• We now know that there are genetic predispositions to the risk of contracting lung cancer, according to our partner The Conversation.

  • However, these “genetic cancers” appear earlier (before age 50) than “classic” lung cancers (around age 65), and often in non-smokers.

  • The analysis of this discovery was carried out by Patrick Benusiglio, specialist in genetic predispositions to cancer and Jacques Cadranel, pulmonologist.

While smoking remains the main risk factor for lung cancer, there are others.

Some are of occupational origin such as asbestos, others have environmental roots, such as air pollution or radon, a ubiquitous gas naturally present in the atmosphere resulting from the decay of radioactive elements in the ground.

But there are also genetic risk factors, variations present in our genes since birth which, for some, significantly increase the risk of lung cancer.

These mutations are called “pathogenic variants”.

This is called a genetic predisposition to lung cancer.

These “genetic cancers” appear earlier - before age 50 - than conventional lung cancers - around age 65 - often in non-smokers.

Identifying them is essential for the patient, because his medico-surgical management can be optimized.

But it is also and especially for his family, the pathogenic variants being hereditary.

They can, in fact, be transmitted to the offspring and have, most of the time, been inherited from one of the two parents.

Two genes involved

It has been known since the 1960s that having a close relative who has had lung cancer increases the risk of developing one yourself, regardless of possible smoking.

More recently, studies of twin pairs have proven the importance of genetic factors.

The risk of developing lung cancer for the "real" twin (monozygous, in other words from the same egg cell) of a patient who has declared lung cancer is, in fact, higher than that incurred by a "false" twin. »Twin (dizygotic, two different egg cells).

While monozygotic twins have the same genetic makeup, dizygotic twins share only about half.

In the presence of a similar carcinogenic exposure (tobacco, pollution, asbestos, radon, etc.), the increased risk observed in the former thus attests to the share of the risk attributable to our genes.

The risk of developing lung cancer for the “real” twin of a patient who has declared lung cancer is higher than that for a “false” twin © Juliane Liebermann / Unsplash

We now know two major genes of predisposition to lung cancer: 


(Tumor protein P53) and


(Epidermal Growth Factor Receptor). Both are implicated in pulmonary adenocarcinoma, the most common lung cancer, but probably not in its other types, the cancers being classified according to their microscopic characteristics.

Pathogenic variants of


are responsible for a rare genetic disease: Li-Fraumeni syndrome. In those who have it, the risk of developing many types of cancer increases, often at a young age. The most frequently encountered are breast cancer, bone and soft tissue tumors (sarcomas), brain tumors, leukemias and certain cancers of the adrenal glands (glands that produce stress hormones).

But it is only recently that the increased risk of lung cancer has been convincingly demonstrated.

In the early 2010s, nearly 300 people with Li-Fraumeni syndrome but cancer-free were followed by magnetic resonance imaging (MRI).

During the first examination, lung cancer was diagnosed in 9 of them.

Lung anatomy: detail of the alveolar sacs (clusters of alveoli), pulmonary alveoli and circulation © Patrick J. Lynch / Wikimedia CC BY-SA 2.5

The role of the EGFR gene, the second major predisposition gene for lung cancer, was first discovered in non-smokers with pulmonary adenocarcinoma.

In these patients, a pathogenic variant was found in cancer cells, but not in "normal" cells, the cancer acquiring these EGFR variants as it progresses and as it becomes exposed to treatment.

This discovery literally transformed the treatment of lung cancer by enabling the development of therapies specifically targeting the gene in the cancer cell.

In rare patients, however, the pathogenic variant is also found in normal cells, which then leads to a syndrome of genetic predisposition.

Unlike Li-Fraumeni syndrome, patients are only at risk of developing lung cancer.

As common as breast cancer in France

In light of the growing interest in the subject and advances in genetic analysis capabilities, knowledge of genetic predispositions to lung cancer is set to advance considerably in the years to come with the identification of new genes.

Recent data suggests in particular that the



could also be associated with lung cancer.

This gene predisposing to breast and pancreatic cancer is, moreover, responsible for a neurodegenerative disease in children: ataxia telangiectasia.

Bronchioloalveolar carcinoma, mucinous type.

The alveoli are lined with tall, cylindrical cup-shaped tumor cells and are filled with mucin © Yale Rosen / Wikimedia CC BY-SA 2.0

A genetic predisposition to lung cancer is identified only in a small proportion of patients with the disease (in 1 to 2% of adenocarcinomas, for example).

In absolute numbers, a pathogenic variant would nevertheless be found in several hundred new patients per year in France, if research were systematically launched to study suspected cases.

By adding the other carriers in the family, we arrive at around 1,000 new people affected each year.

It can be noted that the proportion of pulmonary adenocarcinomas of genetic origin is quite close to that observed in breast cancer, yet the medical world and non-specialists are much more familiar with this second disease.

The identification of a genetic predisposition is beneficial first of all for the treated patient and secondly for his family.

In fact, the treatment of the patient can be optimized, for example by avoiding radiotherapy, the toxicity of which is increased in the case of Li-Fraumeni syndrome, or by the administration of targeted therapies of the latest generation, in the case of Li-Fraumeni syndrome. of a pathogenic variant of EGFR.

The identification of healthy carriers among the relatives of the patient makes it possible to consider screening for lung cancer, for example with the performance of chest MRIs at regular intervals as well as strict recommendations not to smoke.

Our "Cancer" file

The diagnosis of lung cancer in a young person who often does not smoke is a real cataclysm.

Faced with a disease that is naturally associated with tobacco and with age, a feeling of incomprehension predominates.

The evocation of a genetic cause brings a beginning of explanation and a relief from a personal responsibility in the occurrence of the disease.

A genetic predisposition, when it is identified, makes it possible to act since it is then possible to better treat the patient and protect his relatives.


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This analysis was written by Patrick Benusiglio, university lecturer and hospital practitioner at AP-HP and specialist in genetic predispositions to cancer at Sorbonne University, and Jacques Cadranel, pulmonologist at Tenon hospital and at the Sorbonne University Faculty of Medicine. .

The original article was published on The Conversation website.

Declaration of interests

Patrick B


has received funding from the AstraZeneca, Janssen and Roche Diagnostics laboratories within the framework of consulting missions or invited conferences.

He is also a member of the scientific committee of the Geneticancer patient association.

Jacques Cadranel received funding within the framework of costly innovative techniques support programs from the ministry and research support from AstraZeneca, Boerhinger Ingelheim, Pfizer and Novartis laboratories.

  • Twins

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