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Germline Variants in Types of Cancer Without Hereditary Testing Guidelines


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In a study reported in JAMA Network Open, Timothy A. Yap, MBBS, PhD, FRCP, and colleagues found that a substantial proportion of patients with cancer types that lacked hereditary testing guidelines harbored germline pathogenic/likely pathogenic variants.

Study Details

The study included data from 34,642 patients in the Tempus Inc clinicogenomic database on patients with bladder, brain, lung, esophageal, head and neck, breast, ovarian, pancreatic, prostate, endometrial, or colorectal cancers, or cholangiocarcinoma. Patients underwent Tempus xT tumor/normal-matched assay testing for 50 reportable hereditary cancer genes between November 2017 and August 2021.

A total of 14,038 patients had cancers lacking testing guidelines—eg, bladder, brain, lung, esophageal, and head and neck cancers, as well as cholangiocarcinoma. A total of 20,604 patients had cancers with available testing guidelines—eg, breast, ovarian, pancreatic, prostate, endometrial, and colorectal cancers.


This study may present the largest retrospective analysis to date of de-identified real-world data from patients diagnosed with advanced cancer with tumor/normal matched sequencing data and the prevalence of pathogenic or likely pathogenic germline variants in cancer types lacking hereditary cancer testing guidelines. The findings suggest there may be clinical implications for patients and their at-risk family members in cancers for which germline assessment primarily based on the cancer diagnosis is rarely obtained.
— Timothy A. Yap, MBBS, PhD, FRCP, and colleagues

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Key Findings

Overall, germline pathogenic/likely pathogenic variants were identified in 759 (5.4%) of 14,038 patients with cancers lacking guidelines and in 1,775 (8.6%) of 20,604 patients with cancers with available guidelines. Cancers without guidelines with the highest proportion of germline pathogenic/likely pathogenic variants were bladder cancer, with variants identified in 79 (6.6%) of 1,188 patients, and lung cancer, with variants identified in 448 (5.8%) of 7,668 patients. In comparison, the cancers with guidelines with the highest proportion of germline pathogenic/likely pathogenic variants were ovarian cancer, with variants identified in 380 (13.8%) of 2,756 patients, and breast cancer, with variants identified in 494 (10.8%) of 4,581 patients.

In addition, germline variants were identified in 4.8% of esophageal cancer cases, 4.6% of brain cancer cases, 4.3% of cholangiocarcinoma cases, and 4.2% of head and neck cancer cases (among cancers lacking guidelines), and in 8.6% of prostate cancer cases, 7.7% of pancreatic cancer cases, 5.8% of colorectal cancer cases, and 4.9% of endometrial cancer cases among cancers with guidelines.  

Monoallelic MUTYH was the most common germline variant across most tumor types; it was identified in 23 of 79 patients with bladder cancer and 122 of 448 patients with lung cancer with germline variants. Among all tumor types, the DNA repair genes ATM and BRCA1/2 were the most common genes with clinically actionable germline variants; variants in ATM, BRCA1, and BRCA2 were identified in 7, 5, and 10 patients, respectively, with bladder cancer, and in 60, 20, and 51 patients, respectively, with lung cancer with germline variants. 

The investigators concluded, “This study may present the largest retrospective analysis to date of de-identified real-world data from patients diagnosed with advanced cancer with tumor/normal matched sequencing data and the prevalence of pathogenic or likely pathogenic germline variants in cancer types lacking hereditary cancer testing guidelines. The findings suggest there may be clinical implications for patients and their at-risk family members in cancers for which germline assessment primarily based on the cancer diagnosis is rarely obtained.”

Dr. Yap, of The University of Texas MD Anderson Cancer Center, is the corresponding author for the JAMA Network Open article.

Disclosure: The study was supported by Tempus Labs Inc. For full disclosures of the study authors, visit jamanetwork.com.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
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