Next Generation Sequencing Reveals Novel Mutations in Mismatch Repair Genes and Other Cancer Predisposition Genes in Asian Patients with Suspected Lynch Syndrome

Ow, Samuel G.W.; Tan, Kar Tong; Yang, Henry; Yap, Hui-Kim; Sapari, Nur Sabrina; Ong, Pei Yi; Soong, Richie; Lee, Soo‐Chin

doi:10.1016/j.clcc.2019.05.007

Cited by 5 publications

(5 citation statements)

References 26 publications

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“…Early reports demonstrate that the regulation of Skp2 turnover is mediated by the anaphase-promoting complex (APC), in association with its substrate-specific factor Cdh1 [24,25]. Moreover, mutation or dysfunction of Cdh1 is implicated in the tumorigenesis of human CRC [49,50]. Our data show that dioscin suppresses Skp2 phosphorylation on S72 and promotes the interaction between Skp2 and Cdh1, thus enhancing Cdh1-mediated Skp2 destruction, and eventually decreasing HK2 protein level and glycolysis in CRC cells.…”

Section: Discussionmentioning

confidence: 58%

Cdh1-mediated Skp2 degradation by dioscin reprogrammes aerobic glycolysis and inhibits colorectal cancer cells growth

Zhou

et al. 2020

EBioMedicine

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Background: The F-box protein S-phase kinase-associated protein 2 (Skp2) is overexpressed and correlated with poor prognosis in human malignancies, including colorectal cancer (CRC). Methods: A natural product library was used for natural compound screening through glycolysis analysis. The expression of Skp2 in CRCs and the inhibitory effect of dioscin on glycolysis were examined through methods of immunoblot, immunofluorescence, immunohistochemical staining, anchorage-dependent and -independent growth assays, EdU incorporation assay, ubiquitination analysis, co-immunoprecipitation assay, CRISPR-Cas9-based gene knockout, and xenograft experiment. Findings: We demonstrated that Skp2 was highly expressed in CRC tissues and cell lines. Knockout of Skp2 inhibited HK2 and glycolysis and decreased CRC cell growth in vitro and in vivo. We screened 88 commercially available natural products and found that dioscin, a natural steroid saponin derived from several plants, significantly inhibited glycolysis in CRC cells. Dioscin decreased the protein level of Skp2 by shortening the half-life of Skp2. Further study showed that dioscin attenuated Skp2 phosphorylation on S72 and promoted the interaction between Skp2 and Cdh1, which eventually enhanced Skp2 lysine 48 (K48)-linked polyubiquitination and degradation. Depletion of Cdh1 impaired dioscin-induced Skp2 reduction, rescued HK2 expression, and glycolysis in CRC cells. Finally, dioscin delayed the in vivo tumor growth, promoted Skp2 ubiquitination, and inhibited Skp2 expression in a mouse xenograft model. Interpretation: This study suggests that in addition to pharmacological inactivation of Skp2, enhancement of ubiquitination-dependent Skp2 turnover is a promising approach for cancer treatment.

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Section: Discussionmentioning

confidence: 58%

Cdh1-mediated Skp2 degradation by dioscin reprogrammes aerobic glycolysis and inhibits colorectal cancer cells growth

Zhou

et al. 2020

EBioMedicine

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“…Three endometrial cancer cases (the mother and two sisters of the patient) and two gastric tumours are the family antecedents. Other authors have associated ERCC4 mutations with endometrial cancer [24,25] and colorectal [26]; however, until now, the relatives with endometrial cancer have refused genetic testing. Both mutations are classified as pathogenic according to the ACMG standards.…”

Section: Discussionmentioning

confidence: 99%

Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer

Velázquez

Leeneer

Esteban-Cardeñosa

et al. 2020

Cancers

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In this study, we aim to gain insight in the germline mutation spectrum of ATM, BARD1, BRIP1, ERCC4, PALB2, RAD51C and RAD51D in breast and ovarian cancer families from Spain. We have selected 180 index cases in whom a germline mutation in BRCA1 and BRCA2 was previously ruled out. The importance of disease-causing variants in these genes lies in the fact that they may have possible therapeutic implications according to clinical guidelines. All variants were assessed by combined annotation dependent depletion (CADD) for scoring their deleteriousness. In addition, we used the cancer genome interpreter to explore the implications of some variants in drug response. Finally, we compiled and evaluated the family history to assess whether carrying a pathogenic mutation was associated with age at diagnosis, tumour diversity of the pedigree and total number of cancer cases in the family. Eight unequivocal pathogenic mutations were found and another fourteen were prioritized as possible causal variants. Some of these molecular results could contribute to cancer diagnosis, treatment selection and prevention. We found a statistically significant association between tumour diversity in the family and carrying a variant with a high score predicting pathogenicity (p = 0.0003).

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“…Early studies have shown that VUS accounts for a high proportion of MMR gene mutations [ 11 ] and that MLH1 mutations account for the greatest proportion of MMR gene mutations [ 12 ]. Recent research has provided more details on this information, showing that MLH1 accounts for >60% of MMR mutations in LS [ 13 ] and that the most common type of mutation in MLH1 is the change in splice sites [ 14 ]. Through NGS and Sanger sequencing, we found that the family members of the proband carried a novel germline mutation ( MLH1 c.1989 + 5G>A).…”

Section: Discussionmentioning

confidence: 99%

“…The average age at diagnosis of LS was 39 years in the first family, which is lower than the median age of 45 years [ 13 ]. We found that this mutation-associated CRC occurred at younger and younger ages in families (ranging from parents in their 40s to children in their 20s) and the disease stages were also late.…”

Section: Discussionmentioning

confidence: 99%

“…Although at least five genes are associated with LS, ∼50% of suspected LS cases are genetically unknown [ 23 ]. Therefore, we recommend that CRC patients with a family history or who fulfil the Amsterdam/Bethesda clinical diagnostic criteria or patients with suspected LS-related tumours undergo screening for MMR gene mutations by genetic testing [ 13 ]. NGS has been increasingly used in clinical settings and research to define the diagnosis and explore the significance of other genes in patients with a personal/family history of hereditary CRC.…”

Section: Discussionmentioning

confidence: 99%

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Classification and genetic counselling for a novel splicing mutation of the MLH1 intron associated with Lynch syndrome in colorectal cancer

Wang

Zou

Lin

et al. 2021

Gastroenterology Report

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Background Lynch-syndrome-associated cancer is caused by germline pathogenic mutations in mismatch repair genes. The major challenge to Lynch-syndrome screening is the interpretation of variants found by diagnostic testing. This study aimed to classify the MLH1 c.1989 + 5G>A mutation, which was previously reported as a variant of uncertain significance, to describe its clinical phenotypes and characteristics, to enable detailed genetic counselling. Methods We reviewed the database of patients with Lynch-syndrome gene detection in our hospital. A novel variant of MLH1 c.1989 + 5G>A identified by next-generation sequencing was further investigated in this study. Immunohistochemical staining was carried out to assess the expression of MLH1 and PMS2 protein in tumour tissue. In silico analysis by Alamut software was used to predict the MLH1 c.1989 + 5G>A variant function. Reverse transcription-polymerase chain reaction and sequencing of RNA from whole blood were used to analyse the functional significance of this mutation. Results Among affected family members in the suspected Lynch-syndrome pedigree, the patient suffered from late-stage colorectal cancer but had a good prognosis. We found the MLH1 c.1989 + 5G>A variant, which led to aberrant splicing and loss of MLH1 and PMS2 protein in the nuclei of tumour cells. An aberrant transcript was detectable and skipping of MLH1 exon 17 in carriers of MLH1 c.1989 + 5G>A was confirmed. Conclusions MLH1 c.1989 + 5G>A was detected in a cancer family pedigree and identified as a pathological variant in patients with Lynch syndrome. The mutation spectrum of Lynch syndrome was enriched through enhanced genetic testing and close surveillance might help future patients who are suspected of having Lynch syndrome to obtain a definitive early diagnosis.

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Next Generation Sequencing Reveals Novel Mutations in Mismatch Repair Genes and Other Cancer Predisposition Genes in Asian Patients with Suspected Lynch Syndrome

Cited by 5 publications

References 26 publications

Cdh1-mediated Skp2 degradation by dioscin reprogrammes aerobic glycolysis and inhibits colorectal cancer cells growth

Cdh1-mediated Skp2 degradation by dioscin reprogrammes aerobic glycolysis and inhibits colorectal cancer cells growth

Germline Genetic Findings Which May Impact Therapeutic Decisions in Families with a Presumed Predisposition for Hereditary Breast and Ovarian Cancer

Classification and genetic counselling for a novel splicing mutation of the MLH1 intron associated with Lynch syndrome in colorectal cancer

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