New germline mutations in BRCA1, ATM, MUTYH, and RAD51D genes in Tuvans early-onset breast cancer patients

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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BRCA2 germline mutations among early onset breast cancer patients unselected for family history of the disease

Journal of Medical Genetics ◽

10.1136/jmg.37.9.e17 ◽

2000 ◽

Vol 37 (9) ◽

pp. 17e-17 ◽

Cited By ~ 9

Author(s):

J. PLASCHKE

Keyword(s):

Breast Cancer ◽

Family History ◽

Cancer Patients ◽

Early Onset ◽

Germline Mutations ◽

Breast Cancer Patients ◽

Early Onset Breast Cancer ◽

History Of

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ATM germline mutations in Spanish early-onset breast cancer patients negative for BRCA1/BRCA2 mutations

Clinical Genetics ◽

10.1111/j.1399-0004.2008.00987.x ◽

2008 ◽

Vol 73 (5) ◽

pp. 465-473 ◽

Cited By ~ 12

Author(s):

J Brunet ◽

S Gutiérrez-Enríquez ◽

A Torres ◽

V Bérez ◽

S Sanjosé ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Early Onset ◽

Germline Mutations ◽

Breast Cancer Patients ◽

Early Onset Breast Cancer ◽

Brca2 Mutations ◽

Brca1 Brca2

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Comparable frequency of BRCA1, BRCA2 and TP53 germline mutations in a multi-ethnic Asian cohort suggests TP53 screening should be offered together with BRCA1/2 screening to early-onset breast cancer patients

Breast Cancer Research ◽

10.1186/bcr3165 ◽

2012 ◽

Vol 14 (2) ◽

pp. R61 ◽

Cited By ~ 5

Author(s):

Daphne SC Lee ◽

Sook-Yee Yoon ◽

Lai Meng Looi ◽

Peter Kang ◽

In Nee Kang ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Early Onset ◽

Germline Mutations ◽

Breast Cancer Patients ◽

Early Onset Breast Cancer ◽

Brca1 Brca2 ◽

Asian Cohort ◽

Tp53 Germline Mutations

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Spectrum and prevalence of BRCA1/2 germline mutations in Pakistani breast cancer patients: results from a large comprehensive study

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-019-0125-5 ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 3

Author(s):

Muhammad Usman Rashid ◽

Noor Muhammad ◽

Humaira Naeemi ◽

Faiz Ali Khan ◽

Mariam Hassan ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Cancer Patients ◽

Male Breast Cancer ◽

Early Onset ◽

Germline Mutations ◽

Male Breast ◽

Breast Cancer Patients ◽

Early Onset Breast Cancer ◽

Pakistani Population

Abstract Background Pathogenic germline mutations in BRCA1 and BRCA2 (BRCA1/2) account for the majority of hereditary breast and/or ovarian cancers worldwide. To refine the spectrum of BRCA1/2 mutations and to accurately estimate the prevalence of mutation in the Pakistani population, we studied 539 breast cancer patients selected for family history and age of diagnosis. Methods Comprehensive screening for BRCA1/2 germline mutations was performed using state-of-the-art technologies. Results A total of 133 deleterious mutations were identified in 539 families (24.7%), comprising 110 in BRCA1 and 23 in BRCA2. The prevalence of BRCA1/2 small-range mutations and large genomic rearrangements was 55.4% (36/65) for families with breast and ovarian cancer, 27.4% (67/244) for families with two or more cases of breast cancer, 18.5% (5/27) for families with male breast cancer, and 12.3% (25/203) for families with a single case of early-onset breast cancer. Nine mutations were specific to the Pakistani population. Eighteen mutations in BRCA1 and three in BRCA2 were recurrent and accounted for 68.2% (75/110) and 34.8% (8/23) of all identified mutations in BRCA1 and BRCA2, respectively. Most of these mutations were exclusive to a specific ethnic group and may result from founder effects. Conclusions Our findings show that BRCA1/2 mutations account for one in four cases of hereditary breast/ovarian cancer, one in five cases of male breast cancer, and one in eight cases of early-onset breast cancer in Pakistan. Our study suggests genetic testing of an extended panel of 21 recurrent BRCA1/2 mutations for appropriately selected patients and their families in Pakistan.

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