Evaluation of Somatic Genetic Testing As a Screening Tool to Detect Hereditary Cancer Predisposition in Patients Diagnosed With Myeloid Malignancies
Cancer Genetics and Therapeutics
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Primary Categories:
- Cancer
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Secondary Categories:
- Cancer
Introduction:
In an oncology setting, genetic counselors see patients with a personal or family history of cancer because these individuals have an increased risk to carry a germline variant in a cancer predisposition gene, given that an estimated 5-10% of cancers occur secondary to a hereditary cancer predisposition. Historically, patients with myeloid malignancies have not been referred for genetic services but emerging evidence suggests that approximately 13% of these cancers are hereditary. This study explored the use of somatic genetic testing, which is routinely ordered as part of the workup and treatment of hematologic malignancies, as a screening tool for hereditary cancer predisposition in patients diagnosed with myeloid malignancies [acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelomonocytic leukemia (AMML), chronic myelomonocytic leukemia (CMML)], with the aim of evaluating evidence that this is an appropriate way to identify additional patients who could benefit from genetics services.
Methods:
An IRB-approved retrospective chart review was conducted to analyze the results of somatic next generation sequencing (NGS) testing (Panel of 75-225 genes) on blood or bone marrow, that was performed at University of California, Irvine between June 9, 2020 and August 31, 2022. Records for 110 participants were assessed using criteria from both the 2023 National Comprehensive Cancer Network (NCCN) guidelines for AML/MDS and the 2022 European LeukemiaNet (ELN) guidelines. Variants with an allele fraction >30% were re-analyzed using multiple databases, including GnomAD, ClinVar, and Cosmic, and only those variants in genes that would be clinically relevant in a germline state were considered further. Bone marrow transplant history and variant allele frequency (VAF) at different time points (i.e.diagnosis, remission) were also evaluated. Microsoft Excel and SPSS V29 were used for data analysis.
Results:
Results showed that 62 out of 110 participants (56%) met criteria for germline genetic testing to assess hereditary cancer risk based on either the NCCN 2023 guidelines for AML/MDS, Breast/Pancreas, and Colon and the 2022 ELN guidelines; however, none were referred to genetics services. Of the 110 participants, 13 (12%) participants had a variant identified (TP53, CEBPA, RUNX1, KRAS, PTPN11; VAF range 34%-84%) on somatic NGS that warranted germline testing; the remaining 49 met criteria based on personal or family history. Of those 13 participants, 9 (69%) did not meet criteria for any reason other than the results of their somatic NGS testing, which included genetic variants that could be germline in origin, and as such, would be clinically relevant. Ordering providers of the somatic tests containing relevant variants found in these 13 participants were contacted using a standardized letter to recommend consideration of referral for germline genetic testing.
Conclusion:
The results of this study indicate that somatic genetic test results can be used as a screening tool to determine whether a patient should receive genetic counseling and consideration of germline testing. Early identification of germline variants is clinically relevant and medically recommended for the management of patients with hematologic malignancies. Given the high percentage of this study’s participants who met criteria for germline genetic testing based on ELN 2022 or NCCN 2023 criteria, it is imperative that clinicians consider these recommendations more consistently and refer patients to genetic counseling services when appropriate. Furthermore, the 2024 NCCN v.3.2024 guidelines recommend germline testing for all patients with MDS and adults diagnosed with AML under age 50.
In an oncology setting, genetic counselors see patients with a personal or family history of cancer because these individuals have an increased risk to carry a germline variant in a cancer predisposition gene, given that an estimated 5-10% of cancers occur secondary to a hereditary cancer predisposition. Historically, patients with myeloid malignancies have not been referred for genetic services but emerging evidence suggests that approximately 13% of these cancers are hereditary. This study explored the use of somatic genetic testing, which is routinely ordered as part of the workup and treatment of hematologic malignancies, as a screening tool for hereditary cancer predisposition in patients diagnosed with myeloid malignancies [acute myeloid leukemia (AML), myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN), acute myelomonocytic leukemia (AMML), chronic myelomonocytic leukemia (CMML)], with the aim of evaluating evidence that this is an appropriate way to identify additional patients who could benefit from genetics services.
Methods:
An IRB-approved retrospective chart review was conducted to analyze the results of somatic next generation sequencing (NGS) testing (Panel of 75-225 genes) on blood or bone marrow, that was performed at University of California, Irvine between June 9, 2020 and August 31, 2022. Records for 110 participants were assessed using criteria from both the 2023 National Comprehensive Cancer Network (NCCN) guidelines for AML/MDS and the 2022 European LeukemiaNet (ELN) guidelines. Variants with an allele fraction >30% were re-analyzed using multiple databases, including GnomAD, ClinVar, and Cosmic, and only those variants in genes that would be clinically relevant in a germline state were considered further. Bone marrow transplant history and variant allele frequency (VAF) at different time points (i.e.diagnosis, remission) were also evaluated. Microsoft Excel and SPSS V29 were used for data analysis.
Results:
Results showed that 62 out of 110 participants (56%) met criteria for germline genetic testing to assess hereditary cancer risk based on either the NCCN 2023 guidelines for AML/MDS, Breast/Pancreas, and Colon and the 2022 ELN guidelines; however, none were referred to genetics services. Of the 110 participants, 13 (12%) participants had a variant identified (TP53, CEBPA, RUNX1, KRAS, PTPN11; VAF range 34%-84%) on somatic NGS that warranted germline testing; the remaining 49 met criteria based on personal or family history. Of those 13 participants, 9 (69%) did not meet criteria for any reason other than the results of their somatic NGS testing, which included genetic variants that could be germline in origin, and as such, would be clinically relevant. Ordering providers of the somatic tests containing relevant variants found in these 13 participants were contacted using a standardized letter to recommend consideration of referral for germline genetic testing.
Conclusion:
The results of this study indicate that somatic genetic test results can be used as a screening tool to determine whether a patient should receive genetic counseling and consideration of germline testing. Early identification of germline variants is clinically relevant and medically recommended for the management of patients with hematologic malignancies. Given the high percentage of this study’s participants who met criteria for germline genetic testing based on ELN 2022 or NCCN 2023 criteria, it is imperative that clinicians consider these recommendations more consistently and refer patients to genetic counseling services when appropriate. Furthermore, the 2024 NCCN v.3.2024 guidelines recommend germline testing for all patients with MDS and adults diagnosed with AML under age 50.