Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer

P, Sharma Bhai; Sharma, Deepak; Saxena, Renu; Ic, Verma

doi:10.1159/000457786

Cited by 5 publications

(2 citation statements)

References 22 publications

(28 reference statements)

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“…XPC p.R579* was identified in MelR041, ATM p.H2555_T2556delinsQ* was found in MelR082, RECQL4 splice acceptor variant (c.2464-1G > C) in MelR158 and POLH in-frame deletion (p.Asp74_Leu75del) in MelR162. Additionally, MelR049 carried nonsense mutation MRE11A p.R364*, conferring a risk of breast/ovarian cancer 37 – 39 . These four genes, POLH, MRE11A, RECQL4 and XPC, are autosomal recessive.…”

Section: Resultsmentioning

confidence: 99%

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

Aoude

Bonazzi

Brosda

et al. 2020

Sci Rep

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Patients with late stage resected cutaneous melanoma have poor overall survival (OS) and experience irreversible adverse events from systemic therapy. There is a clinical need to identify biomarkers to predict outcome. Performing germline/tumour whole-exome sequencing of 44 stage III/IV melanoma patients we identified pathogenic germline mutations in CDKN2A, CDK4, ATM, POLH, MRE11A, RECQL4 and XPC, affecting 7/44 patients. These mutations were associated with poor OS (p = 0.0082). We confirmed our findings in The Cancer Genome Atlas (TCGA) human skin cutaneous melanoma cohort where we identified pathogenic variants in 40/455 patients (p = 0.0203). Combining these cohorts (n = 499) further strengthened these findings showing germline carriers had worse OS (p = 0.0009). Additionally, we determined whether tumour mutation burden (TMB) or BRAF status were prognostic markers of survival. Low TMB rate (< 20 Mut/Mb; p = 0.0034) and BRAF p.V600 mutation (p = 0.0355) were associated with worse progression-free survival. Combining these biomarkers indicated that V600 mutant patients had significantly lower TMB (p = 0.0155). This was confirmed in the TCGA (n = 443, p = 0.0007). Integrative analysis showed germline mutation status conferred the highest risk (HR 5.2, 95% CI 1.72–15.7). Stage IV (HR 2.5, 0.74–8.6) and low TMB (HR 2.3, 0.57–9.4) were similar, whereas BRAF V600 status was the weakest prognostic biomarker (HR 1.5, 95% CI 0.44–5.2).

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Section: Resultsmentioning

confidence: 99%

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

Aoude

Bonazzi

Brosda

et al. 2020

Sci Rep

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“…

This constraint has been overcome with the use of NGS-WES, enabling the study of rare variants broadly across human exomes, for e.g., reports from Southern India indicate role of CHEK2 in addition to BRCA1, BRCA2 in early onset of HBOC (Hereditary Breast and Ovarian cancer) and lung cancer in families with a history of breast and ovarian cancer (Rajkumar, 2003), while genetic alterations in the MRE11A (p.Arg364Ter) are reported in breast cancer without the BRCA1 and BRCA2 mutations (Bhai, 2017). NGS-WES in breast cancer patient revealed three recurrent mutations L719fs, K994fs, H1269fs in RAD50 gene, reduce the chances of recurrence free survival (Fan, 2018).Our earlier study involved NGS-WES in a patient

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confidence: 99%

A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family

Biswas,

Manekar,

Bakshi

2023

Asian Pac J Cancer Prev

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Background: The use of high-throughput genotyping techniques has enabled us to identify the rare germline genetic variants with different pathogenicity and penetrance, and understand their role in cancer predisposition. We report here a familial cancer case, a study from Western Indian. Methods: NGS-WES was carried out in a lung cancer patient who has a family history of multiple cancers across generations, including tongue, lung, brain, cervical, urothelial, and esophageal cancer. The results were validated by data mining from available data bases. I-TASSER, RasMol and PyMol were used for protein structure modelling. Results: The sequencing by NGS-WES revealed PPM1D c.1654C>T (p.Arg552Ter) mutation in hotspot region exon 6 leading to sudden protein truncation and loss of the C-terminal, due to the substitution of C>T. This mutation was classified as a variant of uncertain significance (VUS), due to limited data on lung cancer, The three unaffected siblings of proband did not show any pathogenic variants and comparative analysis of the four siblings indicate 9 shared genetic variants, classified as benign as per ClinVar. Conclusion: PPM1D constitutional genetic alterations are rare and uncommon in different ethnic populations. This gene encodes a phosphatase playing role in regulating the P53 tumor suppressor pathway and DNA damage response. Genetic alterations in the PPM1D gene maybe linked to history of gliomas, breast cancer, and ovarian cancer onset in the proband’s family.

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DNA Repair Pathway Alterations in Metastatic Castration-resistant Prostate Cancer Responders to Radium-223

Ramos

Mostaghel

Pritchard

et al. 2018

Clinical Genitourinary Cancer

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Next-Generation Sequencing Reveals a Nonsense Mutation (p.Arg364Ter) in MRE11A Gene in an Indian Patient with Familial Breast Cancer

Cited by 5 publications

References 22 publications

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

Pathogenic germline variants are associated with poor survival in stage III/IV melanoma patients

A Case Study on PPM1D and 9 Other Shared Germline Alterations in a Family

DNA Repair Pathway Alterations in Metastatic Castration-resistant Prostate Cancer Responders to Radium-223

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