Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing

Llorin, Hannah; Graf, Madeline; Chun, Nicolette M.; Ford, James M.

doi:10.1016/j.cancergen.2022.09.001

Cited by 2 publications

(4 citation statements)

References 16 publications

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Section: Discussionmentioning

confidence: 99%

“…A significant percentage of patients with confirmed pathogenic germline variants identified on tumor CGP do not meet clinical criteria for germline testing, e.g., family and personal cancer history and/or a qualifying diagnosis 3 , 21 – 24 . In a study of patients with tumor CGP-identified mutations in moderate risk breast and ovarian CSGs ( ATM, BRIP1, CHEK2, PALB2, RAD51C , and RAD51D ), 24% of patients with germline variants would not have met criteria for germline testing 24 . In studies of patients with prostate cancer and with various advanced cancers, 50% and 56% respectively, of patients with actionable variants on confirmatory germline testing following tumor-only sequencing would not have been eligible for germline testing based on current guidelines 21 , 37 .…”

Section: Discussionmentioning

confidence: 99%

“…In addition, universal germline testing is now recommended for pancreatic cancer 20 due to identification of pathogenic germline variants in a high percentage of patients with no family history of cancer who would not have met prior screening criteria for testing 21 . Yet even as broader germline testing considerations are incorporated into national and societal guidelines, the potential for missing clinically actionable germline variants when referral for testing is based on clinical guidelines alone has been recurrently demonstrated through studies in which tumor CGP has led to reporting of previously unrecognized pathogenic germline variants 3 , 21 – 24 . Due to the breadth of genes assayed, tumor CGP is particularly poised to identify germline risk in patients with cancer types without established associations with hereditary cancer predisposition syndromes or specific CSGs (i.e., “off-tumor” 6 ) in which pathogenic germline variants are nevertheless detected 2 , 25 , 26 .…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing

Tung

Dougherty²,

Gatof

et al. 2023

npj Precis. Onc.

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Existing guidance regarding clinically informed germline testing for patients with cancer is effective for evaluation of classic hereditary cancer syndromes and established gene/cancer type associations. However, current screening methods may miss patients with rare, reduced penetrance, or otherwise occult hereditary risk. Secondary finding of suspected germline variants that may confer inherited cancer risk via tumor comprehensive genomic profiling (CGP) has the potential to help address these limitations. However, reporting practices for secondary finding of germline variants are inconsistent, necessitating solutions for transparent and coherent communication of these potentially important findings. A workflow for improved confidence detection and clear reporting of potential pathogenic germline variants (PPGV) in select cancer susceptibility genes (CSG) was applied to a research dataset from real-world clinical tumor CGP of > 125,000 patients with advanced cancer. The presence and patterns of PPGVs identified across tumor types was assessed with a focus on scenarios in which traditional clinical germline evaluation may have been insufficient to capture genetic risk. PPGVs were identified in 9.7% of tumor CGP cases using tissue- and liquid-based assays across a broad range of cancer types, including in a number of “off-tumor” contexts. Overall, PPGVs were identified in a similar proportion of cancers with National Comprehensive Cancer Network (NCCN) recommendations for germline testing regardless of family history (11%) as in all other cancer types (9%). These findings suggest that tumor CGP can serve as a tool that is complementary to traditional germline genetic evaluation in helping to ascertain inherited susceptibility in patients with advanced cancer.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing

Tung

Dougherty²,

Gatof

et al. 2023

npj Precis. Onc.

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“…The full listing of the identified documents relevant to Clinical Question 4 is provided in Data Supplement 1 (Table S1), and data from the 14 identified studies is presented in Data Supplement 1 (Table S2). 3,[64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82] The guidance in the identified documents was diverse and frequently specific to the cancer type addressed by the document. One reviewer (H.M.) summarized the recommendations in the guidelines, which were considered by the full panel, who then directed the further systematic review of primary studies noted in the Methods.…”

Section: Development Of Recommendationsmentioning

confidence: 99%

Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline

Tung,

Ricker,

Messersmith

et al. 2024

JCO

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ASCO Guidelines provide recommendations with comprehensive review and analyses of the relevant literature for each recommendation, following the guideline development process as outlined in the ASCO Guidelines Methodology Manual . ASCO Guidelines follow the ASCO Conflict of Interest Policy for Clinical Practice Guidelines . Clinical Practice Guidelines and other guidance (“Guidance”) provided by ASCO is not a comprehensive or definitive guide to treatment options. It is intended for voluntary use by providers and should be used in conjunction with independent professional judgment. Guidance may not be applicable to all patients, interventions, diseases, or stages of diseases. Guidance is based on review and analysis of relevant literature and is not intended as a statement of the standard of care. ASCO does not endorse third-party drugs, devices, services, or therapies and assumes no responsibility for any harm arising from or related to the use of this information. See complete disclaimer in Appendix 1 and Appendix 2 ( online only) for more. PURPOSE To guide use of multigene panels for germline genetic testing for patients with cancer. METHODS An ASCO Expert Panel convened to develop recommendations on the basis of a systematic review of guidelines, consensus statements, and studies of germline and somatic genetic testing. RESULTS Fifty-two guidelines and consensus statements met eligibility criteria for the primary search; 14 studies were identified for Clinical Question 4. RECOMMENDATIONS Patients should have a family history taken and recorded that includes details of cancers in first- and second-degree relatives and the patient's ethnicity. When more than one gene is relevant based on personal and/or family history, multigene panel testing should be offered. When considering what genes to include in the panel, the minimal panel should include the more strongly recommended genes from Table 1 and may include those less strongly recommended. A broader panel may be ordered when the potential benefits are clearly identified, and the potential harms from uncertain results should be mitigated. Patients who meet criteria for germline genetic testing should be offered germline testing regardless of results from tumor testing. Patients who would not normally be offered germline genetic testing based on personal and/or family history criteria but who have a pathogenic or likely pathogenic variant identified by tumor testing in a gene listed in Table 2 under the outlined circumstances should be offered germline testing. Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines .

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Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing

Cited by 2 publications

References 16 publications

Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing

Potential pathogenic germline variant reporting from tumor comprehensive genomic profiling complements classic approaches to germline testing

Selection of Germline Genetic Testing Panels in Patients With Cancer: ASCO Guideline

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