Hereditary Factors in Lung Cancer: How Common Are They, and Who Is Most Affected?

Lung Cancer published the results of the Latin American GERMLUNG study on July 28, 2024. According to its findings,

• in patients meeting criteria such as young age, a family history of lung cancer and no history of smoking, lung adenocarcinoma was associated with a high rate (21%) of inherited genetic alterations.
• These genetic alterations were found to be more common in men and to tend to occur alongside other genetic features that can be targeted by treatment.

Why Hereditary Factors Matter in Lung Cancer

Lung cancer is the leading cause of cancer-related death worldwide in both sexes, and deaths from this disease are expected to increase over the coming decade. Diagnosis at an advanced stage and limited access to new treatments partly explain this situation.

In recent years, the role of hereditary factors in lung cancer has become better understood. This is particularly apparent in patients diagnosed at a young age, cancers in people who do not smoke and the increasing frequency of targetable genomic alterations (HGD). Identifying inherited predispositions is therefore important for assessing risk, diagnosing disease early and determining treatment options for patients with lung cancer and their close relatives.

Across all cancers, PGV prevalence can range from 0.3% to 14.9%. These rates may vary with factors such as ethnicity, cancer stage and study eligibility criteria. Most studies have focused on previously identified cancer-predisposition genes, particularly tumor-suppressor genes.

Two important familial syndromes contributing to hereditary lung cancer involve pathogenic or likely pathogenic germline variants in TP53 and EGFR T790M . Additional PGVs have recently been discovered in DNA damage repair (DDR) genes such as ATM, BRCA1, BRCA2 and CHEK2. Furthermore, nearly 95% of identified PGVs can be used to guide treatment decisions and directly influence treatment selection.

Nevertheless, it remains uncertain who should undergo germline genetic testing for lung cancer. Recent findings suggest that all patients with lung cancer should be assessed for eligibility for genetic testing. Unfortunately, diagnostic genomic tools and genetic counseling remain inaccessible to many people in resource-limited settings.

PGVs found in patients with lung cancer may be associated with certain clinical and pathological features that provide useful information for genetic testing. For example, these alterations are more common in people with a family history of cancer who are diagnosed at a young age (50 years or younger). They may also be more evident in lung adenocarcinoma and in people who do not smoke. These features can help identify people with a predisposition to lung cancer for more detailed assessment, supporting personalized treatment and follow-up plans.

The GERMLUNG Study

The GERMLUNG study was launched to address the need to identify PGVs that predispose people to lung cancer. It aims to use practical genetic assessment criteria to determine PGV prevalence in patients with lung adenocarcinoma. The report documents the first 201 patients who underwent genetic testing, providing important information about PGV frequency and its potential clinical implications.

A cross-sectional cohort study examined PGV rates in patients with lung adenocarcinoma who had a family history of cancer, were diagnosed at a young age, had little or no smoking history, or carried HGD. Sequencing of 144 cancer-predisposition genes was performed using Sophia Hereditary Cancer Solution panel F. Variants classified as pathogenic or likely pathogenic were selected for further analysis.

Results

• Among the 201 patients in this study, 21.4%—or 43 patients—had a pathogenic or likely pathogenic germline variant.
• Of these variants, 64.5% were in DNA damage repair genes, while 86.1% were found to be clinically targetable.
• The most common PGVs were found in the ATM gene at a rate of 9.3%, and in TP53, BRCA2 and CHEK2 at 6.9% each.
• These genetic alterations were also more common in men, who were approximately 2.5 times more likely than women to have them. The alterations also tended to coexist with other genetic features that can be treated, suggesting that patients with such an alteration may have a greater potential to respond to treatment.

In conclusion, the study found a high PGV frequency using the researchers' selection criteria. This is considered an effective strategy for identifying candidates for germline genomic testing, potential screening strategies for close relatives and personalized treatment approaches.