Rare compound heterozygous mutations in gene <i><scp>MSH</scp>6</i> cause constitutive mismatch repair deficiency syndrome

Ling, Chao; Yang, Wei; Sun, Hailang; Ge, Ming; Ji, Yuanqi; Han, Shirui; Zhang, Di; Zhang, Xue

doi:10.1002/ccr3.1564

Cited by 4 publications

(3 citation statements)

References 18 publications

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“…The pathogenic homozygous c.478C>T p.(Gln160*) mutations in MSH6 gene detected in the first family was reported by our group. 14 The pathogenic c.2871dupC p.(Phe958Leufs*5) mutations in MSH6 gene, reported as pathogenic previously in the literature 17,18 , was found to be in homozygous state in both affected siblings in the second family. The c.236G>A variant was reported in heterozygous state ones with a 3.98x 10 -6 allele frequency in GnomAD exomes and never reported in GnomAD genomes.…”

Section: Discussionmentioning

confidence: 86%

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Kara

Paksoy²,

Çağlayan³

et al. 2022

Turk J Pediatr

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Background. Constitutional mismatch repair deficiency (CMMRD) is one of the rare cancer predisposition syndromes. The aim of this study was to evaluate the cerebral developmental venous anomalies in children with central nervous system tumors associated with CMMRD, an area in which there is extremely little experience. Methods. Data from children diagnosed with medulloblastoma and high grade central nervous sytem tumor were retrospectively collected. According to the European CMMRD criteria, nine patients were diagnosed as CMMRD syndrome and the others consisted of the group without CMMRD. All radiological examinations of these children were retrospectively reviewed. Whole exome sequencing was performed to index cases` germline DNA. Results. Nine children from four families, six females and three males, were studied. The median age at the first tumor diagnosis was 4.5 years (range, 9 months to 14 years). All CMMRD patients had café au lait spots, but none fulfilled the diagnostic criteria for neurofibromatosis. The patients developed high-grade glial tumor (n: 7) and medulloblastoma (n: 2). The affected genes in the three families were MSH6 [c.478C > T (p.Gln160Ter)], MSH6 [c.2871dupC (p.Phe958LeufsTer5)] and MLH1 [c.236G > A(p.Arg79Lys)], respectively. Seven patients had multiple developmental venous anomalies; six patients had leptomeningeal enhancement; and five patients had cavernomas. None of these findings were present in the group without CMMRD. Conclusions. Constitutional mismatch repair deficiency should be considered when multiple developmental venous anomalies, cavernomas, and leptomeningeal enhancement are detected, especially in patients with café au lait spots.

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Section: Discussionmentioning

confidence: 86%

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Kara

Paksoy²,

Çağlayan³

et al. 2022

Turk J Pediatr

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“…MMR is a bacterial MUTS homologue and mainly forms a mismatch complex with MSH2 (MSH2-MSH6) to play a role in mismatch repair. 38 , 39 …”

Section: Discussionmentioning

confidence: 99%

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer

Jiao

Zhang

Wang

et al. 2022

CMAR

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Introduction Small cell lung cancer (SCLC), an aggressive subtype of lung cancer characterized by the development of neuroendocrine tumors, is prone to distant metastasis, resistant to platinum-based drugs and has a poor prognosis. The development of next-generation sequencing technology (NGS) has led to the identification of many genetic alterations in SCLC. Few druggable targeted molecules can be used in clinical practice. Currently, NGS is widely employed in routine clinical practice of non-small cell lung cancer to assist in therapeutic options and prognosis evaluation. This study aims to investigate genes involved in small cell lung cancer (SCLC), their occurrence and their significance in clinical events. Methods Tumor tissue specimens from 18 Chinese SCLC patients were collected through a 520 cancer‐related genes panel for next-generation sequencing. First, the association between sequence results and clinical outcomes was examined. Subsequently, data on clinical pathology and sequencing results were analyzed. Results The Kaplan–Meier curve displayed a significant reduction in PFS for SCLC patients with LRP1B or MAP3K13 mutations. Overall survival (OS) of SCLC patients with MSH6 mutation was significantly higher than those with SPEN mutation. Conclusion Next-generation sequencing demonstrates that the genetic landscape of SCLC. Mutation status of LRP1B, MAP3K13, MSH6 and SPEN has prognostic significance, which might be potential therapeutic targets. We found possible genes and related signaling pathways that affect metastasis. These results can improve our understanding of the mutation characteristics of SCLC and identify potential biomarkers to guide targeted therapies.

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“…Familial adenomatous polyposis (Turcot) syndrome, characterized by mutations in APC, predisposes to WNT MB (15). In addition to developmental signaling axes, other molecular processes commonly affected in germline predisposition syndromes with increased risk of MB include germline defects in DNA damage response/ repair machinery, such is in Li-Fraumeni syndrome (TP53 mutations) and constitutional mismatch repair (mutations in MLH1, MSH2, MSH6 or PMS2) (48,56,57,62,88,104).…”

Section: Germline Predispositionsmentioning

confidence: 99%

Medulloblastoma genomics in the modern molecular era

2019

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Medulloblastoma (MB) represents a spectrum of biologically and clinically distinct entities. Initially described histopathologically as a small, round blue cell tumor arising in the cerebellum, MB has emerged as a paradigm for molecular classification in cancer. Recent advances in genomic, transcriptomic and epigenomic profiling of MB have further refined molecular classification and complemented conventional histopathological diagnosis. Herein, we review the main clinical and molecular features of the four consensus subgroups of MB (WNT, SHH, Group 3 and Group 4). We also highlight hereditary predisposition syndromes associated with increased risk of MB. Finally, we explore advances in the classification of the consensus molecular groups while also presenting cutting-edge frontiers in identifying intratumoral heterogeneity and cellular origins of MB.

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Rare compound heterozygous mutations in gene MSH6 cause constitutive mismatch repair deficiency syndrome

Cited by 4 publications

References 18 publications

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Cerebral developmental venous anomalies in children with mismatch repair deficiency

Genetic Alteration and Their Significance on Clinical Events in Small Cell Lung Cancer

Medulloblastoma genomics in the modern molecular era

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