Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition

Macquère, Pierre; Orazio, Sébastien; Bonnet, Fabrice; Jones, Natalie; Bubien, Virginie; Chiron, Jennifer; Lafon, D; Barouk-Simonet, Emmanuelle; Tinat, Julie; Vénat-Bouvet, Laurence; Gesta, Paul; Longy, Michel; Sévenet, Nicolas

doi:10.1038/s10038-022-01014-3

Cited by 3 publications

(2 citation statements)

References 36 publications

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“…Therefore, NGS has implemented the potential for the detection of pathogenic variants in HBOC genes other than BRCA1 and BRCA2 and for the identification of subjects with pathogenic variants in more than one cancer predisposition gene. In fact, although not frequently, HBOC patients have been described with double heterozygous pathogenic variants in ATM, BRCA1, BRCA2, CHEK2, MSH6, MUTYH, NBN/NBS1 and RAD50 following gene panel testing (7)(8)(9)(10)(11)(12)(13) with a frequency of approximately 0.3% (10,13). Not surprisingly, double heterozygous carriers are more frequently detected in populations enriched with founder variants (14).…”

Section: Introductionmentioning

confidence: 99%

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

et al. 2023

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The widespread adoption of gene panel testing for cancer predisposition is leading to the identification of an increasing number of individuals with clinically relevant allelic variants in two or more genes. The potential combined effect of these variants on cancer risks is mostly unknown, posing a serious problem for genetic counseling in these individuals and their relatives, in whom the variants may segregate singly or in combination. We report a female patient who developed triple-negative high grade carcinoma in the right breast at the age of 36 years. The patient underwent bilateral mastectomy followed by combined immunotherapy and chemotherapy (IMpassion030 clinical trial). Two years later she developed a skin recurrence on the right anterior chest wall. Despite intensive treatment, the patient died at 40-year-old due to disease progression. Gene panel testing of patient’s DNA revealed the presence of a protein truncating variant in ATM [c.1672G>T; p.(Gly558Ter)] and of a not previously reported variant in the BRCA1 exon 22 donor splice site [c.5406+6T>C], whose clinical significance was unknown. The analysis of patient’s RNA revealed the up-regulation of two alternative BRCA1 mRNA isoforms derived from skipping of exon 22 and of exons 22-23. The corresponding predicted protein products, p.(Asp1778GlyfsTer27) and p.(Asp1778_His1822del) are both expected to affect the BRCA1 C Terminus (BRCT) domain. The two variants were observed to co-occur also in the proband’s brother who, in addition, was heterozygous for a common variant (c.4837A>G) mapped to BRCA1 exon 16. This allowed to ascertain, by transcript-specific amplification, the lack of functional mRNA isoforms expressed by the c.5406+6T>C allele and provided evidence to classify the BRCA1 variant as pathogenic, according to the guidelines of the Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) consortium. To our knowledge, excluding two cases detected following the screening of population specific recurrent variants, only one ATM/BRCA1 double heterozygote has been reported in the literature, being the case here described the one with the youngest age at cancer onset. The systematic collection of cases with pathogenic variants in more than one cancer predisposition gene is needed to verify if they deserve ad hoc counseling and clinical management.

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Section: Introductionmentioning

confidence: 99%

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

et al. 2023

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“…Ataxia-telangiectasia mutated (ATM) protein kinase, one of the master regulatory factors in the progress of DNA double-strand break response, is an important cell-cycle checkpoint kinase to maintain the stability of the genome ( 4 , 5 ). The mutations or dysfunctions of the ATM gene have been detected during the carcinogenesis and development of various cancer types including breast cancer, ovarian cancer, and prostate cancer ( 6 – 8 ). In recent years, the efficacy-predicting role of ATM mutations for poly-ADP-ribose polymerase inhibitors (PARPi) in patients with ovarian cancer and metastatic castration-resistant prostate cancer has been preliminarily investigated ( 9 , 10 ).…”

Section: Introductionmentioning

confidence: 99%

Positive response to niraparib in chemo-refractory patients with metastatic appendiceal mucinous adenocarcinoma harboring ATM mutations: A case report

Wang

Huang²,

Xu³

et al. 2023

Front. Oncol.

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BackgroundAppendiceal mucinous adenocarcinoma, one kind of specific colorectal cancer, is lowly prevalent and rarely diagnosed in clinical practice. In addition, there have been limited standard treatment strategies established for patients with appendiceal mucinous adenocarcinoma, especially with metastatic disease. The regimens for colorectal cancer, which were adopted in appendiceal mucinous adenocarcinoma, usually resulted in limited effectiveness.Case presentationHerein, we presented a case of chemo-refractory patient with metastatic appendiceal mucinous adenocarcinoma harboring ATM pathological mutation of exon 60, c.8734del, p.R2912Efs*26, and who has achieved a persistent response to salvage treatment of niraparib, with disease control time that reached 17 months and still in extension.ConclusionsWe supposed that appendiceal mucinous adenocarcinoma patients harboring ATM pathological mutations may respond to the treatment of niraparib, even without a homologous recombination deficiency (HRD) status; however, it needs further confirmation in a larger cohort.

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Classification of the immune microenvironment associated with 12 cell death modes and construction of a prognostic model for squamous cell lung cancer

Bin

Ding

Liu

et al. 2023

J Cancer Res Clin Oncol

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Increased incidence of pathogenic variants in ATM in the context of testing for breast and ovarian cancer predisposition

Cited by 3 publications

References 36 publications

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

A novel BRCA1 splicing variant detected in an early onset triple-negative breast cancer patient additionally carrying a pathogenic variant in ATM: A case report

Positive response to niraparib in chemo-refractory patients with metastatic appendiceal mucinous adenocarcinoma harboring ATM mutations: A case report

Classification of the immune microenvironment associated with 12 cell death modes and construction of a prognostic model for squamous cell lung cancer

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