A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours

Schofield, Lyn; Grieu, Fabienne; Goldblatt, Jack; Amanuel, Benhur; Iacopetta, Barry

doi:10.1007/s10689-011-9494-2

Cited by 24 publications

(12 citation statements)

References 26 publications

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“…MMR testing is commonly requested without prior selection in the 5% of colon cancers that develop before age 50 [29-31]. Our study thus focused on patients ≥50 years of age, 23% of whom had MMR deficient colon cancers with loss of MLH1/PMS2 in 86% of the cases.…”

Section: Discussionmentioning

confidence: 99%

Efficient and reproducible identification of mismatch repair deficient colon cancer: validation of the MMR index and comparison with other predictive models

Joost

Bendahl

Halvarsson³

et al. 2013

BMC Clin Pathol

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BackgroundThe identification of mismatch-repair (MMR) defective colon cancer is clinically relevant for diagnostic, prognostic and potentially also for treatment predictive purposes. Preselection of tumors for MMR analysis can be obtained with predictive models, which need to demonstrate ease of application and favorable reproducibility.MethodsWe validated the MMR index for the identification of prognostically favorable MMR deficient colon cancers and compared performance to 5 other prediction models. In total, 474 colon cancers diagnosed ≥ age 50 were evaluated with correlation between clinicopathologic variables and immunohistochemical MMR protein expression.ResultsFemale sex, age ≥60 years, proximal tumor location, expanding growth pattern, lack of dirty necrosis, mucinous differentiation and presence of tumor-infiltrating lymphocytes significantly correlated with MMR deficiency. Presence of at least 4 of the MMR index factors identified MMR deficient tumors with 93% sensitivity and 76% specificity and showed favorable reproducibility with a kappa value of 0.88. The MMR index also performed favorably when compared to 5 other predictive models.ConclusionsThe MMR index is easy to apply and efficiently identifies MMR defective colon cancers with high sensitivity and specificity. The model shows stable performance with low inter-observer variability and favorable performance when compared to other MMR predictive models.

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Section: Discussionmentioning

confidence: 99%

Efficient and reproducible identification of mismatch repair deficient colon cancer: validation of the MMR index and comparison with other predictive models

Joost

Bendahl

Halvarsson³

et al. 2013

BMC Clin Pathol

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“…Widening the inclusion criteria by adding indicators, resulted in increased sensitivity compared with the clinical criteria described above (89%, 95% CI 86% to 92%), and reduced specificity (53%, 95% CI 49% to 58%) 42Clinicopathological criteria to identify mismatch repair gene mutations Bethesda Guidelines (1997) 53Colorectal tumours should be tested for MSI in any of the following situations: Individuals with cancer in families that meet the Amsterdam Criteria Individuals with two HNPCC-related cancers, including synchronous and metachronous colorectal cancers or associated extracolonic cancers* Individuals with colorectal cancer, and a first-degree relative with colorectal cancer and/or HNPCC-related extracolonic cancer and/or a colorectal adenoma; one of the cancers diagnosed at age <45 years, and the adenoma diagnosed at age <40 years Individuals with colorectal cancer or endometrial cancer diagnosed at age <45 years Individuals with right-sided CRC with an undifferentiated pattern (solid/cribriform) on histopathology diagnosed at age <45 years Individuals with CRC which was composed of >50% signet ring cells and diagnosed at age <45 years Individuals with adenomas diagnosed at age <40 years. Revised Bethesda Guidelines (2004) 23Colorectal tumours should be tested for MSI in any of the following situations: CRC diagnosed at age <50 years Presence of synchronous or metachronous HNPCC-related tumours,† regardless of age CRC with MSI-high histology‡ diagnosed in individuals aged <60 years CRC diagnosed in one or more first-degree relatives with an HNPCC-related tumour, with one of the cancers being diagnosed at age <50 years CRC diagnosed in two or more first-degree or second-degree relatives with HNPCC-related tumours†, regardless of age Melbourne Criteria (2005) 54 Individuals with CRC diagnosed at age <45 years irrespective of family history should be tested for mismatch repair deficiency using IHC. Perth Criteria (2012) 57 Individuals with CRC diagnosed at age <60 years irrespective of family history should be tested for MSI. Jerusalem Recommendation (2010) 22 Individuals with CRC diagnosed at age <70 years irrespective of family history should be tested for MSI or mismatch repair deficiency using IHC. *Endometrial, ovarian, gastric, hepatobiliary, small bowel, ureter and renal pelvis tumours.†colorectal, endometrial, stomach, small bowel, ovarian, pancreas, ureter and renal pelvis, biliary tract, and brain tumours, sebaceous gland adenomas and keratoacanthomas.‡Presence of tumour-infiltrating lymphocytes, Crohn's-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern.HNPCC, Hereditary non-polyposis colorectal cancer; CRC, colorectal cancer; MSI, microsatellite instability; IHC, immunohistochemistry.…”

Section: Clinicopathological Criteriamentioning

confidence: 99%

“…Perth Criteria (2012) 57 Individuals with CRC diagnosed at age <60 years irrespective of family history should be tested for MSI. …”

Section: Clinicopathological Criteriamentioning

confidence: 99%

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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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“…As a result, tumors from MMR gene mutation carriers characteristically demonstrate MMR deficiency, defined as the presence of microsatellite instability (MSI) at high levels (MSI-H) and/or loss of MMR protein expression determined by immunohistochemistry (IHC). 11 There have been several alternative recommendations for colorectal tumor testing for MMR deficiency by IHC and/or MSI testing using different ages of colorectal cancer diagnosis as a cut-off, regardless of family history; for example, age 50 years 12 , 13 or 60 years 14 , 15 or 70 years. 16 However, several groups recommend that all cases of colorectal cancer should be tested for MMR deficiency regardless of their age at diagnosis or family history 17 – 22 given that a proportion of colorectal cancers caused by MMR mutations occur at old age.…”

Section: Introductionmentioning

confidence: 99%

Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome)

Buchanan¹,

Rosty²,

Clendenning³

et al. 2014

TACG

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Carriers of a germline mutation in one of the DNA mismatch repair (MMR) genes have a high risk of developing numerous different cancers, predominantly colorectal cancer and endometrial cancer (known as Lynch syndrome). MMR gene mutation carriers develop tumors with MMR deficiency identified by tumor microsatellite instability or immunohistochemical loss of MMR protein expression. Tumor MMR deficiency is used to identify individuals most likely to carry an MMR gene mutation. However, MMR deficiency can also result from somatic inactivation, most commonly methylation of the MLH1 gene promoter. As tumor MMR testing of all incident colorectal and endometrial cancers (universal screening) is becoming increasingly adopted, a growing clinical problem is emerging for individuals who have tumors that show MMR deficiency who are subsequently found not to carry an MMR gene mutation after genetic testing using the current diagnostic approaches (Sanger sequencing and multiplex ligation-dependent probe amplification) and who also show no evidence of MLH1 methylation. The inability to determine the underlying cause of tumor MMR deficiency in these “Lynch-like” or “suspected Lynch syndrome” cases has significant implications on the clinical management of these individuals and their relatives. When the data from published studies are combined, 59% (95% confidence interval [CI]: 55% to 64%) of colorectal cancers and 52% (95% CI: 41% to 62%) of endometrial cancers with MMR deficiency were identified as suspected Lynch syndrome. Recent studies estimated that colorectal cancer risk for relatives of suspected Lynch syndrome cases is lower than for relatives of those with MMR gene mutations, but higher than for relatives of those with tumor MMR deficiency resulting from methylation of the MLH1 gene promoter. The cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely due to either unidentified germline MMR gene mutations, somatic cell mosaicism, or biallelic somatic inactivation. Determining the underlying cause of tumor MMR deficiency in suspected Lynch syndrome cases is likely to reshape the current triaging schemes used to identify germline MMR gene mutations in cancer-affected individuals and their relatives.

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A state-wide population-based program for detection of lynch syndrome based upon immunohistochemical and molecular testing of colorectal tumours

Cited by 24 publications

References 26 publications

Efficient and reproducible identification of mismatch repair deficient colon cancer: validation of the MMR index and comparison with other predictive models

Efficient and reproducible identification of mismatch repair deficient colon cancer: validation of the MMR index and comparison with other predictive models

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

Clinical problems of colorectal cancer and endometrial cancer cases with unknown cause of tumor mismatch repair deficiency (suspected Lynch syndrome)

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