An Inherited Cancer Syndrome Due to a Germline Monoallelic EGFR Mutation with Loss of Heterozygosity in Lung and Breast Tumors

The epidermal growth factor receptor (EGFR) exon-19 deletion is one of the most common mutations detected in lung cancer patients. Although exon-19 deletion is frequently detected in adenocarcinoma, observing this mutation in germline cells is very rare. Besides, the co-occurrence of homozygous and heterozygous mutations in dual primary cancers in a person is very uncommon. This article presents a 53-year-old Iranian woman with no history of smoking who was diagnose with two primary cancers; invasive ductal carcinoma, and primary pulmonary lung adenocarcinoma. The case reported a history of breast cancer in her sister and a history of lung cancer in her father. To select the best choice of treatment the EGFR gene was analyzed with Sanger’s sequencing method from DNA extracted from the patient’s lung tissue sample. Observing two primary cancers in this patient and considering her family pedigree, germline cells were also analyzed using samples recruited from the patient’s peripheral blood to investigate any EGFR mutations in her germline cells. The obtained data revealed that the lung tissue of the patient carried a homozygous form of EGFR exon-19 deletion while her peripheral blood contained a heterozygous form of this mutation, which is exceptionally rare.


Introduction
Epidermal growth factor receptor (EGFR) is a member of the ErbB family of receptor tyrosine kinases that applies its roles in the physiology of epithelial cells. Mutations in the EGFR coding gene are reported in different types of cancers including lung cancers. It is the target of several cancer therapies that are currently being adopted (e.g., Erlotinib and Gefitinib) [1].  deletions are the most common mutations in EGFR, which contribute to oncogenesis [2,3]. It is demonstrated that these mutations are correlated with sensitivity to inhibition of EGFR tyrosine kinase by the above-mentioned drugs [4]. Moreover, researches have shown that the exon-19 deletion of EGFR in non-small cell lung cancer patients is linked to an unusual pattern of brain metastasis [5]. It is well established that these mutations are heterozygous in the tumor tissues of patients, and identification of a disease-causing mutation with the homozygous form is extremely infrequent [6]. Besides, the co-occurrence of lung and breast cancers in the same person at the same time is indeed rare. Besides, data are extremely scarce about gene mutations that would predispose the incidence of two different cancers with different sources, simultaneously [7]. Herein, we report the effect of a germline EGFR mutation on the cooccurrence of lung and breast cancers in a 53-year-old patient with a family history of breast cancer in her sibling and a history of lung cancer in her parent. The result of this study can be used for clinical screening in patients who suffer lung cancer accompanied by breast cancer.

Case Presentation, Methods, and Results
A 53-year-old Iranian female presented with progressive dyspnea. The patient also complained of sharp upper back pain which was progressive, 10/10 in intensity, and alleviated with supine posture and analgesic medications. No significant motor or sensory symptoms, bladder or bowel incontinence were seen. She had been postmenopausal for 4 years with no history of alcohol intake, cigarette smoking, or oral contraceptive pill use. Figure 1A illustrates the family pedigree status of the patient. The proband (patient IV.1) was the oldest of four children. A history of breast cancer was raised in her sister (case IV.1) who died at age 34 and the proband's father (case III.1), who died at the age of 55, suffered from lung cancer.
On primary examination, the patient was cachectic, tachypneic (respiratory rate 24 times/min), and saturating index of oxygen was at 96% on ambient room air. Other vital signs were within normal range. On percussion of chest and auscultation breath, sounds were normal. There was a soft, non-tender, freely mobile mass in the upper outer quadrant of her right breast. No nipple or areolar discharge was detected. Supraclavicular and axillary lymph nodes were impalpable.
Other Cardiovascular, abdominal, and neurological examinations were noncontributory.

Discussion
EGFR mutations not only promote lung adenocarcinoma but also are linked to the sensitivity to erlotinib and gefitinib. These mutations, when occurring in the kinase domain of EGFR, affect the molecular structure of this receptor, lead to abnormal activation of EGFR, and influence the downstream kinases, and cause anti-apoptotic and/or proliferation signaling [8].
EGFR exon-19 deletion, specifically, is reported to be responsible for the responsiveness to gefitinib in lung cancer [9]. It is demonstrated that exon-19 deletion (both germline and somatic mutations) elevates the autophosphorylation of EGFR, activates AKT and STAT pathways, and consequently promotes cell survival. In-silico analysis revealed that exon-19 deletion can shift the inactive form of EGFR to its active form [10]. This mutation can be detected in a homozygous or heterozygous manner [11,12]

Data Availability Statement
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Author Contributions
Hanifeh Mirtavoos-Mahyari defined the study protocol, contributed to the laboratory work, analyzed the data, and drafted the manuscript. Farbod Bahreini analyzed the data, provided the final revision of the manuscript, and was in charge of the submission process. Hassan Vahidnezhad analyzed the data and drafted the manuscript. All the authors have given the final approval of the version to be published and they take responsibility for appropriate portions of the content.