Predicting Aggresive Metastasis-Prone Lung Cancer by Identification of Abnormally Activated Genes Authors’ Interview: Sophie Rousseaux and Saadi Khochbin

INSERM, U823; Université Joseph Fourier, Grenoble 1; Institut Albert Bonniot, Grenoble F-38700, France. What are the main findings of the study?

Answer: We first discovered that all cancer cells lose the ability to maintain gene silencing and therefore activate genes that should normally remain silent. Although present in all cells, some genes are normally expressed (or “active”) only in one cell type. For example, normal lung cells do not express genes that are only active in germ cells (i. e., cells that will become spermatozoa), but lung cancerous cells activate some of these germ cells-specific genes. In this work we designed a specific approach to detect these aberrant gene expressions and found that they occur in all cancers of all origins.

We then decided to exploit this phenomenon to help the detection of cancers and predict their evolution. For this purpose, we chose to focus on lung cancer to establish “a proof of principle”.

We found that, among all the genes wrongly expressed in the tumour cells, the activation of 26 of them enabled us to identify the most aggressive lung cancers. Compared with the existing information currently available for doctors (i.e.; tumour size, its pathological subtype…), our approach brings much more precision in predicting the evolution of the tumours and the prognosis of the patients. Were any of the findings unexpected?

Answer: Up to now, research on cancers had mostly focused on gene alterations, including mutations, genomic aberrations, oncogene activations or tumor suppressor silencing. We show now that the aberrant activation of normal genes is more tightly associated with tumor aggressiveness than the clinical or molecular indicators, including p53 mutation, which are usually considered by medical doctors and researchers.

Although we have not yet discovered the mechanisms underlying this phenomenon, our data open an unexpected field of research in cancer biology, exploring how these “out of context” gene activations could contribute to malignant transformation.

Additionally, the identification of the most aggressive tumours, independently of all the usual parameters, allowed us to discover their common characteristics: these “killing tumours” are those pushing their proliferation while hiding themselves from our body natural anti-tumours surveillance system. What should clinicians and patients take away from your report?

Answer: Our work proposes a test to predict, at the time of diagnosis, which cancers are at high risk of causing a relapse of the disease and lead to a fatal outcome, even in cases where the tumour was conventionally treated at an early stage of its development. This ability to distinguish lung cancer patients with different fates will enable doctors to propose a personalized surveillance and dispensation of care.

However the test developed here for lung cancer patients will need to undergo the required validations and authorization procedures before it is available to the patients. What recommendations do you have for future research as a result of this study?

Answer: In the case of lung tumours, our ability to isolate a group of very aggressive tumours allowed us to better study their biology. This revealed unique characteristics of these cells and will guide researchers to design specific anti-cancer therapeutic strategies based on targeting their now apparent potential “Achilles heel”. Future research should focus on the common molecular aspects of these very aggressive lung tumours (identified using the 26 genes) to discover new critical oncogenic mechanisms, which these tumours rely on to survive and spread, and to define shared “drugable” pathways.

The approach described in the paper for lung cancer can be applied to any type of cancer. We can foresee that it will not only enable predicting high risk tumours of any origin but also help finding the most appropriate and efficient treatment adapted to each individual tumour, leading us to a better management of cancer diseases.


Ectopic activation of germline and placental genes identifies aggressive metastasis-prone lung cancers.

Rousseaux S, Debernardi A, Jacquiau B, Vitte AL, Vesin A, Nagy-Mignotte H, Moro-Sibilot D, Brichon PY, Lantuejoul S, Hainaut P, Laffaire J, de Reyniès A, Beer DG, Timsit JF, Brambilla C, Brambilla E, Khochbin S.

INSERM, U823; Université Joseph Fourier, Grenoble 1; Institut Albert Bonniot, Grenoble F-38700, France.

Sci Transl Med. 2013 May 22;5(186):186ra66.
doi: 10.1126/scitranslmed.3005723.

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