Abstract 4104
Background
Women treated for breast cancer (BC) are at risk to develop a subsequent lung cancer (LC; relative risk ranging from 1.38 to 5.05), especially in case of smoking history and if adjuvant radiation (aRT) was administered for BC. We hypothesized that genetic variants might predispose patients (Pts) to develop LC after BC. Our aim was to perform whole exome sequencing (WES) to identify genes associated with such predisposition.
Methods
28 women with diagnosis of LC after BC (Study Population, SP) were enrolled, as well as 32 women treated for BC and with no secondary cancer after a follow-up ≥10 years (control population; CP). DNA was extracted from tumors and normal tissue samples from both SP and CP. Libraries were prepared with Agilent SureSelect All Exon kit and sequenced on Illumina HiSeq2500. Variant calling was performed with FreeBayes software.
Results
The median age of SP at BC diagnosis was 63.5 years (range: 47-76); the median interval between diagnosis of BC and occurrence of LC was 4.5 years (range: 0-11). 13 Pts (46%) were never-smokers and, among the 21 Pts who had received aRT, 13 (62%) developed ipsilateral LC. At somatic analysis, no common mutation among known driver genes was shared between each BC and LC pair in SP Pts. WES performed on BC and LC samples identified two mutational signatures (S1 and S2). S1 (C>T substitutions) was observed in all BC samples and 16/28 (57%) LC samples and was more frequent in never-smokers (11 vs. 5 Pts) and among Pts who developed ipsilateral LC after aRT (10 vs. 6 Pts). S2 (C>A transversions) was observed in 12/28 LC samples (43%) and was strongly associated with smoking habit (10 vs. 2 Pts). When compared with COSMIC libraries, S2 results were similar to COSMIC 4, common in LC samples collected from smokers. Since S1 was largely shared between paired BC and LC samples, we explored the eventuality of a genetic predisposition to S1-related malignancies with a gene-based burden test over rare germline variants in normal tissue of S1-LC Pts compared with CP Pts; 249 candidate genes were identified (FDR<0.05).
Conclusions
Our data identified two mutational signatures underlying the LC development. Germline analysis suggests that genetic variants may contribute to increase the risk of LC after BC.
Clinical trial identification
Legal entity responsible for the study
Ospedale Policlinico San Martino.
Funding
Italian Ministry of Health (GR-2011-02350922).
Editorial Acknowledgement
Disclosure
F. Grossi: Honoraria: BMS, MSD, AstraZeneca, Pierre Fabre, Boehringer Ingelheim, Pfizer, Celgene, Amgen, Roche. C. Genova: Honoraria: AstraZeneca, Boehringer Ingelheim, BMS, MSD, Roche. G. Barletta: Employee: AstraZeneca. All other authors have declared no conflicts of interest.
Resources from the same session
4784 - Tranilast inhibits TGF-beta-induced EMT and invasion/metastasis via the suppression of Smad4 in lung cancer cell lines.
Presenter: Koji Takahashi
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
767 - Integrin beta-like 1 overexpression stimulates invasiveness of ovarian cancer cells in vitro
Presenter: Alexander Cortez
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
938 - MiR-449a suppresses endometrial cancer invasion and metastasis by targeting NDRG1
Presenter: Lihua Qiu
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4866 - Cancer-associated fibroblasts-derived VEGFA mediates the migration of gastric cancer cells through VEGFR1
Presenter: xiaoxun Wang
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4934 - Risk prediction of metastasis through study of circulating tumor cells
Presenter: Panagiotis Apostolou
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
3289 - First step to metastasis: miRNAome abnormalities impair cell-cell adhesion and facilitate detachment of breast cancer cells
Presenter: Volodymyr Halytskiy
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4110 - Extracellular matrix of normal brain tissue is affected by temozolomide during anti-glioblastoma treatment
Presenter: Alexandra Tsidulko
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
1526 - Study of the activation of TLR receptors in neurospheres from glioblastoma cells in vitro
Presenter: David Albert Bellver
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
4862 - 5-Fluorouracil induced up-regulation of exosomal PD-L1 causing immunosuppression in gastric cancer patients
Presenter: Zhang Min
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract
635 - Thrombocytosis and leukocytosis: are they negative prognostic factors in solid tumours?
Presenter: Filip Kohutek
Session: Poster display session: Basic science, Endocrine tumours, Gastrointestinal tumours - colorectal & non-colorectal, Head and neck cancer (excluding thyroid), Melanoma and other skin tumours, Neuroendocrine tumours, Thyroid cancer, Tumour biology & pathology
Resources:
Abstract