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Downloadedfromhttps://journals.lww.com/md-journalbyBhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3XI41p+sDLxYskzzWJHpwFHXx2UUNwud7G8BZL/qjX4o=on09/09/2020

A new pathogenic mutation of the BRCA1 gene in a patient with ovarian cancer A case report Niu Yizhen, MDa,b, Li Kemin, MDa,b, Li Qingli, PhDa,b, Wang Danqing, PhDa,b, Yin Rutie, PhDa,b,

∗ , Song Liang, PhDa,b

Abstract Rationale: The breast cancer susceptibility gene (BRCA) is an important tumor suppressor gene and tumor susceptibility gene. Germ line BRCA1/2 mutations significantly increase the risk of breast cancer and other cancers in women.

Patient concerns: A 48-year-old woman was diagnosed with breast cancer at the age of 42 and subsequently diagnosed with ovarian cancer at the age of 48. Her sister had a history of breast cancer and her mother died from ovarian cancer.

Diagnoses: The patient has a family history of tumors. BRCA1/2 mutations was proved in this family members.

Interventions: Sanger sequencing was used to evaluate the BRCA1/2 gene status of the patient and her sister to identify the genetic mutation sites.

Outcomes: They had the same genetic mutation, namely, the c.3487_3488insA (p.Thr1163AsnfsX2) mutation in the BRCA1 gene, which is a novel mutation.

Lessons: This novel mutation may be a new pathogenic mutation of the BRCA1 gene. Its relationship to breast and ovarian cancers needs to be further verified in more patient cases. Moreover, mutant protein functions in both cell and animal models are also needed.

Abbreviations: BRCA = breast cancer susceptibility gene, CT = computed tomography.

Keywords: BRCA, mutation, ovarian cancer, pathogenic

1. Introduction

Ovarian cancer is one of the common malignant tumors of the female reproductive system, with an incidence rate that ranks it as the third most common gynecologic cancer behind cervical and uterine cancers. However, ovarian cancer is the gynecologic malignancy with the highest mortality rate. Clarifying the methods of timely detection, diagnosis, and prevention of ovarian cancer to

decrease its incidence and mortality rate has been the key goal of gynecologic oncologists for decades. With the development of precision medicine, mutations in the breast cancer susceptibility genes (BRCAs) including BRCA1 and BRCA2, have come to be known to be related to the pathogenesis of hereditary ovarian and breast cancer. Approximately 30% of hereditary ovarian and/or breast cancer occurrences are associated with BRCA1/2 gene mutations.[1,2] To date, there are thousands of mutation positions that have been discovered in the BRCA1/2 genes. In the general population, the risk of breast cancer is about 10%, and for ovarian cancer it is about 1%, whereas the risk of breast or ovarian cancer in women with BRCA missense mutations exceeds 80%.[1,2]

Therefore, it is necessary to conduct early screening and clinical interventions in these high-risk populations. Herein, we report the case of a woman diagnosed with ovarian and breast cancer, with a mutation in the BRCA1 gene that may be a new pathogenic mutation.

2. Case report

A 48-year-old woman, gravida 3, para 1, had been postmeno- pausal for 2 years. At the age of 42 she underwent a left breast radical mastectomy due to breast cancer on the left side, without postoperative adjuvant therapy. She maintained regular outpa- tient follow-ups. In 2016, she presented and was admitted to our hospital due to complaints of “bloating for more than 1 month and progressive worsening.” Transvaginal color Doppler ultra- sound detected a 16.1�11.4�15.6cm mixed cystic and solid pelvic mass with an irregular shape and a blood flow signal resistive index=0.64 (Fig. 1A). An abdomen and pelvis computed tomography (CT) scan revealed irregularly shaped

Editor: N/A.

Ethics approval and consent to participate: The study has been approved by the West China Second Hospital of Sichuan University Ethics Committee.

Consent for publication: We obtained the patient’s informed consent orally with respect to the publication of this case.

Funding/support: Lateral research: ovarian cancer individualized treatment (16H0797).

The authors have no conflicts of interest to discloce. a Department of Gynecology and Obstetrics, b Key Laboratory of Obstetrics and Gynaecologic and Paediatric Diseases and Birth Defects of Ministry of Education, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR China. ∗ Correspondence: Yin Rutie, Department of Gynecology and Obstetrics, West

China Second University Hospital, Sichuan University, Chengdu, Sichuan, PR China (e-mail: [email protected]).

Copyright © 2018 the Author(s). Published by Wolters Kluwer Health, Inc. This is an open access article distributed under the terms of the Creative Commons Attribution-Non Commercial-No Derivatives License 4.0 (CCBY-NC- ND), where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal.

Medicine (2018) 97:38(e12371)

Received: 25 April 2018 / Accepted: 21 August 2018

http://dx.doi.org/10.1097/MD.0000000000012371

Clinical Case Report Medicine ®

OPEN

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cystic and solid masses in the bilateral ovaries and fallopian tubes the left mass measured approximately 8.1�5.2�15.6cm and was predominantly solid. The right mass measured approxi- mately 10.3�8.2�9.8cm and was predominantly cystic

(Fig. 1B). Enhanced CT scanning demonstrated uneven enhance- ment, with an “ovarian vascular pedicle” on each side (Fig. 1C). The serum cancer antigen 125 level was 3952.6U/mL. The patient underwent 3 separate paracentesis procedures, with a

Figure 1. (A) Preoperative transvaginal ultrasound (the lesions were marked by red arrow heads), (B) preoperative CT (the lesions were marked by red arrow heads), and (C) preoperative enhanced CT (the lesions were marked by red arrow heads). CT=computed tomography.

Yizhen et al. Medicine (2018) 97:38 Medicine

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total of 6200mL of light yellow ascites removed. The ascitic fluid was positive for tumor cells. At that time, a malignant tumor was suspected, possibly originating from the reproductive system. On the recto-vaginal and abdominal examinations, huge cystic-solid masses in the pelvis and abdomen, suspected severe intestinal adhesions, and extensive hard nodular lesions on the sacroiliac ligaments were detected. Three gynecologic oncology specialists and imaging specialists evaluated the CT scan images and the findings scored 10(10/23) according to the Bristow standard, which indicated that the predictive index score ≥4 would be helpful to more accurately identify patients with advanced epithelial ovarian carcinoma that were unlikely to undergo optimal primary cytoreductive surgery.[3] They suggested that such patients would not achieve satisfactory results from tumor reduction surgery, and instead, preoperative adjuvant chemo- therapy should be recommended. For our patient, a preoperative paclitaxel–cisplatin combined regimen (paclitaxel 175mg/m2

intravenous guttae (ivgtt)+cisplatin 75mg/m2 ivgtt, at intervals of 3 weeks) was administered for a total of 3 courses. In late 2016, she underwent a laparoscopic hysterectomy, bilateral salpingo- oophorectomy, omentectomy, and pelvic and para-aortic lymph node dissection. The surgical outcome was satisfactory with no residual cancer foci. The postoperative biopsy results demon- strated high-grade serous adenocarcinoma of the bilateral ovaries that also involved the bilateral fallopian tubes and bilateral pelvic walls, but there was no lymph node involvement (Fig. 2). Subsequently, the patient received a postoperative paclitaxel– cisplatin regimen that included carboplatin (paclitaxel 175mg/m2

ivgtt+cisplatin 75mg/m2 ivgtt/carboplatin 400mg/m2 ivgtt, at intervals of 3 weeks) for 8 courses. The chemotherapy was completed in mid-2017 and the patient has continued close follow-up to this point. During chemotherapy she suffered from severe vomiting,

fatigue, and moderate bone marrow suppression. Her symptoms were significantly relieved after symptomatic support treatment. Her serum cancer antigen 125 decreased significantly to 10U/mL after 3 cycles of preoperative chemotherapy, and it declined progressively during the postoperative chemotherapy finally reaching 5.1U/mL at the end of the chemotherapy course. Follow-up lung and pelvic CT scans were performed after 3 and 8 courses of postoperative chemotherapy, respectively. Both results showed that the patient was in a state of complete remission (CR).

After 3 courses of postoperative chemotherapy, our patient’s blood was subjected to BRCA testing (Sanger sequencing, Shenzhen BGI Clinical Laboratory Center). The results demon- strated a frame shift mutation of the BRCA1 gene c.3487_3488insA (p.Thr1163AsnfsX2). This patient had a family history of malignancy, as her sister was diagnosed with breast cancer at the age of 41 (Fig. 3). Further Sanger sequencing confirmed that the sister had the same BRCA1 gene mutation as our patient. In mid-2016, the sister underwent laparoscopic hysterectomy with bilateral salpingo-oophorectomy at our hospital. No malignant tumors were found on biopsy. She was discharged 2 days later and had all normal follow-up evaluations. Their mother was diagnosed with ovarian cancer at the age of 57, which was her ultimate cause of death, and their father has gastric cancer (Fig. 3).

3. Discussion

BRCAs are important tumor suppressor genes and tumor susceptibility genes, comprising BRCA1 and BRCA2, which play important roles in the homologous recombination mechanism in DNA repair. Germ line BRCA1/2 mutations significantly increase the risk of breast, ovarian, and other cancers in women. According to the classification systems from the National Cancer Institute (NCI),[4] the American College of Medical Genetics and Genomics (ACMG),[5] and the Evidence-based Network Interpretation of Germline Mutant Alleles (ENIGMA),[6] the BRCA genemutations are divided into the following 5 grades, listed here with risks from highest to lowest: pathogenic (grade 5, pathogenic probability> 0.99), possible pathogenic (grade 4, pathogenic probability 0.95– 0.99), meaning unknown (grade 3, pathogenic probability 0.05– 0.949), possible benign (grade 2, pathogenic probability 0.001– 0.049), and benign (grade 1, pathogenic probability <0.001). Considering that 2 members of that family (the patient with breast cancer and ovarian cancer, and her sister with breast cancer) had the genetic mutation at the same site, this novel frame shift mutation in the BRCA1 gene may be a grade 5 pathogenic mutation. Thus, women with genetic mutations at this site are extremely likely to have the highest risk of breast and ovarian cancers.

Figure 2. Ovarian high-grade serous adenocarcinoma (HE �100). Figure 3. Family tree of the patient. BC=breast cancer, GC=gastric cancer, OC=ovarian cancer.

Yizhen et al. Medicine (2018) 97:38 www.md-journal.com

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BRCA mutation classification is based on the published data in Europe and the United States. In 2017, for the first time and based on a large sample, Wu et al reported that the BRCA mutation rate in patients with ovarian cancer in China was 27.8%, of which 20.8% were BRCA1 mutations and 7.6% were BRCA2 mutations.[7] However, China has not yet established a large database of gene mutations. Whether the mutation sites are different from those in the European and American populations needs to be determined from clinical and basic research combined with patient and family histories. Continuing discoveries and studies of new pathogenic gene mutation sites and types could provide important guidance for screening, early diagnosis, intervention, and treatment of ovarian cancer in China. In this report, BRCA gene tests found a BRCA1 gene frame shift mutation c.3487_3488insA (p.Thr 1163AsnfsX2) that resulted in an encoding length of 1163 amino acids, which represented a truncated polypeptide chain since the normal BRCA1 gene encodes 1863 amino acids. Until now, there has been no report on the functional studies and clinical significance of this mutation, and its frequency is 0 in the One Thousand Genomes Project. This mutation is suspected to be pathogenic. Moreover, our ovarian cancer patient had a history of breast cancer and a significant family history of malignant tumors. Therefore, clinically it is recommended to escalate the frame shift mutation of the BRCA1 gene c.3487_3488insA (p. Thr1163AsnfsX2) to a pathogenic grade. This is a newly discovered pathogenic mutation in the Chinese population and imparts great value to the screening and early diagnosis of ovarian/breast cancer. However, the new mutation has been identified only in 2 cases in this family, because the patient’s mother died of ovarian cancer many years ago, and therefore, testing of the mother could not be performed. In addition, the protein function associated with this mutation has yet to be completed.

4. Conclusion

The c.3487_3488insA (p.Thr1163AsnfsX2) BRCA1 mutation may be a new pathogenic mutation in the BRCA1 gene. Its

association with breast and ovarian cancers needs to be further verified through more case studies. Moreover, mutant protein function research in both human cells and animal models are also needed.

Author contributions

Design: Kemin Li, Rutie Yin; Collection: Yizhen Niu, Rutie Yin, Qingli Li; Analysis: Kemin Li, Danqing Wang, Liang Song; Writing: Yizhen Niu. Data curation & resourcces: Qingli Li. Formal analysis: Danqing Wang, Liang Song. Methodology & Supervision: Kemin Li. Writing – original draft: Yizhen Niu. Writing – review & editing: Rutie Yin. Rutie Yin orcid: 0000-0002-9221-6727

References

[1] Berek JS, Crum C, Friedlander M. Cancer of the ovary, fallopian tube, and peritoneum. Int J Gynaecol Obstet 2012;119(Suppl 2):S118.

[2] Paluch-Shimon S, Cardoso F, Sessa C, et al. Prevention and screening in BRCA mutation carriers and other breast/ovarian hereditary cancer syndromes: ESMO Clinical Practice Guidelines for cancer prevention and screening. Ann Oncol 2016;27:v103.

[3] Bristow RE, Duska LR, Lambrou NC, et al. A model for predicting surgical outcome in patients with advanced ovarian carcinoma using computed tomography. Cancer 2015;89:1532–40.

[4] Plon SE, Eccles DM, Easton D, et al. Sequence variant classification and reporting: recommendations for improving the interpretation of cancer susceptibility genetic test results. Hum Mutat 2008;29:1282–91.

[5] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24.

[6] Consortium E. ENIGMA BRCA1/2 Gene variant Classification Criteria (Version2.5,2017). Available from: https://enigmaconsortium.org/wp- content/uploads/2017/12/ENIGMA_Rules_2017-06-29.pdf. (Accessed 29 Jun 2017).

[7] Wu X, Wu L, Kong B, et al. The first nationwide multicenter prevalence study of germline BRCA1 and BRCA2 mutations in Chinese ovarian cancer patients. Int J Gynecol Cancer 2017;27:1650–7.

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