Family Matters: Germline Testing in Thoracic Cancers

Area of Science:

• Oncology
• Genetics
• Environmental Health

Background:

• Most thoracic cancers result from somatic mutations due to carcinogens like tobacco or asbestos.
• A subset of thoracic cancers arises from heritable pathogenic germline variants (PGVs), increasing cancer risk through gene-environment interactions.

Purpose of the Study:

• To highlight the role of pathogenic germline variants (PGVs) in thoracic cancer development.
• To discuss the clinical suspicion and implications of specific PGVs, such as EGFR and BAP1, in lung cancer and mesothelioma.
• To emphasize the need for genetic counseling and future research in managing thoracic cancers associated with PGVs.

Main Methods:

• Review of existing literature on pathogenic germline variants (PGVs) in thoracic cancers.
• Analysis of PGV rates in specific thoracic cancer subtypes (e.g., nonsquamous non-small-cell lung cancer, mesothelioma).
• Discussion of gene-environment interactions and their impact on cancer risk and prognosis.

Main Results:

• Pathogenic germline variants (PGVs) in EGFR are found in 0.3%-0.9% of nonsquamous non-small-cell lung cancer, warranting suspicion during genetic sequencing.
• BAP1 PGVs occur in 2.8%-8% of sporadic mesothelioma cases, correlating with a favorable prognosis and accelerated tumorigenesis post-asbestos exposure.
• Gene-environment interactions involving PGVs significantly elevate lung cancer risk (1.5- to 3.2-fold).

Conclusions:

• Pathogenic germline variants (PGVs) play a significant role in a subset of thoracic cancers, influencing risk, prognosis, and potentially treatment response.
• Routine germline genetic testing is not standard, underscoring the need for expert genetic counseling for affected individuals.
• Further research into the natural history of PGVs is essential for advancing cancer prevention, counseling, and management strategies.