DOI: https://doi.org/10.21203/rs.3.rs-1680356/v1
Almost 5–10% of breast cancer cases have inherited mutations. TP53 tumor suppressor gene is frequently mutated in human malignancies, including breast cancer. In addition, BRCA1 and BRCA 2 are the most frequently mutated genes in breast cancer. Nearly 80% of BRCA1 mutation carriers are diagnosed with breast cancer at a young age before menopause. There are currently no report of early onset breast cancer with both BRCA1 and TP53 germline mutations. Here, we report the case of a 14-years-old female diagnosed with triple-negative breast cancer (TNBC) with a family history of malignant tumors. The cancer metastasized to multiple lymph nodes 1 year and 4 months after surgery, and the progression-free survival (PFS) after subsequent chemotherapy and surgery has been over 2 years and 9 months. The patient’s white blood cells were screened against a panel of 11 cancer-related genes, and both germline mutations of BRCA1 and TP53 were identified. Genetic tests on the patient’s family members revealed the same BRCA1 mutation in her father and brother but no mutation was detected in other members. The case indicates that a multiple gene panel screening should be performed for the family members of breast cancer patients with an early age of onset and a family history of cancer.
The incidence of breast cancer ranks first among all cancers according to the latest report released by International Association of Cancer Research [1].The median age at which breast cancer is diagnosed is 61 years, and only 7% of the cases occur in young women [2]. The hormone receptor positive(HR+)/human epithelial growth factor receptor 2 positive(HER2+), triple-negative and HR-/HER2 + subtypes are more prevalent among the younger breast cancer patients, who are also more likely to present with more advanced stages of the disease (III/IV) compared to older women [3]. In addition, young age is an independent risk factor for disease recurrence and death [4]. Breast cancer is relatively rare among the adolescents – defined as ages between 10–19 years according to WHO – and very few reports exist for adolescent breast cancer [3, 5, 6]. Furthermore, there is lack of awareness regarding the potential risk of developing breast cancer at young age, and diagnosis is often late since routine breast examination is not recommended for young women [6]. Early onset breast cancer is frequently familial, and about 50% of the patients under the age of 30 carry a germline mutation in BRCA1, BRCA2 or TP53 [7, 8]. Thus, evaluation of family history and genetic testing after diagnosis is critical for adolescent breast cancer.
Our patient is a 19-year-old girl from Chongqing, a southwest city of China, who was diagnosed with TNBC at the age of 14. She presented for consultation after metastasis and recurrence. The patient had no previous medical problems but had a family history of cancer. Her paternal grandmother died of lung cancer at an early age and her maternal grandfather died of nasopharyngeal carcinoma. The patient was diagnosed with a mass in the right breast through ultrasound imaging when she was 14 years old. Then, she underwent protective and radical operation of the breast mass and sentinel lymph node biopsy in December 2017. The breast mass measured 3.2×1.8 cm, and histopathological examination revealed grade III invasive carcinoma of non-specific type, with ki-67 proliferation index of 70%, and estrogen receptor (ER), progesterone receptor (PR) and Her2/neu negative subtype. Eight sentinel nodes were retrieved using the blue dye and radioisotope methods, and no metastasis was detected. The patient was diagnosed with stage IIA invasive carcinoma of the breast. She received 6 cycles adjuvant chemotherapy with TEC (taxotere-epirubicin-cyclophosphamide) regimen, followed by 25 sessions of adjuvant radiotherapy and 6 cycles of electron therapy. The adjuvant treatment was completed by the April of 2018.
However, ultrasound examination during follow-up in April 2019 indicated enlarged supraclavicular lymph nodes, and biopsy of them showed metastasized breast tumor cells. Immunohistochemistry revealed that the metastatic mass was negative for ER, PR and Her-2, with ki-67 proliferation index of 40%. Computerized tomography (CT) scanning and brain magnetic resonance imaging (MRI) did not indicate visceral or brain metastasis. The disease-free survival (DFS) was one year and four months. Then, patient received 4 cycles of Vinorelbine and cisplatin (NP) as first-line chemotherapy. Radical supraclavicular and axillary lymph nodes dissection was subsequently performed, and the histopathological examination revealed complete response. Subsequently, two cycles of NP regimen followed by radiotherapy were performed after surgery. Right after conventional anti-cancer therapy, the patient started to take LCSJ (mongolian snakegourd pericarp, edible tulip, catclaw buttercup root, safflower, rugose rose flower, shorthorned epimedium herb, radix astragali, tuckahoe, oyster shell, radix glycyrrhizae and cimicifugae rhizome) a Chinese herbal medicine used for anti-recurrence in TNBC. She is on regular follow-up and disease free presently. The PFS has been 2 years and 8 months till now.
Given the early onset of TNBC and the familial history of cancer, genetic testing was conducted after metastasis. White blood cells were collected from the patient (proband, III2) and subjected to a next generation sequencing (NGS)-based genetic test using a panel of 11 cancer-related genes. After quality control, the raw reads were aligned to the standard human genome reference obtained from the NCBI database (GRCh37) through Burrows Wheeler Aligner (BWA). The alignment file in bam format was then used to calculate the reads coverage of the targeted region, sequencing depth computation, SNP and INDEL calling, and CNV detection. Pathogenic mutations were identified in TP53 (chr17: 7673802C > T) and BRCA1 (chr17: 43124030C > CT) (Figure.1&2).
In order to delineate the inheritance pattern of mutations in her family, we also tested genes of the patient’s family members and detected the same BRCA1 mutation in the patient’s father and brother (II2, III1), but no mutations in other family members. The family tree is shown in Figure.3.
This is the first case report of adolescent breast cancer with both TP53 and BRCA1 germline mutations. Jay et al reported a case of adolescent breast cancer with TP53 mutation, who was also diagnosed with Li-Fraumeni syndrome [9]. Our patient has a family history of cancer, with her paternal grandmother dying of lung cancer at the age of 29 and her maternal grandfather from nasopharyngeal carcinoma. Therefore, we characterized the inheritance of both mutations by sequencing the sliva samples of family members. The 11-gene panel identified a pathogenic mutation with repeated insertion of adenine at base 66 of NM_007294.3 transcript of BRCA1 gene that resulted in a frameshift mutation of glutamic acid at position 23 (p.Glu23fs), and a pathogenic substitution mutation (G > A) at nucleotide position 818 of TP53 gene that caused replacement of arginine by histidine at position 273. The patient’s father and brother are carriers of the same BRCA1 mutation, indicating a paternal origin. On the other hand, the TRP53 germline mutation was only detected in the patient, which makes her the proband.
In addition, TP53 and BRCA1/2 are involved in hereditary syndromes including breast and ovarian cancer syndrome (HBOCs) and Li Fraumeni syndrome (LFS). BRCA1/2 are the two major inherited susceptibility genes for breast cancer. They are tumor suppressor genes that mediate DNA double-strand break repair through a homologous recombination mechanism [10]. BRCA1/2 mutation is also the causal mutation of HBOC syndrome, which is inherited in an autosomal-dominant manner[11]. BRCA1/2 germline mutation occurs in about 9.2% in all breast cancer cases in China. However, the mutation rate is as high as 24.1% in patients with a family history of breast cancer [12]. Moreover, BRCA1/2 mutations account for 16% of all TNBC cases [12], and the prevalence of TNBC is high in patients with early onset of breast cancer. HBOC syndrome is associated with early-onset of breast cancer as well as an increased risk of ovarian, pancreatic, stomach, laryngeal, fallopian tube and prostate cancers [11]. It accounts for 5–7% of all cases of breast cancer [10]. For BRCA1/2 mutation carriers, the lifetime risk of developing breast cancer increases to approximately 45–65%, and 20–50% for ovarian cancer [13–15].
TP53 regulates the cellular response to diverse stresses and maintains genomic integrity, which is critical to its role in tumor suppression [16]. The mutations of TP53 increase the lifetime risk of developing cancer to 75% in males and almost 100% in females [17]. TP53 is mutated in 30% of all breast cancers and is the most frequently mutated gene in human malignancies [18] [19, 20]. LFS was first reported in 1969 by Li and Fraumeni [21], and is characterized by TP53 germline mutations and increased susceptibility to premenopausal breast cancer, soft tissue sarcomas, brain tumors, leukemias and adrenocortical carcinomas [22]. In a large cohort study of 10,053 unselected breast cancer patients in China, around 0.5% of the patients carried a pathogenic TP53 germline mutation, and the frequency of this mutation increased to 3.8% in those with very early onset breast cancer (age ≤ 30 years) [23]. Thus, both HOBCs or LFS are associated with early onset of cancers, and patients with LFS even develop cancer during childhood and adolescence [11, 22]. Based on the criteria provided by NCCN guideline, our patient can be diagnosed with both HBOC and LFS [24]. In this case, the patient was diagnosed with TNBC when she was only 14 years old which is also consistent with the features of both LFS and HBOC.
In addition to increased incidence and early onset of cancer, TP53 mutation is also an independent risk factor for poor recurrence-free survival (RFS), distant recurrence-free survival (DRFS) and overall survival (OS) [23]. Thus, whole body MRI (rapid non-contrast examinations) at later follow-ups of breast cancer patients is recommended to monitor tumor recurrence and metastasis, as well as any possibility of ovarian cancer and pancreatic cancer. TP53 is also an indicator of cisplatin sensitivity [23]. Thus, cisplatin-related regimens is recommended during disease progression.
In conclusion, we have reported a case of an adolescent TNBC with germline mutations in BCRA1 and TP53 with a well-characterized inheritance pattern. She was diagnosed at the age of 14 and suffered recurrence 1 year and 4 months after surgery. The first-line PFS is currently 2 years and 9 months, which portends favorable prognosis. The case underscores the importance of genetic risk evaluation in patient with a family history of cancer. For patients with co-existing hereditary tumor syndromes, it is critical to monitor cancer susceptibility.
Acknowledgements
This work was supported by Developmental funding of Traditional Chinese Medicine of Beijing(JJ-2020-88). Genetron Holdings Limited provided the gene test for the patient’s family members.
Author Contributions Statement
DC was a major contributor in writing the manuscript; MY contributed to the medical history taking. DW and DC contributed to the design of the work. All authors participated in the treatment of the patient. All authors read and approved the final manuscript.
Funding
This work was supported by Beijing developmental funding of Traditional Chinese Medicine (JJ-2020-88) and personnel training program of China-Japan Friendship Hospital elite project(ZRJY2021-TD05).
Availability of data and materials
All the dataset presented in this manuscript are available from the corresponding author by request.
Ethics approval and consent to participate
All procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee(Medical Ethics Committee of China-Japan Friendship Hospital) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Written informed consent was obtained from the individual(s) including the patient presented in this case and her family members who presented for the publication of any potentially identifiable images or data included in this article.
Competing interests
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.