Mutation analysis of BRIP1/BACH1 in BRCA1/BRCA2 negative Chinese women with early onset breast cancer or affected relatives

Abstract Background: Germline alterations in ATM, BRCA1, BRCA2, and other genes are responsible for early-onset breast cancer. However, up to 20% of molecular tests report genetic variant of unknown significance (VUS) or novel variants that have never been previously described and their clinical significance are unknown. An existing open access databases (ClinVar, BIC, and ENIGMA and other) play an important role in the interpretation of VUS, but in Asian populations the interpretation of VUS is still difficult due to restricted data. This study aimed to reclassify the genetic variants by using the ActiveDriveDB database that annotates variants through the lens of sites of post-translational modifications.Methods: Our study included young Buryat BC patients, anthropologically belonging to the Central Asia. Genomic DNA was used to prepare libraries. NGS sequencing was performed on a NextSeq 500 System. Results: We re-examined 135 rare variants (41 VUS, 25 conflicting, 64 benign and 5 new variants). We identified 10 out of 135 (7.4%) mutations that affected the sites of post-translational modification in proteins. Of 135 rare mutations, 1 benign variant was reclassified as network-rewiring - motif loss mutation, 3 VUS and 1 new variant were reclassified as distal PTM- mutations, 2 new and 1 benign variant were classified as proximal PTM- mutations and 1 benign and 1 conflicting variant were classified as direct PTM- mutations.Conclusions: For the first time, 7.4% (10 out of 135) of mutations that affected the sites of post-translational modification in proteins were identified among Buryat women with early-onset breast cancer.

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The spectrum of BRCA1 and BRCA2 mutations and clinicopathological characteristics in Chinese women with early-onset breast cancer

Breast Cancer Research and Treatment ◽

10.1007/s10549-020-05573-x ◽

2020 ◽

Vol 180 (3) ◽

pp. 759-766

Author(s):

Lili Chen ◽

Fangmeng Fu ◽

Meng Huang ◽

Jinxing Lv ◽

Wenzhe Zhang ◽

...

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Chinese Women ◽

Clinicopathological Characteristics ◽

Early Onset Breast Cancer ◽

Brca1 And Brca2 ◽

Brca2 Mutations ◽

Brca1 And Brca2 Mutations

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Somatic and germline mutation profiles of Chinese breast cancer patients younger than 35.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.554 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 554-554

Author(s):

Ning Liao ◽

Guo-Chun Zhang ◽

Xiaoqing Chen ◽

Weikai Xiao ◽

Jianguo Lai ◽

...

Keyword(s):

Breast Cancer ◽

Cell Cycle ◽

Cancer Patients ◽

Germline Mutation ◽

Early Onset ◽

Chinese Women ◽

Germline Mutations ◽

Breast Cancer Patients ◽

Early Onset Breast Cancer ◽

Younger Women

554 Background: Limited studies have investigated the molecular underpinnings driving breast cancer development in Chinese younger women. Based from our previous data, more Chinese women are diagnosed with early-onset breast cancer than in the West. In our study, we aim to investigate the comprehensive mutational profile of Chinese women 35 years old and younger (≤35y) diagnosed with breast cancer. Methods: Targeted sequencing was performed on surgically-removed tumor tissues and blood samples collected from 589 women diagnosed with stage I-III breast cancer of various molecular subtypes at the Guangdong Provincial People’s Hospital (GPDH) using a gene panel interrogating 520 cancer-related genes. We compared the data of 53 women aged ≤35y from our cohort to the data from 33 breast cancer patients aged ≤35y included in The Cancer Genome Atlas (TCGA) dataset. Results: Among the women aged ≤35y with early-stage breast cancer from both cohorts, our cohort had more number of hormone receptor-positive (HR+) patients (GPDH, 72% vs. TCGA, 61%, P< 0.001). Analysis revealed an overall mutation detection rate of 98% in our cohort, with mutations affecting genes involved in the PI3K pathway (47%) and cell cycle pathway (23%). TP53 and PIK3CA were the most commonly mutated genes, with mutation rates of 51% and 25% from our cohort. No statistical difference in mutation profile was found between GPDH and TCGA cohorts. Moreover, germline mutations considered as pathogenic and likely pathogenic (P/LP) in breast cancer susceptibility genes including BRCA1 (n = 4), BRCA2 (n = 2), PALB2 (n = 1), PMS2 (n = 1), PTEN (n = 1), and ATM (n = 1) were detected from 18.9% (10/53) of the patients from our cohort. Women aged ≤35y had significantly more germline BRCA1 mutations than patients > 35y from our cohort (7.5%, 4/53 vs. 2.1%, 11/536 P= 0.049). Conclusions: Our study has identified the involvement of PI3K and cell cycle as the two key pathways in the early development of breast tumors in younger women. In addition, our results also support the role of P/LP germline mutations in breast oncogenesis in Chinese patients with early-onset breast cancer, indicating the need to include a more comprehensive germline mutation screening in our population.

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