Turcot Syndrome


Turcot Syndrome is characterised by malignant tumors of the central nervous system (mostly astrocytomas and medulloblastoma) associated with familial polyposis of the colon. There are different sub-types (Paraf F et al, 1997).

Literature Analysis

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Tag cloud generated 29 August, 2019 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (5)

How to use this data tableClicking on the Gene or Topic will take you to a separate more detailed page. Sort this list by clicking on a column heading e.g. 'Gene' or 'Topic'.

PMS2 7p22.1 MLH4, PMSL2, HNPCC4, PMS2CL Germline
-PMS2 mutations in Turcot Syndrome
MLH1 3p22.2 FCC2, COCA2, HNPCC, hMLH1, HNPCC2 Germline
-MLH1 mutations in Turcot Syndrome
APC 5q22.2 GS, DP2, DP3, BTPS2, DP2.5, PPP1R46 Germline
-APC mutations in Turcot Syndrome
MSH2 2p21 FCC1, COCA1, HNPCC, LCFS2, HNPCC1 Germline
-MSH2 mutations in Turcot Syndrome
MSH6 2p16 GTBP, HSAP, p160, GTMBP, HNPCC5 Germline
-MSH6 mutations in Turcot Syndrome

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Useful Links (4 links)

Latest Publications

Yozu M, Kumarasinghe MP, Brown IS, et al.
Australasian Gastrointestinal Pathology Society (AGPS) consensus guidelines for universal defective mismatch repair testing in colorectal carcinoma.
Pathology. 2019; 51(3):233-239 [PubMed] Related Publications
Lynch syndrome is the most common hereditary form of colorectal carcinoma caused by a constitutional pathogenic mutation in a DNA mismatch repair gene. Identifying Lynch syndrome is essential to initiate intensive surveillance program for the patient and affected relatives. On behalf of the Australasian Gastrointestinal Pathology Society (AGPS), we present in this manuscript consensus guidelines for Lynch syndrome screening in patients with colorectal carcinoma. The goal of this consensus document is to provide recommendations to pathologists for diagnosis of Lynch syndrome with discussion of the benefits and limitations of each test. Universal screening for defective mismatch repair is recommended, in agreement with the recent endorsement of universal testing by the National Health and Medical Research Council in Australia and the New Zealand Ministry of Health. The value of evaluating defective mismatch repair is acknowledged not only for Lynch syndrome screening but also for therapeutic decision information in patient management. AGPS advocates appropriate government funding for the molecular tests necessary for Lynch syndrome screening (BRAF mutation, MLH1 methylation testing).

Buecher B, Le Mentec M, Doz F, et al.
[Constitutional MMR deficiency: Genetic bases and clinical implications].
Bull Cancer. 2019; 106(2):162-172 [PubMed] Related Publications
Inherited mono-allelic mutation in one of the 4 major MMR genes results in Lynch syndrome which predisposes, in adulthood, mainly to colorectal and endometrial tumors characterized by microsatellite instability (MSI phenotype). Individuals with bi-allelic mutations of one of these genes developed early and multiple malignancies, most often in childhood. This recessively inherited condition is named CMMRD for Constitutional Mismatch Repair Deficiency. The spectrum of tumors is distinct from Lynch syndrome. Malignant brain tumors are at least as frequent as gastrointestinal tumors and in more than a third of cases haematological malignancies were also reported. Patients also displayed clinical features similar of neurofibromatosis type 1, especially café au lait spots. The most commonly involved genes are PMS2 and MSH6 while bi-allelic MLH1 and MSH2 mutations are rare. The digestive tumors of these patients show MSI whereas the brain tumors can be "microsatellite stable". Because of variable clinical presentation and phenotypical overlaps with other cancer syndromes, CMMRD syndrome is frequently unrecognized by clinicians and its incidence is almost certainly underestimated. A better knowledge of clinical criteria and diagnosis methods should improve the identification of these patients at least at the time when they develop their first tumor or even before. This will allow adjusting treatment modalities and offering surveillance strategies of other tumor risks, not only for patients themselves but also for their relatives.

Cheung AH, Chow C, Yu MY, et al.
Mismatch repair deficiency is implicated in carcinoma arising from ovarian teratoma.
Pathology. 2019; 51(1):67-73 [PubMed] Related Publications
Malignant transformation of benign mature ovarian teratoma can result in a wide spectrum of cancer, including a variety of carcinoma, sarcoma, or melanoma. The role of mismatch repair defects in such malignant transformation is still elusive. In view of current immunotherapy, the role of mismatch repair deficiency can have significant implications on therapeutic strategy. Thus, we aimed to investigate the possible involvement of mismatch repair deficiency in somatic-type carcinoma arising from teratoma. We examined seven cases of malignant transformation of ovarian teratoma to carcinoma from the years 2000-2017. Mismatch repair deficiency was demonstrated in two cases, one of which was a squamous carcinoma and another a sebaceous carcinoma. By immunohistochemistry and molecular studies, we detected mismatch repair protein deficiency, microsatellite instability (MSI) and MLH1 promoter methylation in the derived carcinoma, but not in the benign teratoma, indicating mismatch repair deficiency was implicated in the process of malignant transformation. Our findings expand the spectrum of genetic alterations which are known to accompany malignant changes in benign teratoma. This finding is also of potential therapeutic significance, as mismatch repair deficient tumours can often be responsive to immune checkpoint blockade because of the high mutational load. In conclusion, we report that a subset of teratoma-derived carcinoma harbours MLH1 promoter methylation which underlies DNA mismatch repair deficiency, and this subset of patients has the potential to benefit from immunotherapy.

Baig SM, Fatima A, Tariq M, et al.
Hereditary brain tumor with a homozygous germline mutation in PMS2: pedigree analysis and prenatal screening in a family with constitutional mismatch repair deficiency (CMMRD) syndrome.
Fam Cancer. 2019; 18(2):261-265 [PubMed] Related Publications
Precise genetic counseling and prenatal diagnosis are often hindered by incomplete penetrance of risk variance and complex patterns of inheritance. Here, we performed a clinical and genetic study of a five-generation Pakistani family with a history of multiple cases of childhood brain tumors. Six affected individuals died of brain tumors at very early ages and three were confirmed as having a homozygous mutation in exon 6 of the PMS2 gene (c.543delT). Fifteen members of the family were identified as heterozygous carriers of this mutation with a lack of cancer incidence. Both clinical manifestations and genetic test results of brain tumor patients in the family support the diagnosis of constitutional mismatch repair deficiency (CMMRD) syndrome, a condition in which individuals carry homozygous germline mutations in mismatch repair machinery genes with an early onset of malignancies such as glioma. This information was used to guide prenatal diagnosis with genetic testing on chorionic villus samples for the family. This is the first report of prenatal genetic diagnosis of hereditary brain tumor.

Hu XR, Xu C, Kang Y, et al.
[Correlation between mismatch-repair protein expression and clinicopathologic features in 658 colorectal cancers].
Zhonghua Bing Li Xue Za Zhi. 2018; 47(11):827-833 [PubMed] Related Publications

Poulos RC, Wong YT, Ryan R, et al.
Analysis of 7,815 cancer exomes reveals associations between mutational processes and somatic driver mutations.
PLoS Genet. 2018; 14(11):e1007779 [PubMed] Free Access to Full Article Related Publications
Driver mutations are the genetic variants responsible for oncogenesis, but how specific somatic mutational events arise in cells remains poorly understood. Mutational signatures derive from the frequency of mutated trinucleotides in a given cancer sample, and they provide an avenue for investigating the underlying mutational processes that operate in cancer. Here we analyse somatic mutations from 7,815 cancer exomes from The Cancer Genome Atlas (TCGA) across 26 cancer types. We curate a list of 50 known cancer driver mutations by analysing recurrence in our cohort and annotations of known cancer-associated genes from the Cancer Gene Census, IntOGen database and Cancer Genome Interpreter. We then use these datasets to perform binary univariate logistic regression and establish the statistical relationship between individual driver mutations and known mutational signatures across different cancer types. Our analysis led to the identification of 39 significant associations between driver mutations and mutational signatures (P < 0.004, with a false discovery rate of < 5%). We first validate our methodology by establishing statistical links for known and novel associations between driver mutations and the mutational signature arising from Polymerase Epsilon proofreading deficiency. We then examine associations between driver mutations and mutational signatures for AID/APOBEC enzyme activity and deficient mismatch repair. We also identify negative associations (odds ratio < 1) between mutational signatures and driver mutations, and here we examine the role of aging and cigarette smoke mutagenesis in the generation of driver mutations in IDH1 and KRAS in brain cancers and lung adenocarcinomas respectively. Our study provides statistical foundations for hypothesised links between otherwise independent biological processes and we uncover previously unexplored relationships between driver mutations and mutagenic processes during cancer development. These associations give insights into how cancers acquire advantageous mutations and can provide direction to guide further mechanistic studies into cancer pathogenesis.

He Y, Tao X, Huang F, et al.
Clinicopathologic features of endometrial cancer in Chinese patients younger than 50 years with a family history of cancer.
Medicine (Baltimore). 2018; 97(43):e12968 [PubMed] Free Access to Full Article Related Publications
Genetic factors play an important role in shaping the biologic characteristics of malignant tumors, especially in young patients. We aimed to determine the clinicopathologic features of endometrial cancer (EC) in patients younger than 50 years with a family history of cancer.Overall, 229 patients with EC, including 40 with a positive family history of cancer (PFH) and 189 with a negative family history of cancer (NFH), were enrolled in this case-control study. The family history of cancer in a 2-generation pedigree was recorded for the PFH group. Clinicopathologic features such as menarche age, body mass index, personal cancer history, grade, and histologic type were compared between the 2 groups. Mismatch repair (MMR) proteins including MLH1, PMS2, MSH2, and MSH6 were assessed by immunohistochemistry (IHC) in surgical samples. Univariate (Pearson Chi-squared test, Fisher exact test, T test, Wilcoxon rank sum test, logistic regression) statistics and stepwise multivariate logistic regression were used to identify factors associated with PFH in the analysis.Among young patients with EC, the PFH group had younger age-of-onset age of endometrial cancer (≤40 years) (odds ratio [OR] = 2.21, 95% confidence interval [95% CI]: 1.01-4.82) than the NFH group. The proportion of overweight/obese patients was high in both the NFH (58.7%) and PFH (80%) groups. Colorectal, lung, endometrial, breast, and hepatocellular carcinoma accounted for 58.6% of all cancer types among 1st- and 2nd-degree relatives. Additionally, 19.2% of patients displayed deficiency in at least 1 MMR protein, with a significantly higher proportion of MMR protein deficiency in the PFH group than in the NFH group (adjusted OR = 4.81, 95% CI: 2.14-8.83).Clinicopathologic features differ for young patients with EC with and without a family history of cancer. Surveillance of age-of-onset and family history of endometrial cancer, reduction of barriers to healthy lifestyles, and development of risk-appropriate Lynch syndrome screening tools, such as IHC, are needed for these women in Shanghai and other developing cities in China.

Casey RT, Giger O, Seetho I, et al.
Rapid disease progression in a patient with mismatch repair-deficient and cortisol secreting adrenocortical carcinoma treated with pembrolizumab.
Semin Oncol. 2018; 45(3):151-155 [PubMed] Free Access to Full Article Related Publications
CONTEXT: Metastatic adrenocortical carcinoma (ACC) is an aggressive malignancy with a poor prognosis and limited therapeutic options. A subset of ACC is due to Lynch syndrome, an inherited tumor syndrome resulting from germline mutations in mismatch repair (MMR) genes. It has been demonstrated that several cancers characterized by MMR deficiency are sensitive to immune checkpoint inhibitors that target PD-1. Here, we provide the first report of PD-1 blockade with pembrolizumab in a patient with Lynch syndrome and progressive cortisol-secreting metastatic ACC.
CASE REPORT: A 58-year-old female with known Lynch syndrome presented with severe Cushing's syndrome and was diagnosed with a cortisol-secreting ACC. Three months following surgical resection and adjuvant mitotane therapy the patient developed metastatic disease and persistent hypercortisolemia. She commenced pembrolizumab, but her second cycle was delayed due to a transient transaminitis. Computed tomography performed after 12 weeks and 2 cycles of pembrolizumab administration revealed significant disease progression and treatment was discontinued. After 7 weeks, the patient became jaundiced and soon died due to fulminant liver failure.
CONCLUSION: Treatment of MMR-deficient cortisol-secreting ACC with pembrolizumab may be ineffective due to supraphysiological levels of circulating corticosteroids, which may in turn mask severe drug-induced organ damage.

Roseweir AK, Halcrow ES, Chichilo S, et al.
ERK and p38MAPK combine to improve survival in patients with BRAF mutant colorectal cancer.
Br J Cancer. 2018; 119(3):323-329 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: In colorectal cancer (CRC), BRAF mutations influence tumour progression. In mismatch repair-deficient (dMMR) tumours, BRAF mutations are associated with a good prognosis, whereas in MMR-competent tumours, they are detrimental. The differential expression of the downstream MAPK pathway members, which are constitutively activated in BRAF mutant patients, may account for these differences.
METHODS: Phosphorylation of ERK, p38MAPK and JNK was assessed by immunohistochemistry, utilising CRC tissue microarrays. A discovery cohort (n = 187) and a validation cohort (n = 801) were analysed for associations with BRAF mutations, clinicopathological characteristics and cancer-specific survival (CSS).
RESULTS: In 801 CRC patients, nuclear ERK phosphorylation (HR 0.65 95% CI 0.48-0.88, p = 0.004) and the combined nuclear pERK/p-p38 score (HR 0.61 95% CI 0.45-0.82, p = 0.001) were independently associated with CSS, and were further associated with increased BRAF mutations (p = 0.003 and p = 0.002). When stratified for BRAF status, only MMR-competent patients harbouring the mutation and a strong combined nuclear pERK/p-p38 score (HR 0.49 95% CI 0.27-0.89, p = 0.016) demonstrated improved CSS. This improvement in CSS was specific to stage III CRC (HR 0.25 95% CI 0.10-0.64, p = 0.002).
CONCLUSIONS: MMR-competent stage III tumours harbouring BRAF mutations have an improved prognosis when strong nuclear phosphorylation of both ERK and p38MAPK is present.

Leenders EKSM, Westdorp H, Brüggemann RJ, et al.
Cancer prevention by aspirin in children with Constitutional Mismatch Repair Deficiency (CMMRD).
Eur J Hum Genet. 2018; 26(10):1417-1423 [PubMed] Free Access to Full Article Related Publications
Constitutional MisMatch Repair Deficiency (CMMRD) is caused by homozygous or compound heterozygous germline variants in one of the mismatch repair (MMR) genes (MSH2, MSH6, PMS2, MLH1). This syndrome results in early onset colorectal cancer, leukemia and lymphoma, brain tumors and other malignancies. Children with CMMRD are at high risk of developing multiple cancers and cancer surveillance does not guarantee detection of cancer at a curable stage. The development of a preventive treatment strategy would be a major step forward. Long-term daily use of acetylsalicylic acid (ASA) has been shown to reduce cancer risk in individuals with Lynch syndrome (LS). LS is caused by heterozygous germline variants of MSH2, MSH6, PMS2 and MLH1 and characterized by an increased risk of developing colorectal and endometrial cancer at adult age. Here we discuss the potential use of ASA for cancer prevention in patients with CMMRD.

Bush L, Aronson M, Tabori U, et al.
Delineating a new feature of constitutional mismatch repair deficiency (CMMRD) syndrome: breast cancer.
Fam Cancer. 2019; 18(1):105-108 [PubMed] Related Publications
Constitutional mismatch repair deficiency (CMMRD) syndrome is a rare autosomal recessive hereditary cancer condition, characterized by an exceptionally high risk of cancer, a propensity for childhood malignancies, and cutaneous features reminiscent of neurofibromatosis type 1 (NF1). We report on two sisters originally suspected of having CMMRD syndrome due to their history of colonic polyps and NF1 associated skin findings, both were subsequently found to have biallelic MSH6 mutations. After years of CMMRD syndrome follow-up, the proband was diagnosed with breast cancer at age 29, while her sister was diagnosed with a glioblastoma at age 27. Immunohistochemistry analysis on the breast tumor tissue revealed weak MSH6 protein staining. Exome sequencing revealed a hypermutated breast tumor and an ultra-hypermutated brain tumor. Multi-gene panel testing was also performed and revealed no additional mutations which might explain the proband's early onset breast cancer. This is the first documented case of breast cancer in an individual with CMMRD syndrome. We summarize the evidence supporting the possible association between breast cancer and biallelic MMR mutations. Healthcare providers should be aware of this possible association and follow-up appropriately for suspicious breast findings. In addition, this case highlights the need for frequent central nervous system screenings due to rapid progression of brain tumors.

Stewart CJR, Pearn A, Pachter N, Tan A
Peritumoral granulomatous reaction in endometrial carcinoma: association with DNA mismatch repair protein deficiency, particularly loss of PMS2 expression.
Histopathology. 2018; 73(3):428-437 [PubMed] Related Publications
AIMS: The observation of peritumoral granulomatous reactions (PGRs) in two endometrial carcinomas (ECs) with a PMS2-deficient/MLH1-intact expression pattern led us to investigate whether PGRs in EC were specifically associated with DNA mismatch repair (MMR) protein deficiency, particularly PMS2 loss.
METHODS AND RESULTS: Hysterectomy specimens from 22 MMR protein-intact and 54 MMR protein-deficient ECs were reviewed with specific attention to the presence of a PGR and a tumour-associated lymphoid reaction [including tumour-infiltrating lymphocytes (TILs) and stromal lymphoid infiltrates]. The MMR protein-deficient ECs included 22 cases with combined MLH1/PMS2 loss, 11 with combined MSH2/MSH6 loss, 11 with isolated MSH6 loss, and 10 with PMS2 loss but intact MLH1 staining (including the two 'index' cases). Overall, PGRs were identified in seven of 54 (13%) MMR protein-deficient ECs, five of which showed a PMS2-deficient/MLH1-intact immunophenotype; three of these patients had germline PMS2 mutations and one additional patient had a germline MSH6 mutation. None of the MMR protein-intact tumours showed a PGR. Although five of the seven PGR-positive ECs had a high-grade histological component, six were stage I. Most ECs with PGRs also showed TILs and stromal lymphoid reactions, similarly to MMR protein-deficient ECs in general.
CONCLUSIONS: MMR protein-deficient ECs, particularly those with PMS2 loss, occasionally show PGRs in addition to stromal lymphoid infiltrates and TILs. Therefore, PGRs could be considered to constitute a histological prompt for consideration of Lynch syndrome. The potential prognostic significance of PGRs in EC requires further study.

Cenin DR, Naber SK, Lansdorp-Vogelaar I, et al.
Costs and outcomes of Lynch syndrome screening in the Australian colorectal cancer population.
J Gastroenterol Hepatol. 2018; 33(10):1737-1744 [PubMed] Free Access to Full Article Related Publications
BACKGROUND AND AIM: Individuals with Lynch syndrome (LS) are at increased risk of LS-related cancers including colorectal cancer (CRC). CRC tumor screening for mismatch repair (MMR) deficiency is recommended in Australia to identify LS, although its cost-effectiveness has not been assessed. We aim to determine the cost-effectiveness of screening individuals with CRC for LS at different age-at-diagnosis thresholds.
METHODS: We developed a decision analysis model to estimate yield and costs of LS screening. Age-specific probabilities of LS diagnosis were based on Australian data. Two CRC tumor screening pathways were assessed (MMR immunohistochemistry followed by MLH1 methylation (MLH1-Pathway) or BRAF V600E testing (BRAF-Pathway) if MLH1 expression was lost) for four age-at-diagnosis thresholds-screening < 50, screening < 60, screening < 70, and universal screening.
RESULTS: Per 1000 CRC cases, screening < 50 identified 5.2 LS cases and cost $A7041 per case detected in the MLH1-Pathway. Screening < 60 increased detection by 1.5 cases for an incremental cost of $A25 177 per additional case detected. Screening < 70 detected 1.6 additional cases at an incremental cost of $A40 278 per additional case detected. Compared with screening < 70, universal screening detected no additional LS cases but cost $A158 724 extra. The BRAF-Pathway identified the same number of LS cases for higher costs.
CONCLUSIONS: The MLH1-Pathway is more cost-effective than BRAF-Pathway for all age-at-diagnosis thresholds. MMR immunohistochemistry tumor screening in individuals diagnosed with CRC aged < 70 years resulted in higher LS case detection at a reasonable cost. Further research into the yield of LS screening in CRC patients ≥ 70 years is needed to determine if universal screening is justified.

Polom K, Böger C, Smyth E, et al.
Synchronous metastatic gastric cancer-molecular background and clinical implications with special attention to mismatch repair deficiency.
Eur J Surg Oncol. 2018; 44(5):626-631 [PubMed] Related Publications
BACKGROUND: Current guidelines recommend that metastatic gastric cancer should not be treated with surgery unless this is required for symptom control. We hypothesized that patients with mismatch repair deficiency (MMRd) gastric cancer and metastatic disease detected at the timepoint of surgical resection would have superior survival compared to patients with MMRd cancers in the same setting.
METHODS: Clinicopathological details and survival data were collected from prospective databases at two large European centers on patients who had undergone surgery and were diagnosed with synchronous stage IV gastric cancer (distant lymph nodes, positive peritoneal cytology, peritoneal, and distant metastases) at the timepoint of surgery. Resection specimens were tested for the presence of microsatellite instability using a standard 5 mononucleotide repeat panel.
RESULTS: One hundred and seventy six patients with resected stage IV gastric cancer were identified. 14/176 (8.0%) had MSI-H (high) disease. There was no significant difference between the clinical and pathological characteristics of MSI and microsatellite stable (MSS) patients. No differences in the type of metastases were observed between MSI and MSS groups. Patients who were MSI-H had superior OS compared to MSS patients (median OS 15.9 vs. 8 months, p = 0.023). However, in Cox regression multivariate analysis only liver and peritoneal metastases were independent predictors of survival.
CONCLUSIONS: Surgically treated patients with MSI-H stage IV gastric cancer have a better survival than patients with MSS gastric cancer. Further analysis of the role of surgery in MSI stage IV GC is required.

Solomon BL, Garrido-Laguna I
Upper gastrointestinal malignancies in 2017: current perspectives and future approaches.
Future Oncol. 2018; 14(10):947-962 [PubMed] Free Access to Full Article Related Publications
The advent of immune checkpoint inhibitors (PD-1, PD-L1 and CTLA-4) has resulted in unprecedented long-term remissions of unresectable cancers. The efficacy of checkpoint inhibitors was recently demonstrated in gastrointestinal malignancies with mismatch repair deficiencies (dMMR). Pembrolizumab became the first tissue-agnostic US FDA-approved drug based on the presence of the predictive biomarker dMMR. In addition, the FDA in 2017 approved pembrolizumab for PD-L1-positive advanced gastric cancer in third-line and second-line hepatocellular therapy. Novel treatment strategies such as using anti-carcinoembryonic antigen (CEA) bispecific T cells have led to remarkable responses in microsatellite instability-low colorectal cancer. Other major breakthroughs in treating upper gastrointestinal malignancies in 2017 are discussed.

Salem ME, Puccini A, Grothey A, et al.
Landscape of Tumor Mutation Load, Mismatch Repair Deficiency, and PD-L1 Expression in a Large Patient Cohort of Gastrointestinal Cancers.
Mol Cancer Res. 2018; 16(5):805-812 [PubMed] Related Publications
The efficacy of immunotherapy varies widely among different gastrointestinal cancers. Response to immune checkpoint inhibitors is shown to correlate with tumor mutation load (TML), mismatch repair deficiency (dMMR) status, and programmed cell death-ligand 1 (PD-L1) expression. Herein, we quantify TML, dMMR, and PD-L1 expression and determine their interrelationship in gastrointestinal cancers. Here, a total of 4,125 tumors from 14 different gastrointestinal cancer sites were studied using validated assays. Next-generation sequencing was performed on genomic DNA isolated from formalin-fixed paraffin-embedded tumor specimens using the NextSeq platform. TML was calculated using only somatic nonsynonymous missense mutations sequenced with a 592-gene panel. Microsatellite instability (MSI) was assessed using direct analysis of altered known MSI loci in the target regions of the sequenced genes. PD-L1 expression was analyzed by IHC. Interestingly, right-sided colon and small-bowel adenocarcinomas had the highest prevalence of TML-high tumors (14.6% and 10.2%, respectively). Pancreatic neuroendocrine tumors and gastrointestinal stromal tumors had the lowest rates of TML-high (1.3% and 0%, respectively). TML-high was strongly associated with MSI-H (

Zhao X, May A, Lou E, Subramanian S
Genotypic and phenotypic signatures to predict immune checkpoint blockade therapy response in patients with colorectal cancer.
Transl Res. 2018; 196:62-70 [PubMed] Free Access to Full Article Related Publications
Immune checkpoint blockade therapy (ICBT) has resulted in extended overall survival for some patients with certain types of cancer, most prominently including colorectal cancer (CRC) associated with microsatellite instability (MSI). However, most patients with CRC whose phenotypes have microsatellite stability (MSS) are unresponsive to ICBT. In efforts to understand the responsiveness of CRC tumors to ICBT, genotypic and phenotypic signatures of CRC tumors are now being investigated. The MSI and MSS classification has been clinically validated as helpful in predicting response vs nonresponse to ICBT in patients with CRC. Other potential predictive markers include mutational and neoantigen loads, T-cell receptor diversity, and the immune score system, all of which have mechanistic connections to ICBT response. These novel predictive signatures could provide unprecedented insights into patients with CRC associated with MSS. Clinical trials or prospective cohort studies using standardized methodologies for biomarker quantification should be illuminating. Further validation of these novel predictive signatures will be essential to tailoring treatment of patients whose CRC is most likely to respond to ICBT.

Xiao X, Dong D, He W, et al.
Mismatch repair deficiency is associated with MSI phenotype, increased tumor-infiltrating lymphocytes and PD-L1 expression in immune cells in ovarian cancer.
Gynecol Oncol. 2018; 149(1):146-154 [PubMed] Related Publications
OBJECTIVE: The role of mismatch repair (MMR) deficiency in ovarian cancer (OC) pathogenesis and its association with other clinicopathologic features, such as microsatellite instability (MSI) and expression of checkpoint proteins, remain largely elusive.
METHODS: We performed Immunohistochemistry (IHC) for MLH1, MSH2, MSH6 and PMS2 on full-section slides from 419 OCs to assess the MMR status. The clinical relevance of MMR deficiency was analyzed in combination with clinical data. The MSI status (by MSI assay) and expression of CD3, CD8, PD-1 and PD-L1 (by IHC) were compared in OCs with different MMR status.
RESULTS: We found that 2.6% OCs were MMR-negative, 4.3% OCs were MMR-low, and 63.6% of MMR-negative OCs were of endometrioid subtype. A significantly higher proportion of MMR-negative OCs were diagnosed at stage I or II compared to MMR-proficient OCs (p=0.0041). MSI was observed in all tested MMR-negative OCs, 14.3% of tested MMR-low OCs and 3.2% of tested MMR-proficient OCs. In addition, MMR-negative OCs had better progression free survival compared to MMR-proficient and MMR-low OCs (p=0.0046). Furthermore, the majority of OCs were PD-1-positive in intratumoral lymphocytes regardless of MMR status; while MMR-negative OCs exhibited significantly increased CD3+ and CD8+ tumor-infiltrating lymphocytes, and PD-L1+ intratumoral immune cells compared to MMR-proficient OCs.
CONCLUSION: Our data suggests that MMR deficient OC is a unique molecular subgroup, characterized by early stage of diagnosis, MSI phenotype, and increased tumor-infiltrating lymphocytes. These patients may be good candidates for anti-PD-1/PD-L1 therapy.

Grant M, Haydon A, Au L, et al.
Immunohistochemistry testing for mismatch repair deficiency in Stage 2 colon cancer: A cohort study of two cancer centres.
Int J Surg. 2018; 51:71-75 [PubMed] Related Publications
BACKGROUND/OBJECTIVES: Adjuvant chemotherapy for Stage II colon cancer offers a small (2-3%) overall survival benefit and is not universally recommended. Mismatch repair deficiency (dMMR) confers an improved prognosis identifying patients unlikely to benefit from adjuvant chemotherapy. The aim of this study was to investigate the use of dMMR immunohistochemistry in two major cancer treatment centres.
METHODS: Prospective data were collected on all patients with resected Stage II colon cancer between 2010 and 2015 across two large Australian hospitals. Data collected included patient demographics, tumour histology, dMMR immunohistochemistry, chemotherapy use, and outcomes.
RESULTS: All 355 patients (56.1% female, median age 81) with resected Stage 2 Colon cancer entered on to the surgical database were included in this analysis. MMR testing was performed on 167 patient samples (47%), most occurred post-2013 (73.1% vs. 26.9% patients). dMMR rates were 34.1%. 25 (7.3%) received adjuvant chemotherapy, with no patient >80 years receiving treatment. Presence of ≥2 high-risk feature increased the likelihood of adjuvant chemotherapy. Only 3.6% dMMR patients received chemotherapy; both were young with high-risk features. 27/288 (7.6%) patients (with follow up) relapsed, with 7 disease-free post-resection of metastatic disease, 9 are alive with metastatic disease, and 11 deceased.
CONCLUSIONS: Unlike clinical trial populations, Stage 2 colon cancer patients are often elderly, have high rates of dMMR tumours, are rarely offered chemotherapy, yet still have excellent outcomes. dMMR immunohistochemistry is being increasingly used to identify Stage 2 patients who do not require chemotherapy.

Ciombor KK, Goldberg RM
Hypermutated Tumors and Immune Checkpoint Inhibition.
Drugs. 2018; 78(2):155-162 [PubMed] Related Publications
Microsatellite instability-high/DNA mismatch repair deficient tumors are found across the cancer spectrum and often harbor markedly increased numbers of mutations when compared to microsatellite stable/DNA mismatch repair proficient tumors. As a result of this high mutational load, tumor-infiltrating lymphocyte density is increased and more immunogenic neoepitopes are expressed, leading to upregulation of immune checkpoints in these tumors. Checkpoint inhibitors such as pembrolizumab and nivolumab, both immunoglobulin G4 (IgG4) monoclonal antibodies that block interactions between the programmed cell death receptor-1 and its ligands, have significant activity in this tumor class. This review will focus on hypermutated tumors and immuno-oncology drug development for this biologically unique tumor type, with an emphasis on FDA-approved immunotherapies for these cancers, as well as a short discussion of the many therapeutic and scientific challenges ahead in order to optimize the uses of this new class of drug.

Gan Q, Crumley S, Broaddus RR
Molecular Modifiers of Hormone Receptor Action: Decreased Androgen Receptor Expression in Mismatch Repair Deficient Endometrial Endometrioid Adenocarcinoma.
Int J Gynecol Pathol. 2019; 38(1):44-51 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
Endometrial endometrioid carcinoma is related to estrogen excess and expression of estrogen and progesterone receptors. Epidemiological evidence suggests that exposure to elevated androgens, as in polycystic ovarian syndrome, increases the risk of endometrial cancer. Factors impacting androgen receptor (AR) expression are not well studied. Mismatch repair (MMR) deficiency due to MLH1 gene methylation is one of the most common molecular alterations in endometrial cancer, occurring in 15% to 20% of cases. MLH1 methylation can be associated with decreased expression of other genes, so we examined the effect of MMR status on AR expression. As NF-κB is known to induce AR, this transcription factor was also examined. Three hundred forty-four unselected endometrial carcinomas were evaluated for DNA MMR. Loss of expression of MLH1 with MLH1 methylation was defined as MMR deficient, and positive expression of MMR proteins was defined as MMR intact. A case-control cohort of 96 grade 2 endometrioid carcinomas was studied from this set (47 MMR deficient, 49 MMR intact). Cases were matched for histotype, grade, and age. AR and NF-κB immunohistochemical expression were evaluated by 2 different scoring systems (CAP/ASCO and Allred) used for estrogen receptor. Despite higher levels of NF-κB, MMR deficiency was associated with a significantly lower mean percentage of AR expression. The MMR deficient group had more variable AR expression, with more cases scoring on the lower end of the spectrum. These findings have implications for clinical trials of AR antagonists in gynecologic cancers.

Keogh N, Chan KY, Li GM, Lahue RS
MutSβ abundance and Msh3 ATP hydrolysis activity are important drivers of CTG•CAG repeat expansions.
Nucleic Acids Res. 2017; 45(17):10068-10078 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
CTG•CAG repeat expansions cause at least twelve inherited neurological diseases. Expansions require the presence, not the absence, of the mismatch repair protein MutSβ (Msh2-Msh3 heterodimer). To evaluate properties of MutSβ that drive expansions, previous studies have tested under-expression, ATPase function or polymorphic variants of Msh2 and Msh3, but in disparate experimental systems. Additionally, some variants destabilize MutSβ, potentially masking the effects of biochemical alterations of the variations. Here, human Msh3 was mutated to selectively inactivate MutSβ. Msh3-/- cells are severely defective for CTG•CAG repeat expansions but show full activity on contractions. Msh3-/- cells provide a single, isogenic system to add back Msh3 and test key biochemical features of MutSβ on expansions. Msh3 overexpression led to high expansion activity and elevated levels of MutSβ complex, indicating that MutSβ abundance drives expansions. An ATPase-defective Msh3 expressed at normal levels was as defective in expansions as Msh3-/- cells, indicating that Msh3 ATPase function is critical for expansions. Expression of two Msh3 polymorphic variants at normal levels showed no detectable change in expansions, suggesting these polymorphisms primarily affect Msh3 protein stability, not activity. In summary, CTG•CAG expansions are limited by the abundance of MutSβ and rely heavily on Msh3 ATPase function.

Goey KKH, Elias SG, van Tinteren H, et al.
Maintenance treatment with capecitabine and bevacizumab versus observation in metastatic colorectal cancer: updated results and molecular subgroup analyses of the phase 3 CAIRO3 study.
Ann Oncol. 2017; 28(9):2128-2134 [PubMed] Related Publications
Background: The phase 3 CAIRO3 study showed that capecitabine plus bevacizumab (CAP-B) maintenance treatment after six cycles capecitabine, oxaliplatin, and bevacizumab (CAPOX-B) in metastatic colorectal cancer (mCRC) patients is effective, without compromising quality of life. In this post hoc analysis with updated follow-up and data regarding sidedness, we defined subgroups according to RAS/BRAF mutation status and mismatch repair (MMR) status, and investigated their influence on treatment efficacy.
Patients and methods: A total of 558 patients with previously untreated mCRC and stable disease or better after six cycles CAPOX-B induction treatment were randomised to either CAP-B maintenance treatment (n = 279) or observation (n = 279). Upon first progression, patients were to receive CAPOX-B reintroduction until second progression (PFS2, primary end point). We centrally assessed RAS/BRAF mutation status and MMR status, or used local results if central assessment was not possible. Intention-to-treat stratified Cox models adjusted for baseline covariables were used to examine whether treatment efficacy was modified by RAS/BRAF mutation status.
Results: RAS, BRAF mutations, and MMR deficiency were detected in 240/420 (58%), 36/381 (9%), and 4/279 (1%) patients, respectively. At a median follow-up of 87 months (IQR 69-97), all mutational subgroups showed significant improvement from maintenance treatment for the primary end point PFS2 [RAS/BRAF wild-type: hazard ratio (HR) 0.57 (95% CI 0.39-0.84); RAS-mutant: HR 0.74 (0.55-0.98); V600EBRAF-mutant: HR 0.28 (0.12-0.64)] and secondary end points, except for the RAS-mutant subgroup regarding overall survival. Adjustment for sidedness instead of primary tumour location yielded comparable results. Although right-sided tumours were associated with inferior prognosis, both patients with right- and left-sided tumours showed significant benefit from maintenance treatment.
Conclusions: CAP-B maintenance treatment after six cycles CAPOX-B is effective in first-line treatment of mCRC across all mutational subgroups. The benefit of maintenance treatment was most pronounced in patients with RAS/BRAF wild-type and V600EBRAF-mutant tumours.
ClinicalTrials.gov number: NCT00442637.

Spetsotaki KN, Tsiambas E, Stamatelopoulos A, et al.
DNA mismatch repair deficiency in lung and oral cavity carcinomas: the role of histogenetic origin.
J BUON. 2017 May-Jun; 22(3):606-609 [PubMed] Related Publications
DNA mismatch repair system (DNA MMR) is a crucial genetic mechanism for DNA homeostasis in prokaryotic and eukaryotic cells. During DNA replication and also recombination, point intra-nucleotide errors including base deletion, insertion, and mis-incorporation happen. These raised abnormalities in the newly synthesized DNA strand could affect negatively the stability of the molecule and the function of the corresponding genes. DNA MMR proteins prevent these errors by recognizing and repairing them, securing directly the normal anatomy of the DNA double strand and indirectly the expression of the genes. Specific genomic alterations - mutations, loss of heterozygosity (LOH), or promoter hypermethylation - regarding the MMR genes (human homologues) hMLH1, hMSH2, hMSH3, hMSH6, hPMS1 and hPMS2 modify negatively their expression leading to loss of their function in repairing the corresponding base to base errors. The result known as microsatellite instability (MSI) was initially recognized in colonic carcinoma, especially in its inherited aspect - the Lynch syndrome -, the most common form of hereditary colon carcinoma. Since then, acquired deficiencies in specific DNA MMR genes have been detected in a broad spectrum of malignancies including different anatomic regions and histologies such as stomach, prostate, esophageal, endometrial, lung and head & neck. In the current special review we explored the role of DNA MMR deficiency in lung and oral cavity carcinomas in order to identify similarities and differences regarding the corresponding genes alterations.

El Jabbour T, Ross JS, Sheehan CE, et al.
PD-L1 protein expression in tumour cells and immune cells in mismatch repair protein-deficient and -proficient colorectal cancer: the foundation study using the SP142 antibody and whole section immunohistochemistry.
J Clin Pathol. 2018; 71(1):46-51 [PubMed] Related Publications
AIMS: Routine application of PD-L1 immunohistochemistry (IHC) in colorectal cancer (CRC) is limited due to lack of standardized scoring criteria, antibody clones, and intratumoral staining heterogeneity. We assessed PD-L1 protein expression on full face CRC tissue sections and applied two algorithms based on the published clinical trials that support the recent FDA approval for immune checkpoint inhibitors (ICPI) therapy in non-small cell lung cancer (NSCLC).
METHODS: PD-L1/CD274 IHC (Roche/Ventana, clone SP142) was performed on representative tumour blocks from 52 mismatch repair-deficient (MMR-D) and 52 MMR-proficient (MMR-P) CRCs. Membranous PD-L1 expression was scored for the tumour cell (TC) and tumour-infiltrating immune cell (IC) components. PD-L1 positivity status was determined based on the published NSCLC clinical trials that utilized the Ventana SP142 assay. Hybrid capture-based comprehensive genomic profiling (CGP) was performed on a separate set of 2268 clinically advanced CRCs and the frequency of PD-L1/PD-L2 amplification was determined.
RESULTS: PD-L1 expression in the TC and IC correlated with MMR-D (p=0.013, p<0.0001), T stage (p=0.036, p=0.0036) and clinical stage (p=0.022, p=0.0037). PD-L1 positivity status correlated with MMR-D by two algorithms. Five of 2268 (<1%) advansced CRCs demonstrated amplification of either the
CONCLUSIONS: PD-L1 expression in TC and IC is associated with advanced stage and MMR-D. PD-L1 positivity status by the published algorithm is associated with MMR-D.

Westdorp H, Kolders S, Hoogerbrugge N, et al.
Immunotherapy holds the key to cancer treatment and prevention in constitutional mismatch repair deficiency (CMMRD) syndrome.
Cancer Lett. 2017; 403:159-164 [PubMed] Related Publications
Monoallelic germline mutations in one of the DNA mismatch repair (MMR) genes cause Lynch syndrome, with a high lifetime risks of colorectal and endometrial cancer at adult age. Less well known, is the constitutional mismatch repair deficiency (CMMRD) syndrome caused by biallelic germline mutations in MMR genes. This syndrome is characterized by the development of childhood cancer. Patients with CMMRD are at extremely high risk of developing multiple cancers including hematological, brain and intestinal tumors. Mutations in MMR genes impair DNA repair and therefore most tumors of patients with CMMRD are hypermutated. These mutations lead to changes in the translational reading frame, which consequently result in neoantigen formation. Neoantigens are recognized as foreign by the immune system and can induce specific immune responses. The growing evidence on the clinical efficacy of immunotherapies, such as immune checkpoint inhibitors, offers the prospect for treatment of patients with CMMRD. Combining neoantigen-based vaccination strategies and immune checkpoint inhibitors could be an effective way to conquer CMMRD-related tumors. Neoantigen-based vaccines might also be a preventive treatment option in healthy biallelic MMR mutation carriers. Future studies need to reveal the safety and efficacy of immunotherapies for patients with CMMRD.

Villani A, Greer MC, Kalish JM, et al.
Recommendations for Cancer Surveillance in Individuals with RASopathies and Other Rare Genetic Conditions with Increased Cancer Risk.
Clin Cancer Res. 2017; 23(12):e83-e90 [PubMed] Related Publications
In October 2016, the American Association for Cancer Research held a meeting of international childhood cancer predisposition syndrome experts to evaluate the current knowledge of these syndromes and to propose consensus surveillance recommendations. Herein, we summarize clinical and genetic aspects of RASopathies and Sotos, Weaver, Rubinstein-Taybi, Schinzel-Giedion, and NKX2-1 syndromes as well as specific metabolic disorders known to be associated with increased childhood cancer risk. In addition, the expert panel reviewed whether sufficient data exist to make a recommendation that all patients with these disorders be offered cancer surveillance. For all syndromes, the panel recommends increased awareness and prompt assessment of clinical symptoms. Patients with Costello syndrome have the highest cancer risk, and cancer surveillance should be considered. Regular physical examinations and complete blood counts can be performed in infants with Noonan syndrome if specific

Clendenning M, Huang A, Jayasekara H, et al.
Somatic mutations of the coding microsatellites within the beta-2-microglobulin gene in mismatch repair-deficient colorectal cancers and adenomas.
Fam Cancer. 2018; 17(1):91-100 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
In colorectal cancers (CRCs) with tumour mismatch repair (MMR) deficiency, genes involved in the host immune response that contain microsatellites in their coding regions, including beta-2-microglobulin (B2M), can acquire mutations that may alter the immune response, tumour progression and prognosis. We screened the coding microsatellites within B2M for somatic mutations in MMR-deficient CRCs and adenomas to determine associations with tumour subtypes, clinicopathological features and survival. Incident MMR-deficient CRCs from Australasian Colorectal Cancer Family Registry (ACCFR) and the Melbourne Collaborative Cohort Study participants (n = 144) and 63 adenomas from 41 MMR gene mutation carriers from the ACCFR were screened for somatic mutations within five coding microsatellites of B2M. Hazard ratios (HR) and 95% confidence intervals (CI) for overall survival by B2M mutation status were estimated using Cox regression, adjusting for age at CRC diagnosis, sex, AJCC stage and grade. B2M mutations occurred in 30 (20.8%) of the 144 MMR-deficient CRCs (29% of the MLH1-methylated, 17% of the Lynch syndrome and 9% of the suspected Lynch CRCs). No B2M mutations were identified in the 63 adenomas tested. B2M mutations differed by site, stage, grade and lymphocytic infiltration although none reached statistical significance (p > 0.05). The HR for overall survival for B2M mutated CRC was 0.65 (95% CI 0.29-1.48) compared with B2M wild-type. We observed differences in B2M mutation status in MMR-deficient CRC by tumour subtypes, site, stage, grade, immune infiltrate and for overall survival that warrant further investigation in larger studies before B2M mutation status can be considered to have clinical utility.

Abu Freha N, Leibovici Weissman Y, Fich A, et al.
Constitutional mismatch repair deficiency and Lynch syndrome among consecutive Arab Bedouins with colorectal cancer in Israel.
Fam Cancer. 2018; 17(1):79-86 [PubMed] Related Publications
We assessed the molecular characteristics and the frequency of mutations in mismatch-repair genes among Bedouin patients with colorectal cancer (CRC) in Israel. Bedouin patients with a diagnosis of CRC at a major hospital in the southern part of Israel were deemed eligible for this study. The primary screening method was immunohistochemical staining for mismatch-repair proteins (MLH1, MSH2, MSH6, and PMS2). For subjects with abnormal immunohistochemical staining, we performed microsatellite instability (MSI) analyses, and for tumors with a loss of MLH1 expression we also performed BRAF testing. In MSI high cases we searched further for germline mutations. Of the 24 patients enrolled, four subjects (16.7%) had MSI high tumors: one subject was found to harbor a biallelic PMS2 mutation, one subject had Lynch syndrome (LS) with MSH6 mutation and two subjects had a loss of MLH1/PMS2 proteins/BRAF

Le DT, Durham JN, Smith KN, et al.
Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade.
Science. 2017; 357(6349):409-413 [PubMed] Article available free on PMC after 01/01/2020 Related Publications
The genomes of cancers deficient in mismatch repair contain exceptionally high numbers of somatic mutations. In a proof-of-concept study, we previously showed that colorectal cancers with mismatch repair deficiency were sensitive to immune checkpoint blockade with antibodies to programmed death receptor-1 (PD-1). We have now expanded this study to evaluate the efficacy of PD-1 blockade in patients with advanced mismatch repair-deficient cancers across 12 different tumor types. Objective radiographic responses were observed in 53% of patients, and complete responses were achieved in 21% of patients. Responses were durable, with median progression-free survival and overall survival still not reached. Functional analysis in a responding patient demonstrated rapid in vivo expansion of neoantigen-specific T cell clones that were reactive to mutant neopeptides found in the tumor. These data support the hypothesis that the large proportion of mutant neoantigens in mismatch repair-deficient cancers make them sensitive to immune checkpoint blockade, regardless of the cancers' tissue of origin.

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