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. 2024 Feb 14:2:101829.
doi: 10.1016/j.gimo.2024.101829. eCollection 2024.

Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes

Nihat B Agaoglu  1 , Brittany L Bychkovsky  1   2   3   4 , Carolyn Horton  5 , Min-Tzu Lo  5 , Linda Polfus  5 , Cassidy Carraway  5 , Parichehr Hemyari  5 , Colin Young  5 , Marcy E Richardson  5 , Rochelle Scheib  1   2   3   4 , Judy E Garber  1   2   3   4 , Huma Q Rana  1   2   4
Affiliations

Cancer burden in individuals with single versus double pathogenic variants in cancer susceptibility genes

Nihat B Agaoglu et al. Genet Med Open. .

Abstract

Purpose: As panel testing expands, more individuals with double pathogenic variants (DPVs) in cancer susceptibility genes are likely to be identified. Little is known about the effects of DPVs on cancer phenotype, although this information is crucial for genetic counseling and risk management. We sought to describe the cancer phenotype among individuals with DPVs in cancer susceptibility genes.

Methods: A retrospective study of individuals with DPVs identified through a single testing laboratory from 2012 to 2017 was conducted. DPV combinations were enumerated. For DPV gene combinations that occurred >10 times, cancer histories of individuals with DPVs were compared with cancer histories of controls with a single PV matched by gene.

Results: Among 644 individuals with DPVs, combinations that included the ATM, BRCA1, BRCA2, CHEK2, and PALB2 genes occurred >10 times. There were 8883 matched controls for a single PV in these genes. The median age of first cancer diagnosis was younger with ATM+CHEK2 (43), compared with ATM (47, P = .016) or CHEK2 (47, P = .015) alone. Similar findings were observed when comparing age at first breast cancer (BC) for the ATM+CHEK2 with single-gene controls. Individuals with 2 CHEK2 PVs also were younger at first cancer diagnosis (40) compared with single CHEK2 PV controls (47, P = .0038). This difference was not driven by age at first BC diagnosis among females.

Conclusion: Individuals with ATM+CHEK2 or 2 CHEK2 PVs have a greater cancer burden than single gene controls. These findings can be used to counsel individuals with DPVs and their families and inform cancer screening recommendations.

Keywords: Breast cancer; Genetics; Germline; Hereditary cancer; Multiple pathogenic variants.

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Conflict of interest statement

Carolyn Horton, Min-Tzu Lo, Dr Polfus, Cassidy Carraway, Parichehr Hemyari, and Colin Young report employment at Ambry Genetics, a commercial lab. Min-Tzu Lo reports current employment at Monogram Biosciences. Judy E. Garber reports research collaboration with Ambry Genetics and Invitae (no compensation). Huma Q. Rana reports research collaboration with Invitae and Ambry Genetics (no compensation). All other authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Flow DiagramofDPVCohort. DPVs, double pathogenic or likely pathogenic variants in one individual (plural noun); MPVs, multiple pathogenic or likely pathogenic variants in one individual (plural noun); PV, pathogenic or likely pathogenic variant (single noun); PVs, pathogenic or likely pathogenic variants (plural noun).
Figure 2
Figure 2
Heatmap of DPVGeneCombinations.
Figure 3
Figure 3
A. Median age of first breast cancer (BC) diagnosis. With exception of the CHEK2+CHEK2 combination, P values are statistically significant after the Bonferroni correction if P < .025. When CHEK2+CHEK2 was compared with monoallelic CHEK2, the P value is statistically significant if P < .05. B. Median age of first cancer diagnosis. With exception of the CHEK2+CHEK2 combination, P values are statistically significant after the Bonferroni correction if P < .025. When CHEK2+CHEK2 was compared with monoallelic CHEK2, the P value is statistically significant if P < .05.
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