Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

Nguyen-Dumont, Tú; Dowty, James G.; Steen, Jason A.; Renault, Anne-Laure; Hammet, Fleur; Mahmoodi, Maryam; Theys, Derrick; Rewse, Amanda; Tsimiklis, Helen; Winship, Ingrid; Giles, Graham G.; Milne, Roger L.; Hopper, John L.; Southey, Melissa C.

doi:10.3390/cancers13061378

Cited by 6 publications

(5 citation statements)

References 53 publications

(31 reference statements)

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“…PVs in BRCA1 and BRCA2 have frequencies of 0.21% and 0.31% in the European population [46], while the frequencies of ATM and CHEK2 PVs reach 1% [47] and 1.4% [48]. These estimations, taken together, and given the scarcity of double-heterozygotes reports, indicate that the prevalence of digenic coinheritance is likely underestimated.…”

Section: Discussionmentioning

confidence: 92%

Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients

Freire,

Martin,

Segers

et al. 2024

JPM

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Background/Objectives: BRCA1, BRCA2, ATM, and CHEK2 are known cancer predisposition genes (CPGs), but tumor risk in patients with simultaneous pathogenic variants (PVs) in CPGs remains largely unknown. In this study, we describe six patients from five families with multiple cancers who coinherited a combination of PVs in these genes. Methods: PVs were identified using NGS DNA sequencing and were confirmed by Sanger. Results: Families 1, 2, and 3 presented PVs in BRCA2 and ATM, family 4 in BRCA2 and BRCA1, and family 5 in BRCA2 and CHEK2. PVs were identified using NGS DNA sequencing and were confirmed by Sanger. The first family included patients with kidney, prostate, and breast cancer, in addition to pancreatic adenocarcinomas. In the second family, a female had breast cancer, while a male from the third family had prostate, gastric, and pancreatic cancer. The fourth family included a male with pancreatic cancer, and the fifth family a female with breast cancer. Conclusions: The early age of diagnosis and the development of multiple cancers in the reported patients indicate a very high risk of cancer in double-heterozygous patients associated with PVs in HR-related CPGs. Therefore, in families with patients who differ from other family members in terms of phenotype, age of diagnosis, or type of cancer, the cascade testing needs to include the study of other CPGs.

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Section: Discussionmentioning

confidence: 92%

Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients

Freire,

Martin,

Segers

et al. 2024

JPM

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“…We previously calculated cumulative risk estimates for CHEK2 in the ABCFR and observed that the penetrance estimates for pathogenic variants in CHEK2 and ATM are not statistically different (Fig. 1) [8]. There is an urgent and currently unmet need to provide robust information that can inform risk management strategies for carriers of pathogenic variants in intermediate risk genes such Cumulative risk (%)…”

Section: Discussionmentioning

confidence: 99%

“…Bloodderived germline DNA from 1480 case probands and 864 control probands were screened by targeted-sequencing of the coding regions and proximal intron-exon junctions of BRCA1 (NM_007294.4), BRCA2 (NM_000059.4) and ATM (NM_000051.4). Details of study participant characteristics and selection, sequencing and data processing and variant filtering and annotation methods have been published previously [8] and are summarized in Additional file 1: Fig. S1.…”

Section: Study Participants and Genomic Data Generationmentioning

confidence: 99%

“…Hazard ratios (HRs) and age-specific cumulative risks (penetrance) were estimated as described in detail in [8]. Briefly, HRs for carriers of pathogenic ATM variants were estimated by segregation analysis as implemented in the statistical package MENDEL version 3.2, then the estimated cumulative risk to a given age was derived from the estimated HR.…”

Section: Statistical Analysesmentioning

confidence: 99%

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Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

et al. 2022

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Background Multigene panel tests for breast cancer predisposition routinely include ATM as it is now a well-established breast cancer predisposition gene. Methods We included ATM in a multigene panel test applied to the Australian Breast Cancer Family Registry (ABCFR), a population-based case–control–family study of breast cancer, with the purpose of estimating the prevalence and penetrance of heterozygous ATM pathogenic variants from the family data, using segregation analysis. Results The estimated breast cancer hazard ratio for carriers of pathogenic ATM variants in the ABCFR was 1.32 (95% confidence interval 0.45–3.87; P = 0.6). The estimated cumulative risk of breast cancer to age 80 years for heterozygous ATM pathogenic variant carriers was estimated to be 13% (95% CI 4.6–30). Conclusions Although ATM has been definitively identified as a breast cancer predisposition gene, further evidence, such as variant-specific penetrance estimates, are needed to inform risk management strategies for carriers of pathogenic variants to increase the clinical utility of population testing of this gene.

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“…Estimates were adjusted for clinic-based ascertainment using the retrospective likelihood method [ 18 ]. For each gene, the cumulative risk (penetrance) to a given age was calculated as one minus the exponential of minus the cumulative incidence for carriers, which itself was the sum from age zero to the given age of the estimated HR multiplied by the non-carriers’ prostate cancer age-specific incidence [ 19 ]. Non-carrier incidences were set equal to the age-specific population incidence rates for Australia in the period 1998–2002 [ 20 ].…”

Section: Methodsmentioning

confidence: 99%

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

Mondschein

Bolton

Clouston

et al. 2022

Cancers

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Background: Germline mutations in BRCA2 are associated with aggressive prostate cancer. Additional information regarding the clinical phenotype of germline pathogenic variants in other prostate cancer predisposition genes is required. Clinical testing has been limited by evidence, further restricting knowledge of variants that contribute to prostate cancer development. Objective: Prostate cancer patients who were first- and second-degree relatives from multi-case prostate cancer families underwent a gene panel screen to identify novel (non-BRCA) germline pathogenic variants in cancer predisposition genes and define clinical phenotypes associated with each gene. Methods: The germline genomic DNA (gDNA) of 94 index cases with verified prostate cancer from families with a minimum of two verified prostate cancer cases was screened with an 84-cancer-gene panel. Families were recruited for multi-case breast/ovarian cancer (n = 66), or multi-case prostate cancer (n = 28). Prostate cancer characteristics associated with each gene were compared with prostate cancer cases of confirmed non-mutation carriers (BRCAX), also from multi-case prostate cancer families (n = 111), and with data from the Prostate Cancer Outcomes Registry (PCOR). Results: Ninety-four prostate cancer index cases underwent gene panel testing; twenty-two index cases (22/94; 23%) were found to carry a class 4–5 (C4/5) variant. Six of twenty-two (27%) variants were not clinically notifiable, and seven of twenty-two (31.8%) variants were in BRCA1/2 genes. Nine of twenty-two (40.9%) index cases had variants identified in ATM (n = 4), CHEK2 (n = 2) and HOXB13G84 (n = 3); gDNA for all relatives of these nine cases was screened for the corresponding familial variant. The final cohort comprised 15 confirmed germline mutation carriers with prostate cancer (ATM n = 9, CHEK2 n = 2, HOXB13G84 n = 4). ATM and CHEK2-associated cancers were D’Amico intermediate or high risk, comparable to our previously published BRCA2 and BRCAX prostate cancer cohort. HOXB13G84 carriers demonstrated low- to intermediate-risk prostate cancer. In the BRCAX cohort, 53.2% of subjects demonstrated high-risk disease compared with 25% of the PCOR cohort. Conclusions:ATM and CHEK2 germline mutation carriers and the BRCAX (confirmed non-mutation carriers) cohort demonstrated high risk disease compared with the general population. Targeted genetic testing will help identify men at greater risk of prostate-cancer-specific mortality. Data correlating rare variants with clinical phenotype and familial predisposition will strengthen the clinical validity and utility of these results and establish these variants as significant in prostate cancer detection and management.

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Population-Based Estimates of the Age-Specific Cumulative Risk of Breast Cancer for Pathogenic Variants in CHEK2: Findings from the Australian Breast Cancer Family Registry

Cited by 6 publications

References 53 publications

Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients

Digenic Inheritance of Mutations in Homologous Recombination Genes in Cancer Patients

Population-based estimates of age-specific cumulative risk of breast cancer for pathogenic variants in ATM

Novel Germline Mutations in a Cohort of Men with Familial Prostate Cancer

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