Establishing Links Between Germline Mutations and Oncogenesis

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In part 1 of a 2-part series, Bryant Furlow discusses advances in the understanding of inherited cancer syndromes and screening techniques for early tumor detection in high-risk patients.
In part 1 of a 2-part series, Bryant Furlow discusses advances in the understanding of inherited cancer syndromes and screening techniques for early tumor detection in high-risk patients.

This summer, scientists at the National Cancer Institute (NCI) reported that rapid whole-body magnetic resonance imaging (MRI) for cancer screening is a feasible strategy for detecting early-stage disease among patients with Li-Fraumeni syndrome.1,2

Despite a false-positive rate of 30%, the researchers found that 7% of patients had an asymptomatic new malignancy.

This highlights the remaining challenges in surveillance and early-detection efforts for people with inherited genetic cancer syndromes, according to senior study author Sharon Savage, MD, branch chief of Clinical Genetics, Division of Cancer Epidemiology & Genetics at the NCI in Rockville, Maryland.

Cancer syndromes like Li-Fraumeni and Lynch syndrome involve germline mutations inherited from one or both parents, rather than somatic mutations acquired in the course of a person's lifetime. They are believed to represent 5% to 10% of all diagnosed cancers.3-8

Among the germline genetic aberrations implicated in these syndromes are oncogenes and mutations in tumor suppressor genes like TP53 or DNA mismatch repair (MMR) genes (Figure 1.) The vast majority of patients with Li-Fraumeni syndrome harbor germline TP53 mutations, contributing to their elevated risks for sarcoma, breast, lung, brain, and other cancers.3,5,6

High-risk variants of the BRCA1 and BRCA2 genes hinder homology-directed DNA repair, increasing the risk of breast or ovarian cancer. MMR mutations are also implicated in the autosomal-dominant mismatch repair cancer syndrome, Lynch syndrome, and hereditary breast-ovarian cancer syndrome. More rarely, such as with Von Hippel-Lindau Disease, germline mutations cause dysregulation of angiogenesis, which can hasten tumor growth.

These types of heritable mutations and advances in rapid genetic sequencing have made genetic testing a plausible and attractive screening strategy for early detection and prevention efforts.1,2

The available evidence shows that whole-body MRI identifies cancers before symptoms emerge among high-risk patients. MRI-based screening also avoids the radiation involved with other imaging modalities.

“Patients with Li-Fraumeni syndrome should limit ionizing radiation exposure because there is concern for potential increased sensitivity to it,” Dr Savage told Cancer Therapy Advisor. “If, however, a diagnostic radiology exam is required based on clinical features, it should be performed.”

False-positive results are a concern for any medical test — and the NCI study's false-positive finding was for baseline or first imaging exams, Dr Savage noted.

“In some instances, an additional evaluation is required to evaluate a finding on whole-body MRI,” she added. “The specific evaluation depends on the location of the finding and the differential diagnosis. Once a patient has a baseline whole-body MRI, we think that there will be fewer false-positive findings because comparison of the new MRI to the old one will be possible. But we are still collecting the data to test that hypothesis.”

Early results from other studies suggest that annual whole-body MRI screening for Li-Fraumeni syndrome patients with TP53 mutations improves survival times.9-11 But those findings need to be confirmed.

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