Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium

Bakry, Doua; Aronson, Melyssa; Durno, Carol; Rimawi, Hala; Farah, Roula; Alharbi, Qasim; Alharbi, Musa; Ashraf, Samina; Ben‐Shachar, Shay; Mistry, Matthew; Constantini, Shlomi; Dvir, Rina; Qaddoumi, Ibrahim; Gallinger, Steven; Lerner‐Ellis, Jordan; Pollett, Aaron; Stephens, Derek; Kelies, Steve; Chao, Elizabeth; Malkin, David; Bouffet, Éric; Hawkins, Cynthia; Tabori, Uri

doi:10.1016/j.ejca.2013.12.005

Cited by 185 publications

(219 citation statements)

References 23 publications

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“…Human patients often present with neurological symptoms such as headaches and seizures, and despite the vast amount of genomic data and novel therapies now available, GBMs recur quickly and aggressively after resection and often lead to death [124]. Several of the human cancer predisposition syndromes include gliomas in their clinical spectrum [127][128][129][130][131][132][133], supporting the genetic risk for development of these tumours.…”

Section: (I) Meningiomamentioning

confidence: 99%

Comparative oncology: what dogs and other species can teach us about humans with cancer

Schiffman

Breen

2015

Phil. Trans. R. Soc. B

290

293

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One contribution of 18 to a theme issue 'Cancer across life: Peto's paradox and the promise of comparative oncology'. Over 1.66 million humans (approx. 500/100 000 population rate) and over 4.2 million dogs (approx. 5300/100 000 population rate) are diagnosed with cancer annually in the USA. The interdisciplinary field of comparative oncology offers a unique and strong opportunity to learn more about universal cancer risk and development through epidemiology, genetic and genomic investigations. Working across species, researchers from human and veterinary medicine can combine scientific findings to understand more quickly the origins of cancer and translate these findings to novel therapies to benefit both human and animals. This review begins with the genetic origins of canines and their advantage in cancer research. We next focus on recent findings in comparative oncology related to inherited, or genetic, risk for tumour development. We then detail the somatic, or genomic, changes within tumours and the similarities between species. The shared cancers between humans and dogs that we discuss include sarcoma (osteosarcoma, soft tissue sarcoma, histiocytic sarcoma, hemangiosarcoma), haematological malignancies (lymphoma, leukaemia), bladder cancer, intracranial neoplasms (meningioma, glioma) and melanoma. Tumour risk in other animal species is also briefly discussed. As the field of genomics advances, we predict that comparative oncology will continue to benefit both humans and the animals that live among us.

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Section: (I) Meningiomamentioning

confidence: 99%

Comparative oncology: what dogs and other species can teach us about humans with cancer

Schiffman

Breen

2015

Phil. Trans. R. Soc. B

290

293

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“…The system is controlled by MMR genes, of which biallelic germline mutations lead to CMMRD syndrome. 3 According to molecular analyses of 146 previously documented patients with CMMRD, ∼58% of cases are caused by PMS2 mutations, as our patient had. Twenty-two percent and 20% of cases are caused by MLH1 or MSH2 and MSH6 mutations, respectively.…”

Section: Discussionmentioning

confidence: 52%

“…A majority of patients with CRC have .10 adenomas. 3 Patients may present with rectal bleeding at a late stage, as our patient did. Metastatic disease is present in ∼50% of cases at the time of diagnosis.…”

Section: Discussionmentioning

confidence: 96%

Colorectal Cancer due to Constitutional Mismatch Repair Deficiency Mimicking Neurofibromatosis I

et al. 2015

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Colorectal carcinoma (CRC) is an extremely rare tumor of childhood that can be associated with cancer predisposition syndromes. A patient with CRC related to constitutional mismatch repair deficiency (CMMRD) syndrome with features of neurofibromatosis type 1 (NF-1) is presented here. A 13-year-old boy was admitted for a 4-month history of diarrhea and rectal bleeding. The patient had extensive café au lait spots, freckling, and Lisch nodules. He fulfilled the NF-1 diagnostic criteria. Colonoscopy showed numerous polyps and a colorectal mass lesion, of which a biopsy revealed adenocarcinoma, an uncommon pathology associated with NF-1. High microsatellite instability and homozygous mutation of PMS2 gene in tumor tissue and blood lymphocytes, respectively, confirmed the diagnosis of CMMRD. Unfortunately, because family history related to CMMRD was negative, the parents denied the diagnosis and refused the therapy, and the patient was lost to follow-up. CMMRD is a rare cancer predisposition syndrome with phenotypical features resembling NF-1. The disease may be suspected in the setting of NF-1 features and CRC, high-grade brain tumors, or hematologic malignancies. Lack of family history related to CMMRD may be a major obstacle to convincing parents of the presence of an inherited disease in their progeny.The DNA mismatch repair (MMR) system is a key pathway contributing to maintenance of genomic stability. The system recognizes, removes, and restores base substitution and insertion-deletion mismatches during DNA replication. 1 In case of MMR deficiency, erroneously inserted nucleotides give rise to high microsatellite instability, which may result in a distinct spectrum of cancers.MLH1, MSH6, MSH2, and PMS2 genes are involved in the mismatch repair system. Heterozygous mutations of these genes cause the autosomal dominant Lynch syndrome (LS), which predisposes typically to colorectal cancer (CRC), usually after the fourth decade of life. Biallelic mutations of MMR genes cause a distinct autosomal recessively inherited cancer predisposition, namely constitutional mismatch repair deficiency (CMMRD) syndrome. 2 The neoplastic spectrum of CMMRD includes hematologic malignancies, central nervous system tumors, and CRCs at an earlier age than expected. Since the first case reported in 1999, 146 cases of CMMRD from 91 families have been documented. Many patients with CMMRD have café au lait spots (CLS) and other features of neurofibromatosis type 1 (NF-1) such as freckling, neurofibromas, Lisch nodules, tibia pseudoarthrosis, sphenoid wing dysplasia, and optic glioma. 3 Lisch nodules are very rare (5 in 146), and the number of CLS does not always reach diagnostic criterion for NF-1 in majority of patients. Here we report the case of a patient with CMMRD and CRC, without familial CASEA 13-year-old boy presented with rectal bleeding and diarrhea of 4 months' duration. Personal history was unremarkable except poor school performance. His parents were firstdegree cousins. No family history of cancer was described. Fam...

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“…A high rate of consanguinity is observed especially among homozygous cases (17), whereas in Western countries, most of the cases are associated with composite heterozygous mutation in families with no consanguinity (12). In contrast to family members with LS, many of the heterozygous parents will not be affected, especially among families with PMS2 or MSH6 mutations (14,18).…”

Section: Clinical Presentation Of Cmmrdmentioning

confidence: 99%

“…The morphologic features of these gliomas include large, multinucleated giant cells with clumped nuclei and cells with many smaller, eccentrically placed nuclei mimicking pleomorphic xanthroastrocytomas (13). Central nervous system (CNS) embryonal tumors and medulloblastomas have also been reported (11,14).…”

Section: Clinical Presentation Of Cmmrdmentioning

confidence: 99%

Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

Tabori

Hansford

Achatz

et al. 2017

Clinical Cancer Research

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161

188

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Replication proofreading is crucial to avoid mutation accumulation in dividing cells. In humans, proofreading and replication repair is maintained by the exonuclease domains of DNA polymerases and the mismatch repair system. Individuals harboring germline mutations in genes involved in this process are at increased risk of early cancers from multiple organs. Biallelic mutations in any of the four mismatch repair genes MSH2, MSH6, MLH1, and PMS2 result in one of the most aggressive childhood cancer predisposition syndromes, termed constitutional mismatch repair deficiency or constitutional mismatch repair deficiency syndrome (CMMRD). Data gathered in the last decade allow us to better define the clinical manifestations, tumor spectrum, and diagnostic algorithms for CMMRD. In this article, we summarize this information and present a comprehensive consensus surveillance protocol for these individuals. Ongoing research will allow for further definition of replication repairdeficient cancer syndromes, assessing the cost-effectiveness of such surveillance protocols and potential therapeutic interventions for these children and families. Clin Cancer Res; 23(11); e32-e37. Ó2017 AACR.See all articles in the online-only CCR Pediatric Oncology Series.

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Genetic and clinical determinants of constitutional mismatch repair deficiency syndrome: Report from the constitutional mismatch repair deficiency consortium

Cited by 185 publications

References 23 publications

Comparative oncology: what dogs and other species can teach us about humans with cancer

Comparative oncology: what dogs and other species can teach us about humans with cancer

Colorectal Cancer due to Constitutional Mismatch Repair Deficiency Mimicking Neurofibromatosis I

Clinical Management and Tumor Surveillance Recommendations of Inherited Mismatch Repair Deficiency in Childhood

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