Biallelic Mismatch Repair Gene Mutations Research Articles

Constitutional mismatch repair-deficiency: current problems and emerging therapeutic strategies.

Mismatch repair (MMR) proteins remove errors from newly synthesized DNA, improving the fidelity of DNA replication. A loss of MMR causes a mutated phenotype leading to a predisposition to cancer.In the last 20 years, an increasing number of patients have been described with biallelic MMR gene mutations in which MMR defects are inherited from both parents. This leads to a syndrome with recessive inheritance, referred to as constitutional mismatch repair-deficiency (CMMRD). CMMRD is a rare childhood cancer predisposition syndrome. The spectrum of CMMRD tumours is broad and CMMRD-patients possess a high risk of multiple cancers including hematological, brain and intestinal tumors. The severity of CMMRD is highlighted by the fact that patients do not survive until later life, emphasising the requirement for new therapeutic interventions.Many tumors in CMMRD-patients are hypermutated leading to the production of truncated protein products termed neoantigens. Neoantigens are recognized as foreign by the immune system and induce antitumor immune responses. There is growing evidence to support the clinical efficacy of neoantigen based vaccines and immune checkpoint inhibitors (collectively referred to as immunotherapy) for the treatment of CMMRD cancers. In this review, we discuss the current knowledge of CMMRD, the advances in its diagnosis, and the emerging therapeutic strategies for CMMRD-cancers.

Abstract IA02: The discovery of the hereditary colorectal cancer genes: A historical perspective

Abstract IA02: The discovery of the hereditary colorectal cancer genes: A historical perspective

Constitutional Mismatch Repair Deficiency in Israel: High Proportion of Founder Mutations in MMR Genes and Consanguinity.

Heterozygous germline mutations in any of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6, and PMS2, cause Lynch syndrome (LS), an autosomal dominant cancer predisposition syndrome conferring a high risk of colorectal, endometrial, and other cancers in adulthood. Offspring of couples where both spouses have LS have a 1:4 risk of inheriting biallelic MMR gene mutations. These cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited cancer syndrome with a broad tumor spectrum including mainly hematological malignancies, brain tumors, and colon cancer in childhood and adolescence. Many CMMRD children also present with café au lait spots and axillary freckling mimicking neurofibromatosis type 1. We describe our experience in seven CMMRD families demonstrating the role and importance of founder mutations and consanguinity on its prevalence. Clinical presentations included brain tumors, colon cancer, lymphoma, and small bowel cancer. In children from two nonconsanguineous Ashkenazi Jewish (AJ) families, the common Ashkenazi founder mutations were detected; these were homozygous in one family and compound heterozygous in the other. In four consanguineous families of various ancestries, different homozygous mutations were identified. In a nonconsanguineous Caucasus/AJ family, lack of PMS2 was demonstrated in tumor and normal tissues; however, mutations were not identified. CMMRD is rare, but, especially in areas where founder mutations for LS and consanguinity are common, pediatricians should be aware of it since they are the first to encounter these children. Early diagnosis will enable tailored cancer surveillance in the entire family and a discussion regarding prenatal genetic diagnosis.

Glioblastomas, astrocytomas and oligodendrogliomas linked to Lynch syndrome.

Brain tumors represent a rare and relatively uncharacterized tumor type in Lynch syndrome. The national Danish Hereditary Nonpolyposis Colorectal Cancer Register was utilized to estimate the cumulative life-time risk for brain tumors in Lynch syndrome, and the mismatch repair (MMR) status in all tumors available was evaluated. Primary brain tumors developed in 41/288 families at a median age of 41.5 (range 2-73) years. Biallelic MMR gene mutations were linked to brain tumor development in childhood. The risk of brain tumors was significantly higher (2.5%) in MSH2 gene mutation carriers compared to patients with mutations in MLH1 or MSH6. Glioblastomas predominated (56%), followed by astrocytomas (22%) and oligodendrogliomas (9%). MMR status was assessed in 10 tumors, eight of which showed MMR defects. None of these tumors showed immunohistochemical staining suggestive of the IDH1 R132H mutation. In Lynch syndrome brain tumors occurred in 14% of the families with significantly higher risks for individuals with MSH2 gene mutations and development of childhood brain tumors in individuals with constitutional MMR defects.

Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow‐up of a kindred

Heterozygous germline mutations in DNA mismatch repair (MMR) genes cause Lynch syndrome. Biallelic MMR mutations cause a distinct syndrome characterized by brain tumors, lymphoid malignancies, and gastrointestinal cancers during childhood. These children usually succumb to multiple cancers before adulthood. We developed a surveillance protocol aiming at early detection for these individuals and report the 10-year experience with a kindred. On the basis of genetic testing and early age tumors, the kindred started a cancer surveillance protocol based on the crude estimates of cancer risks and available cancer screening: imaging, endoscopy, and hematologic tests. Over the 10-year follow-up period, the screening protocol detected 15 tumors. These included three high-grade adenomatous colonic polyps and two colon cancers. In one child, MRI revealed an asymptomatic anaplastic astrocytoma which was treated by complete resection and radiation. All three cancers identified during surveillance were small and asymptomatic at diagnosis. The two sisters are currently 16 and 18 years of age with no evidence of malignant disease. Both parents have annual colonoscopies and the father at 43 years had two colonic adenomatous polyps. We report on the long-term outcome in patients with biallelic MMR mutations who benefited from prophylactic cancer surveillance. Genetic screening and subsequent surveillance led to earlier recognition of asymptomatic tumors at stages more amenable to resection and probable cure. Multicenter collaboration and implementation of surveillance guidelines is necessary to further determine genotype-phenotype correlations.

Childhood brain tumours due to germline bi-allelic mismatch repair gene mutations

Childhood brain tumours may be due to germline bi-allelic mismatch repair (MMR) gene mutations in MLH1, MSH2, MSH6 or PMS2. These mutations can also lead to colorectal neoplasia and haematological malignancies. Here, we review this syndrome and present siblings with early-onset rectal adenoma and papillary glioneural brain tumour, respectively, due to novel germline bi-allelic PMS2 mutations. Identification of MMR protein defects can lead to early diagnosis of this condition. In addition, assays for these defects may help to classify brain tumours for research protocols aimed at targeted therapies.

The Gastrointestinal Phenotype of Germline Biallelic Mismatch Repair Gene Mutations

A novel cancer syndrome associated with biallelic mismatch repair (MMR) mutations has been described recently. Patients presenting with childhood-onset gastrointestinal (GI) cancers may carry biallelic MMR mutations and have a distinct phenotype from classic Lynch syndrome. The aim of this study was to characterize patients with GI small bowel and/or colorectal cancers (CRCs) who have germline biallelic MMR mutations. A search of a Canadian GI cancer registry and literature review to identify patients with biallelic MMR was conducted. The database identified 237 patients with intestinal cancer diagnosed before the age of 35 years. Five (2.1%) patients had biallelic MMR mutations. Overall, 32 individuals, from 29 families, with biallelic MMR gene mutations and GI cancers were identified by the registry and literature review. Among the 29 patients with CRCs, the mean age of first cancer diagnosis was 16.4 years (range: 5-28). More than one-third of patients had multiple colorectal adenomas (>10 polyps). Six individuals with biallelic MMR gene mutations have been reported with small bowel adenocarcinoma (mean age 20 years (range: 11-41)). Café-au-lait (CAL) macules were reported in 72% and, based on mutation analysis, consanguinity was suspected in 52% of kindred. Of the 29 kindred, 19 (66%) had PMS2 mutations, 6 (21%) had MSH6 mutations, 3 (10%) had MLH1 mutations, and 1 (3%) had MSH2 mutation. Biallelic MMR mutations are an underrecognized cause of small bowel and colonic cancers in children and young adults. This distinct phenotype includes multiple adenomatous polyps and CAL skin lesions. It is important to identify such patients, so that families can be referred for genetic testing and counseling.

M1944 Germline Biallelic Mismatch Repair Gene Mutations As a Novel Cause of Intestinal Cancer in Children and Young Adults

M1944 Germline Biallelic Mismatch Repair Gene Mutations As a Novel Cause of Intestinal Cancer in Children and Young Adults

Pediatric duodenal cancer and biallelic mismatch repair gene mutations

Gastrointestinal malignancies are extremely rare in the pediatric population, and duodenal cancers represent an even more unusual entity. Intestinal cancers in young adults and children have been observed to be associated with functional deficiencies of the mismatch repair (MMR) system causing a cancer-predisposition syndrome. We report the case of a 16-year-old female with duodenal adenocarcinoma and past history of medulloblastoma found to have a novel germline bialleleic truncating mutation (c.[949C>T]+[949C>T]) of the PMS2 gene.

Medulloblastoma, acute myelocytic leukemia and colonic carcinomas in a child with biallelic MSH6 mutations

Background A 13-year-old girl presented with rectal bleeding and was found to have two colonic carcinomas (stage Dukes' C) and multiple colonic polyps. At the age of 7 years she had widespread hyperpigmented and hypopigmented skin lesions, and had developed medulloblastoma, which was treated with chemotherapy and craniospinal irradiation. At the age of 10 years she had developed acute myelocytic leukemia, M5. She was treated with chemotherapy including sibling bone marrow transplant with busulfan/cyclophosphamide conditioning. A three-generation family history identified no relatives with colonic carcinomas or polyposis. Investigations Immunohistochemical analysis was performed on a sample of colonic adenoma. Staining for MLH1 and MSH2 was normal but was absent for MSH6. Direct sequencing of MSH6 was performed in the proband and both parents. Diagnosis Constitutional biallelic mutations in the mismatch repair gene MSH6 were identified in the proband. Both parents are carriers of one mutation. This is the first individual with biallelic MSH6 mutations reported with either medulloblastoma or acute myelocytic leukemia. Management Cascade genetic testing and colonoscopic screening for colorectal carcinoma has been offered to relatives carrying one mutation. The proband underwent panproctocolectomy and received adjuvant capecitabine. Identification of constitutional biallelic mismatch repair gene mutations allows the avoidance of chemotherapeutic agents likely to be ineffective and mutagenic in the context of the underlying mismatch repair deficiency. It is important to consider this diagnosis in children presenting with malignancy and abnormal skin pigmentation, even in the absence of a strong family history of tumors.

Compound heterozygosity for two MSH6 mutations in a patient with early onset of HNPCC-associated cancers, but without hematological malignancy and brain tumor

Heterozygous germline mutations in the human mismatch repair (MMR) genes MLH1, PMS2, MSH2 and MSH6 predispose to the hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Biallelic mutations in these genes have been reported for a limited number of cases resulting in hematological malignancies, brain tumors and gastrointestinal tumors early in childhood. These tumor phenotypes are frequently associated with café-au-lait spots (CALS), one of the clinical hallmarks of neurofibromatosis type 1 (NF1). We report the first case of compound heterozygosity for two MSH6 mutations resulting in a nonconservative amino-acid change of a conserved residue and in a premature stop codon in a patient who developed rectal and endometrial cancer at ages 19 and 24 years, respectively, and presented few CALS in a single body segment. Immunohistochemistry and Western blotting revealed only residual expression of the MSH6 protein in the normal cells. The disease history resembles the HNPCC phenotype rather than a phenotype associated with biallelic MMR gene mutations. Therefore, we assume that one or both mutations abolish protein function only partially, further supported by the parents, which are both carriers of one of the mutations each, and not affected by the disease at ages 57 and 58 years. Our data suggest considering biallelic mutations in MMR genes for patients who develop HNPCC-associated tumors at an unusually young age of onset, even without hematological or brain malignancies.