/or indicative tumour molecular features, underwent MMR germline sequencing. Somatic MMR sequencing was performed when indicative molecular features were unexplained by LS or MLH1 -hypermethylation. The main outcome measures were the prevalence of LS in an unselected EC population and the diagnostic accuracy of clinical and tumour testing strategies for risk stratifying women with EC for MMR germline sequencing. In total, 500 women participated in the study; only 2 (<1%) declined. Germline sequencing was indicated and conducted for 136 and 135 women, respectively. A total of 16/500 women (3.2%, 95% CI 1.8% to 5.1%) had LS, and 11 more (2.2%) had MMR variants of uncertain significance. Restricting testing to age <50 years, indicative family history (revised Bethesda guidelines or Amsterdam II criteria) or endometrioid histology alone would have missed 9/16 (56%), 8/13 (62%) or 9/13 (69%), and 5/16 (31%) cases of LS, respectively. In total 132/500 tumours were MMR deficient by IHC of which 83/132 (63%) had MLH1 -hypermethylation, and 16/49 (33%) of the remaining patients had LS (16/132 with MMR deficiency, 12%). MMR-IHC with targeted MLH1 -methylation testing was more discriminatory for LS than MSI with targeted methylation testing, with 100% versus 56.3% (16/16 versus 9/16) sensitivity ( p = 0.016) and equal 97.5% (468/484) specificity; 64% MSI-H and 73% MMR deficient tumours unexplained by LS or MLH1- hypermethylation had somatic MMR mutations. The main limitation of the study was failure to conduct MMR germline sequencing for the whole study population, w...

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Section: Introductionmentioning

confidence: 99%

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

et al. 2020

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“…Up to 25% of ECs demonstrate disruption of the MMR pathway, revealed by high MSI and/or loss of MMR protein expression (MMR-deficiency) by immunohistochemistry (IHC). Approximately, 13%–25% of MMR-deficient ECs are related to pathogenic germline variants in the MLH1 , MSH2 , MSH6 or PMS2 (Lynch syndrome) genes, while 62%–73% result from somatic hypermethylation of the promoter region of the MLH1 gene [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

An Analysis of Clinical, Surgical, Pathological and Molecular Characteristics of Endometrial Cancer According to Mismatch Repair Status. A Multidisciplinary Approach

Dondi

Coluccelli

Leo

et al. 2020

IJMS

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Since 2016, our hospital has applied tumor testing with immunohistochemistry (IHC) in endometrial cancer in order to detect mutations of mismatch repair genes (MMR). All cases with MMR deficiency proteins expression are sent for genetic testing, except those with MLH1 protein deficiency, in which case genetic testing is performed if negative for promoter hypermethylation. The primary aim of this study was to investigate the ability of our algorithm to identify Lynch syndrome (LS). The Secondary aims were to investigate the relationship between MMR status and clinicopathological features and prognosis of primary endometrial cancer (EC). From January 2016 to December 2018, 239 patients with EC were retrospectively analyzed and subdivided according to MMR status. Patients were divided in three groups: MMR proficient, LS and Lynch-like cancer (LLC). LS was characterized by a lower age and BMI, more use of contraceptive and less use of hormonal replacement therapy, nulliparity and a trend versus a better prognosis. LLC appeared more related to MMR proficient than LS and exhibited a more aggressive behavior. Our multidisciplinary approach permitted a correct diagnosis of germline mutation in patients with newly diagnosis EC and it confirmed clinicopathologic and prognostic characteristics of LS.

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“…In addition, there was a slightly higher prevalence of prior ovary cancer in patients with index breast cancer (3.8%) than the general cancer population (2.4%) [15]. This may be indicative of hereditary cancers (such as hereditary breast and ovarian cancer syndrome, Lynch syndrome, and Li-Fraumeni syndrome) or the effects of previous treatments for prior cancers [35,36].…”

Section: Discussionmentioning

confidence: 99%

Increasing Trends in the Prevalence of Prior Cancer in Newly Diagnosed Lung, Stomach, Colorectal, Breast, and Uterine Cancer Patients: A Population-Based Study

Sato

Matsubayashi

Morishima

et al. 2020

Preprint

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Background: Cancer survivors are frequently excluded from clinical research, resulting in their omission from the development of many cancer treatment strategies. Quantifying the prevalence of prior cancer in newly diagnosed cancer patients can inform research and clinical practice. This study aimed to describe the prevalence, characteristics, and trends of prior cancer in newly diagnosed cancer patients in Japan.Methods: Using Osaka Cancer Registry data, we examined the prevalence, characteristics, and time trends of prior cancer in patients who received new diagnoses of lung, stomach, colorectal, female breast, or uterine cancer between 2004 and 2015. Site-specific prior cancers were examined for a maximum of 15 years before the new cancer was diagnosed. Time trends were evaluated using the Cochran-Armitage trend test.Results: Among 275,895 newly diagnosed cancer patients, 21,757 (7.9%) had prior cancer. The prevalence of prior cancer ranged from 3.3% (breast cancer) to 11.1% (lung cancer). In both sexes, the age-adjusted prevalence of prior cancer had increased in recent years (P values for trend < 0.001), especially in newly diagnosed lung cancer patients. The proportion of smoking-related prior cancers exceeded 50% in patients with newly diagnosed lung, stomach, colorectal, and breast cancer.Conclusions: The prevalence of prior cancer in newly diagnosed cancer patients is relatively high, and has increased in recent years. Our findings suggest that a deeper understanding of the prevalence and characteristics of prior cancer in cancer patients is needed to promote more inclusive clinical research and support the expansion of treatment options.

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The proportion of endometrial cancers associated with Lynch syndrome: a systematic review of the literature and meta-analysis

Cited by 168 publications

References 81 publications

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

The proportion of endometrial tumours associated with Lynch syndrome (PETALS): A prospective cross-sectional study

An Analysis of Clinical, Surgical, Pathological and Molecular Characteristics of Endometrial Cancer According to Mismatch Repair Status. A Multidisciplinary Approach

Increasing Trends in the Prevalence of Prior Cancer in Newly Diagnosed Lung, Stomach, Colorectal, Breast, and Uterine Cancer Patients: A Population-Based Study

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