Performance of PREMM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases

Mercado, Rowena; Hampel, Heather; Kastrinos, Fay; Steyerberg, Ewout W.; Balmañà, Judith; Stoffel, Elena M.; Cohn, David E.; Backes, Floor J.; Hopper, John L.; Jenkins, Mark A.; Lindor, Noralane M.; Casey, Graham; Haile, Robert W.; Madhavan, Subha; Chapelle, Albert de la; Syngal, Sapna

doi:10.1038/gim.2012.18

Cited by 41 publications

(45 citation statements)

References 31 publications

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“…Of them, four used population-based samples,74 82––84 10 used clinic-based samples,71 72 75 85––91 and three used both clinic-based and population-based samples 73 92 93. Given there was significant evidence of heterogeneity between studies, we reported the pooled AUC values from random effect models (detail in table 2).…”

Section: Prediction Modelsmentioning

confidence: 99%

Criteria and prediction models for mismatch repair gene mutations: a review

et al. 2013

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One of the strongest predictors of colorectal cancer risk is carrying a germline mutation in a DNA mismatch repair (MMR) gene. Once identified, mutation carriers can be recommended for intensive screening that will substantially reduce their high colorectal cancer risk. Conversely, the relatives of carriers identified as noncarriers can be relieved of the burden of intensive screening. Criteria and prediction models that identify likely mutation carriers are needed for cost-effective, targeted, germline testing for MMR gene mutation. We reviewed 12 criteria/guidelines and 8 prediction models (Leiden, Amsterdam-plus, Amsterdam-alternative, MMRpro, PREMM 1,2,6 , MMRpredict, Associazione Italiana per lo studio della Familiarità ed Ereditarietà dei tumori Gastrointestinali (AIFEG) and the Myriad Genetics Prevalence table) for identifying mutation carriers. While criteria are only used to identify individuals with colorectal cancer (yes/no for screening followed by germline testing), all prediction models except MMRpredict and Myriad tables can predict the probability of carrying mutations for individuals with or without colorectal cancer. We conducted a meta-analysis of the discrimination performance of 17 studies that validated the prediction models. The pooled estimate for the area under curve was 0.80 (95% CI 0.72 to 0.88) for MMRpro, 0.81 (95% CI 0.73 to 0.88) for MMRpredict, 0.84 (95% CI 0.81 to 0.88) for PREMM, and 0.85 (95% CI 0.78 to 0.91) for Leiden model. Given the high degree of overlap in the CIs, we cannot state that one model has a higher discrimination than any of the others. Overall, the existing statistical models have been shown to be sensitive and specific (at a 5% cut-off ) in predicting MMR gene mutation carriers. Future models may need to: provide prediction of PMS2 mutations, take into account a wider range of Lynch syndrome-associated cancers when assessing family history, and be applicable to all people irrespective of any cancer diagnosis.

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Section: Prediction Modelsmentioning

confidence: 99%

Criteria and prediction models for mismatch repair gene mutations: a review

et al. 2013

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“…These models were validated in the colorectal cancer population for the detection of MLH1 , MSH2 , and MSH6 mutations with favorable results. When applied to the endometrial cancer patient population, however, these models fail to perform at a level that would support their use as a clinical screening tool (8). …”

Section: Introductionmentioning

confidence: 99%

Evaluation of Clinical Criteria for the Identification of Lynch Syndrome among Unselected Patients with Endometrial Cancer

Bruegl¹,

Djordjevic

Batte³

et al. 2014

Cancer Prevention Research

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Clinical criteria, primarily young age of cancer onset and family history of signature cancers, have been developed to identify individuals at elevated risk for Lynch Syndrome with the goals of early identification and cancer prevention. In 2007, the Society of Gynecologic Oncology (SGO) codified criteria for women presenting with gynecologic cancers. These criteria have not been validated in a population-based setting. For 412 unselected endometrial cancers, immunohistochemical expression of DNA mismatch repair proteins and MLH1 methylation were assessed to classify tumors as sporadic or probable Lynch Syndrome. In this cohort, 10.5% of patients were designated as probable Lynch Syndrome based on tumor testing. The sensitivity and specificity of SGO criteria to identify these same cases were 32.6% (95% CI 19.2–48.5) and 77% (95% CI 72.7–81.8), respectively. With the exception of tumor location in the lower uterine segment, multivariate analysis of clinical features, family history, and pathologic variables failed to identify significant differences between the sporadic and probable Lynch Syndrome groups. A simplified cost-effectiveness analysis demonstrated that SGO clinical criteria and universal tissue testing strategies had comparable costs per probable Lynch Syndrome patient identified. In conclusion, SGO criteria successfully identify probable Lynch Syndrome cases among women with endometrial cancer who are young or have significant family history of signature tumors. However, a larger proportion of probable Lynch Syndrome patients who are older and have less significant family history are not detected by this screening strategy. Universal tissue testing may be necessary to capture more individuals at risk for having Lynch Syndrome.

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“…Risk prediction models, such as MMRpredict,15 PREMM,16 MMRPro17 and MsPath,18 calculate an individual's risk of Lynch syndrome, predominantly using a combination of family history, the patient's age at diagnosis, and the site of the colorectal tumour. There is no agreement, however, on the risk threshold meriting formal screening for Lynch syndrome.…”

Section: Discussionmentioning

confidence: 99%

UK colorectal cancer patients are inadequately assessed for Lynch syndrome

Adelson

Pannick

East

et al. 2013

Frontline Gastroenterol

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ObjectiveTo establish whether colorectal cancer patients in two centres in the UK are screened appropriately for Lynch syndrome, in accordance with current international guidance.DesignPatients newly diagnosed with colorectal cancer over an 18-month period were identified from the UK National Bowel Cancer Audit Programme. Their records and management were reviewed retrospectively.SettingTwo university teaching hospitals, Imperial College Healthcare and Oxford Radcliffe Hospitals NHS Trusts.Outcomes measuredWhether patients were screened for Lynch syndrome—and the outcome of that evaluation, if it took place—were assessed from patients' clinical records. The age, tumour location and family history of screened patients were compared to those of unscreened patients.ResultsFive hundred and fifty three patients with newly diagnosed colorectal cancer were identified. Of these, 97 (17.5%) satisfied the revised Bethesda criteria, and should have undergone further assessment. There was no evidence that those guidelines had been contemporaneously applied to any patient. In practice, only 22 of the 97 (22.7%) eligible patients underwent evaluation. The results for 14 of those 22 (63.6%) supported a diagnosis of Lynch syndrome, but only nine of the 14 (64.3%) were referred for formal mismatch repair gene testing. No factors reliably predicted whether or not a patient would undergo Lynch syndrome screening.ConclusionsColorectal teams in the UK do not follow international guidance identifying the patients who should be screened for Lynch syndrome. Patients and their families are consequently excluded from programmes reducing colorectal cancer incidence and mortality. Multidisciplinary teams should work with their local genetics services to develop reliable algorithms for patient screening and referral.

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Performance of PREMM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases

Cited by 41 publications

References 31 publications

Criteria and prediction models for mismatch repair gene mutations: a review

Criteria and prediction models for mismatch repair gene mutations: a review

Evaluation of Clinical Criteria for the Identification of Lynch Syndrome among Unselected Patients with Endometrial Cancer

UK colorectal cancer patients are inadequately assessed for Lynch syndrome

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