Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Nielsen, Sarah M.; Bristow, Sara L.; Garber, Judy E.; Hampel, Heather; Rana, Huma Q.; Samadder, N. Jewel; Shore, Neal D.; Nussbaum, Robert L.

doi:10.1200/po.21.00516

Cited by 24 publications

(32 citation statements)

References 83 publications

(98 reference statements)

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“…9 A recent review further showed that PGVs were found in 3.9%-56.2% of patients with common solid tumors who were unselected for family history or other putative risk factors. 5 Similar data have been demonstrated in hematological malignancies as well. 10 Germline mutations in cancer-predisposing genes were also identified in 8.5%-13% of multiple pan-cancer pediatric studies, 11,12 and family history did not predict the underlying predisposition syndrome in most patients.…”

Section: Where Is the Evidence?supporting

confidence: 73%

Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: Genomics Is the Diagnosis

Subbiah

Kurzrock

2023

JCO

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Advances in the genomic era have led to identification of cancer-causing genes and unprecedented progress in the development of gene-targeted therapies and agents that can unleash the immune system. These advances have improved the outlook for patients with lethal malignancies.Cancer is a genomic disease in that gene alterations drive the cellular growth and immune surveillance perturbations that enable malignant cells to take hold and to metastasize. Hereditary genetic factors play a key role in cancer predisposition, initiation, prognosis, and therapy. In a previous viewpoint, we posited that we need universal (somatic) genomic testing to win the war against cancer. 1 Currently, given the rapidly emerging evidence, we update our view to state that universal germline, in addition to tumor somatic, genomic testing is needed to win the war against cancer. 1 Author affiliations and support information (if applicable) appear at the end of this article.

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Section: Where Is the Evidence?supporting

confidence: 73%

Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: Genomics Is the Diagnosis

Subbiah

Kurzrock

2023

JCO

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“…Next, our analyses were limited to the 21 selected genes, and it is possible that if we evaluated more genes, such as BAP1, CDKN2A, FH, MEN1, MEN2, MITF, POT1, RET, SDHx, TERT, and VHL, additional cancers could be intercepted. For patients found to have genetic risk of melanoma, endocrine neoplasms, and/or renal cell carcinoma, there are efficacious guidelines for screening that should be utilized [30][31][32][33][34][35][36]. We have previously reported on the frequency of unexpected germline PVs among patients with BC [37,38] and on intercepted genetic cancers [39].…”

Section: Discussionmentioning

confidence: 99%

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Bychkovsky

Yussuf

et al. 2023

Breast Cancer Res Treat

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Purpose Herein, we report the frequency and distribution of germline pathogenic variants (PVs) among females with breast cancer (BC) and at least one other non-BC who underwent multi-gene panel testing (MGPT). Among females with PVs diagnosed first with BC or ovarian cancer (OC), we sought to enumerate the frequency of subsequent PV-associated cancers. Methods Females with BC and cancer of ≥ 1 other site (multiple primary cancers, MPC) who underwent MGPT through Ambry Genetics from March 2012 to December 2016 were included if they had testing of at least 21 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53). Phenotypic data were abstracted from test requisition forms and clinical notes. Results Of 6,617 evaluable patients, most were White (70.8%) and median age at first cancer, second cancer, and MGPT was 49 (interquartile range [IQR]: 18), 59 (IQR: 16), and 63 (IQR: 16) years, respectively. PVs were found among 14.1% (932/6617) of the overall cohort and in 16.4% (440/2687) of females who were diagnosed first with BC. Among those, 55.2% (243/440) had an actionable PV associated with a subsequent cancer diagnosis including 150 OCs. Of the 2443 females with breast and ovarian cancer, few (n = 97, 9.5%) were diagnosed first with OC, limiting our analysis. Conclusions Females with MPC, including BC, have a high frequency of germline PVs (14.1%). These data delineate the opportunities for intercepting subsequent cancers associated with genetic risk among females diagnosed first with BC.

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“…One proposed approach would be to perform universal germline testing of all cancer patients, particularly for patient populations whose tumors exceeding a pre-defined threshold for cancer risk (i.e., 10% of all patients will be expected to carry germline P/LP variants). 10,31,32 Another recently proposed approach would be to first consider germline testing based on the patient's personal/family history, in patients with microsatellite unstable tumors, or in patients with a potential germline P/LP variant detected via tumor-only NGS. 33 In our series, the majority of patients with mesothelioma meet one of these aforementioned criteria.…”

Section: Discussionmentioning

confidence: 99%

Prevalence of incidental germline variants detected via tumor-only mesothelioma genomic profiling

Mitchell

Gilliam

Gaudio

et al. 2022

Preprint

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Importance:Patients with mesothelioma often have next generation sequencing (NGS) of their tumor. Tumor-only NGS may incidentally identify germline pathogenic or likely pathogenic (P/LP) variants despite not being designed for this purpose. It is unknown how frequently patients with mesothelioma have germline P/LP variants incidentally detected via tumor-only NGS.Objective:To determine the prevalence of incidental germline P/LP variants detected via tumor-only NGS of mesothelioma.Design:A series of 161 unrelated patients with mesothelioma had tumor-only NGS and germline NGS. These assays were compared to determine which P/LP variants identified via tumor-only NGS were of germline origin.Setting:This was an observational study from a high-volume mesothelioma program. All patients enrolled on Institutional Review Board-approved protocols.Participants:161 unrelated patients with pleural, peritoneal, or bicavitary mesothelioma.Intervention(s) (for clinical trials) or Exposure(s) (for observational studies):No therapeutic interventions were used.Main Outcomes and Measures:The proportion of patients with mesothelioma who had P/LP germline variants incidentally detected via tumor-only NGS.Results:Most (78%) patients had potentially incidental P/LP germline variants. The positive predictive value of a potentially incidental germline P/LP variant on tumor-only NGS was 20%. Overall, 16% of patients carried a P/LP germline variant. Germline P/LP variants were identified inATM, ATR, BAP1, CHEK2, DDX41, FANCM, HAX1, MRE11A, MSH6, MUTYH, NF1, SAMD9L, and TMEM127.Conclusions and Relevance:Most (78%) patients with mesothelioma had potentially incidental germline P/LP variants on tumor NGS, but the positive predictive value of these was modest (20%). Of all patients, 16% had confirmed germline P/LP variants. Given the implications of a hereditary cancer syndrome diagnosis for preventive care and familial counseling, clinical approaches for addressing incidental P/LP germline variants in tumor-only NGS are needed. Tumor-only sequencing should not replace dedicated germline testing. Universal germline testing is likely needed for patients with mesothelioma.

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Universal Germline Genetic Testing for Hereditary Cancer Syndromes in Patients With Solid Tumor Cancer

Cited by 24 publications

References 83 publications

Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: Genomics Is the Diagnosis

Universal Germline and Tumor Genomic Testing Needed to Win the War Against Cancer: Genomics Is the Diagnosis

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception

Prevalence of incidental germline variants detected via tumor-only mesothelioma genomic profiling

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