Penetrance of <i>ATM</i> Gene Mutations in Breast Cancer: A Meta‐Analysis of Different Measures of Risk

Marabelli, Monica; Cheng, Su Chun; Parmigiani, Giovanni

doi:10.1002/gepi.21971

Cited by 118 publications

(94 citation statements)

References 28 publications

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“…Female carriers are considered to have an approximately 2.3 fold increased risk for the development of breast cancer compared to the general population [51–53]. A 2016 meta-analysis found the cumulative risk of breast cancer in carriers to be approximately 6% by age 50 and approximately 30% by age 80 [54]. Standard breast cancer surveillance, including monthly breast self-exams and mammography at the usual schedule for age, is recommended unless an individual has other risk factors (e.g., family history of breast cancer).…”

Section: Introductionmentioning

confidence: 99%

Ataxia telangiectasia: a review

Rothblum-Oviatt

Wright²,

Lefton‐Greif

et al. 2016

Orphanet J Rare Dis

486

488

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Definition of the diseaseAtaxia telangiectasia (A-T) is an autosomal recessive disorder primarily characterized by cerebellar degeneration, telangiectasia, immunodeficiency, cancer susceptibility and radiation sensitivity. A-T is often referred to as a genome instability or DNA damage response syndrome.EpidemiologyThe world-wide prevalence of A-T is estimated to be between 1 in 40,000 and 1 in 100,000 live births.Clinical descriptionA-T is a complex disorder with substantial variability in the severity of features between affected individuals, and at different ages. Neurological symptoms most often first appear in early childhood when children begin to sit or walk. They have immunological abnormalities including immunoglobulin and antibody deficiencies and lymphopenia. People with A-T have an increased predisposition for cancers, particularly of lymphoid origin. Pulmonary disease and problems with feeding, swallowing and nutrition are common, and there also may be dermatological and endocrine manifestations.EtiologyA-T is caused by mutations in the ATM (Ataxia Telangiectasia, Mutated) gene which encodes a protein of the same name. The primary role of the ATM protein is coordination of cellular signaling pathways in response to DNA double strand breaks, oxidative stress and other genotoxic stress.DiagnosisThe diagnosis of A-T is usually suspected by the combination of neurologic clinical features (ataxia, abnormal control of eye movement, and postural instability) with one or more of the following which may vary in their appearance: telangiectasia, frequent sinopulmonary infections and specific laboratory abnormalities (e.g. IgA deficiency, lymphopenia especially affecting T lymphocytes and increased alpha-fetoprotein levels). Because certain neurological features may arise later, a diagnosis of A-T should be carefully considered for any ataxic child with an otherwise elusive diagnosis. A diagnosis of A-T can be confirmed by the finding of an absence or deficiency of the ATM protein or its kinase activity in cultured cell lines, and/or identification of the pathological mutations in the ATM gene.Differential diagnosisThere are several other neurologic and rare disorders that physicians must consider when diagnosing A-T and that can be confused with A-T. Differentiation of these various disorders is often possible with clinical features and selected laboratory tests, including gene sequencing.Antenatal diagnosisAntenatal diagnosis can be performed if the pathological ATM mutations in that family have been identified in an affected child. In the absence of identifying mutations, antenatal diagnosis can be made by haplotype analysis if an unambiguous diagnosis of the affected child has been made through clinical and laboratory findings and/or ATM protein analysis.Genetic counselingGenetic counseling can help family members of a patient with A-T understand when genetic testing for A-T is feasible, and how the test results should be interpreted.Management and prognosisTreatment of the neurologic problems associated wit...

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Section: Introductionmentioning

confidence: 99%

Ataxia telangiectasia: a review

Rothblum-Oviatt

Wright²,

Lefton‐Greif

et al. 2016

Orphanet J Rare Dis

486

488

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“…Another limitation of our study is that we used known age- and sex-based penetrances, which is unlikely to be the case for all variants. However, for many known pathogenic genes, there are multiple estimates of sex- and age-based penetrances available in the literature [27, 28, 36]. Furthermore, when most genotypes and phenotypes are known, small to moderate changes in the penetrance matrix had virtually no effect on the LOD score in our analysis.…”

Section: Discussionmentioning

confidence: 85%

Power of pedigree likelihood analysis in extended pedigrees to classify rare variants of uncertain significance in cancer risk genes

2017

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Rare and private variants of uncertain significance (VUS) are routinely identified in clinical panel, exome, and genome sequencing. We investigated the power of single family co-segregation analysis to aid classification of VUS. We simulated thousands of pedigrees using demographics in China and the United States, segregating benign and pathogenic variants. Genotypes and phenotypes were simulated using penetrance models for Lynch syndrome and breast/ovarian cancer. We calculated LOD scores adjusted for proband ascertainment (LODadj), to determine power to yield quantitative evidence for, or against, pathogenicity of the VUS. Power to classify VUS was higher for Chinese than United States pedigrees. The number of affected individuals explained the most variation in LODadj (21–38%). The distance to the furthest affected relative from the proband explained 1–7% of the variation for the benign VUS and Lynch associated cancers. Minimum age of onset explained 5–13% of the variation in families with pathogenic breast/ovarian cancer variants. Random removal of 50% of the phenotype/genotype data reduced power and the variation in LODadj was best explained by the distance to the furthest affected relative followed by the number of affected individuals and minimum age of onset when the founder was only 2 generations from the proband. Power to classify benign variants was ~2× power to classify pathogenic variants. Affecteds-only analysis resulted in virtually no power to correctly classify benign variants and reduced power to classify pathogenic variants. These results can be used to guide recruitment efforts to classify rare and private VUS.

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“…In contrast, heterozygosity for a pathogenic ATM variant is present in 1% -2% of the adult population [3][4][5] . Those individuals are phenotypically normal, but their risk for breast cancer is higher than that in the general population by a factor of approximately 2-3 8,[16][17][18][19][20] . Assuming a baseline risk of approximately 1 in 10 (10%) 21 , the risk increase translates into a 20%-30% lifetime risk of breast cancer among North American women.…”

Section: Pathophysiology and Clinical Presentationmentioning

confidence: 99%

“…As a result, three recent metaanalyses reported different pooled estimates of breast cancer risk in carriers of pathogenic ATM variants [18][19][20] . In a meta-analysis of the three largest published cohort studies, the relative risk of breast cancer in ATM carriers was 2.8 [95% confidence interval (ci): 2.2 to 3.7; p = 4.7×10 -11 ] 18 .…”

Section: Pathophysiology and Clinical Presentationmentioning

confidence: 99%

“…In a second meta-analysis of four studies, all of which included only patients who belonged to an at family, the relative risk of breast cancer was 3.04 (95% ci: 2.06 to 4.48; p < 0.000001) 19 . Finally, a larger but more heterogeneous meta-analysis of nineteen studies suggested that, by age 80, the cumulative risk of breast cancer among carriers of pathogenic ATM variants is 32.83% (95% credible interval: 24.55% to 40.43%) 20 , approximately 3 times the baseline population risk. In that particular study, ATM variants that were unlikely to be pathogenic were excluded, but a familial link to the at syndrome was not required 20 .…”

Section: Pathophysiology and Clinical Presentationmentioning

confidence: 99%

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