Nav: Home

Mutations unveiled that predispose lung cancers to refractory histologic transformation

June 07, 2017

Cancer pedigree analysis reveals the mutations in RB1 and TP53 genes play a key role in treatment-resistant, cancer cell-type transformation during EGFR inhibitor therapy for lung cancers.

Research led by Korean medical scientists has discovered that a specific type of drug resistance mechanism to EGFR inhibitor therapy in lung cancer is predisposed by mutations in two canonical cancer-related genes: RB1 and TP53. Published in Journal of Clinical Oncology on May 12, the study also found those mutations can be detectable in patients' tumors at the point of clinical diagnosis. Therefore, it can be used as strong markers in clinic for predicting poor outcome for the targeted treatment for lung adenocarcinoma.

Lung adenocarcinoma is the most common type of lung cancer, and about 15% of patients in Western countries and 50% of patients in Asian countries have mutations in the EGFR gene, which is critical for the development of lung cancer. Patients with lung adenocarcinoma harboring the EGFR mutation show favorable responses to EGFR inhibitors such as erlotinib (Tarceva) or gefitinib (Iressa), but ultimately relapse with drug-resistant tumors. Since the initial report in 2006, it has been known that in about 5~15% of patients, the lung adenocarcinoma cells undergo a mysterious transformation into a very different cancer cell type called "small cell lung cancer," a much more aggressive lung cancer subtype, common in cigarette smokers.

To find out the genetic basis of this process, the researchers compared the genome sequences of multiple cancer tissues acquired during the treatment courses of patients whose tumors underwent small-cell transformation. They reconstructed the cancer cell pedigree by comparing mutations between cancer tissues, and identified that RB1 and TP53 genes are completely inactivated by mutations already in their lung adenocarcinoma tissues.

"We tried to compare the somatic mutational profile of pre-EGFR inhibitor treatment lung adenocarcinomas and post-treatment small cell carcinomas and to reconstruct the pedigrees of the cancer evolution in each patient. Strikingly, both copies of RB1 and TP53 genes were already inactivated at the stage of lung adenocarcinomas in all sequenced cases," said Dr. Jake June-Koo Lee, the first author from KAIST.

They further pursued the clinical implications of RB1 and TP53 inactivation by investigating 75 EGFR-mutated lung adenocarcinoma tissues from patients who received EGFR inhibitor therapy, including patients with small-cell transformation. In this analysis, the lung adenocarcinomas with a complete inactivation of both RB1 and TP53 genes tended to have a 43-times greater risk of transformation into small cell lung cancer during their EGFR inhibitor treatment courses.

Dr. Young Seok Ju, the co-last author from KAIST, explained, "This study shows the power of entire genome analyses to better understand the mechanisms underlying mysterious phenomenon encountered in clinic. Upon accurate bioinformatics, we are finding cancer-specific somatic mutations from the whole-genomes of patients' cancer cells. These mutations allow us to track the evolution of cancer cells throughout the extraordinary clinical course of a special set of lung cancers."

The complete inactivation of both RB1 and TP53 tumor suppressor genes is found in a minor (<10%) subset of lung adenocarcinoma. This study suggests that the clinical course against targeted therapy is endogenously different for the cancers in the subgroup, and specific drug-resistance mechanisms are predisposed by the two genetic mutations. Indeed, RB1 and TP53 double inactivation is a genetic hallmark of primary small cell lung cancer, observed in nearly all cases.

"We are actively investigating patient tumor tissues to develop optimal surveillance plans and treatment options for patients with lung adenocarcinomas more prone to small-cell transformation," said Dr. Tae Min Kim, the co-last author from Seoul National University Hospital.

The researchers are implementing their findings into lung cancer clinics by screening the RB1 and TP53 mutational status in lung adenocarcinoma patients receiving EGFR inhibitor treatment, and following their treatment courses to develop a treatment strategy for those patients.
-end-
This research (doi.org/10.1200/JCO.2016.71.9096) was funded by the National Research Foundation of Korea (NRF-2013H1A2A1032691 to J.-K.L., NRF-2014R1A2A2A05003665 to Y.T.K.); Korea Institute of Science and Technology Information (K-16-L03-C02-S02 to J.L.); and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute, which was funded by the Ministry of Health and Welfare (HI14C1234 to T.M.K., HI16C2387 to Y.S.J.)

The Korea Advanced Institute of Science and Technology (KAIST)

Related Lung Cancer Articles:

AI helps to fight against lung cancer
Lung cancer has been the leading cause of cancer-related deaths in 2015 in United States.
Free lung-cancer screening in the Augusta area finds more than double the cancer rate of previous screenings
The first year of free lung cancer screening in the Augusta, Ga., area found more than double the rate seen in a previous large, national study as well as a Massachusetts-based screening for this No.
Antioxidants and lung cancer risk
An epidemiological study published in Frontiers in Oncology suggests that a diet high in carotenoids and vitamin C may protect against lung cancer.
Lung cancer may go undetected in kidney cancer patients
Could lung cancer be hiding in kidney cancer patients? Researchers with the Harold C.
Hitgen and Cancer Research UK's Manchester Institute enter license agreement in lung cancer
Cancer Research UK, Cancer Research Technology (CRT), the charity's commercial arm, and HitGen Ltd, a privately held biotech company focused on early drug discovery, announced today that they have entered into a licence agreement to develop a novel class of drugs against lung cancer.
Radiotherapy for invasive breast cancer increases the risk of second primary lung cancer
East Asian female breast cancer patients receiving radiotherapy have a higher risk of developing second primary lung cancer.
Huntsman Cancer Institute research holds promise for personalized lung cancer treatments
New research from scientists at Huntsman Cancer Institute (HCI) at the University of Utah uncovered distinct types of tumors within small cell lung cancer that look and act differently from one another.
High levels of estrogen in lung tissue related to lung cancer in postmenopausal women
Researchers from Kumamoto University, Japan have found that postmenopausal women with multicentric adenocarcinoma of the lung have a higher concentration of estrogen in non-cancerous areas of the peripheral lung than similar women diagnosed with single tumor lung cancer.
Radiotherapy for lung cancer patients is linked to increased risk of non-cancer deaths
Researchers have found that treating patients who have early stage non-small cell lung cancer with a type of radiotherapy called stereotactic body radiation therapy is associated with a small but increased risk of death from causes other than cancer.
Pericardial window operation less efficient in cases of lung cancer than any other cancer
Pericardial window operation, a procedure, where abnormal quantity of malignant fluid, surrounding the heart, is drained into the neighbouring chest cavity, is commonly applied to patients diagnosed with cancer.

Related Lung Cancer Reading:

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#SB2 2019 Science Birthday Minisode: Mary Golda Ross
Our second annual Science Birthday is here, and this year we celebrate the wonderful Mary Golda Ross, born 9 August 1908. She died in 2008 at age 99, but left a lasting mark on the science of rocketry and space exploration as an early woman in engineering, and one of the first Native Americans in engineering. Join Rachelle and Bethany for this very special birthday minisode celebrating Mary and her achievements. Thanks to our Patreons who make this show possible! Read more about Mary G. Ross: Interview with Mary Ross on Lash Publications International, by Laurel Sheppard Meet Mary Golda...