Reference Detail

Ref Type

Journal Article

PMID

(33151324)

Authors

Ma D, Chen SY, Ren JX, Pei YC, Jiang CW, Zhao S, Xiao Y, Xu XE, Liu GY, Hu X, Liang XZ, Yu KD, Li DQ, Jiang YZ, Shao ZM

Title

Molecular Features and Functional Implications of Germline Variants in Triple-Negative Breast Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of the National Cancer Institute	113	7	2021 Jul 01	884-892	J Natl Cancer Inst

URL

Abstract Text

The germline variant spectrum of triple-negative breast cancer (TNBC) is different from that of other subtypes and has demonstrated ethnic differences. However, the germline variants of TNBC among Chinese patients and its clinical significance remain unclear.Using our multi-omics TNBC cohort (n = 325), we determined the spectrum of germline variants in TNBC and aimed to illustrate their biological and clinical implications.Overall, 16.0% (52 of 325) of TNBC patients harbored at least 1 pathogenic or likely pathogenic germline variant. These germline variants were associated with early onset of TNBC, the occurrence of contralateral breast cancer, the basal-like immune-suppressed mRNA subtype, and the homologous recombination deficiency (HRD) mutation subtype. Somatic allele-specific imbalance was observed in 54.1% of these germline variants, which was correlated with early onset of breast cancer and elevated HRD. The genes BRCA1 (7.4%), RAD51D (2.8%), and BRCA2 (2.2%) were those most frequently mutated. The RAD51D germline variants, especially K91fs, were enriched in Chinese patients with TNBC compared with Caucasian and African American patients. The Chinese-specific RAD51D germline variants were functionally associated with the instability of the RAD51D protein, HRD, and sensitivity to PARP inhibitors.Chinese TNBC patients have a distinct spectrum of germline variants, with a remarkable impact on the clinical and molecular characteristics of the tumor. Integrative germline-somatic analysis may help identify TNBC patients who are most likely to be affected by their germline variants and in performing clinical interventions more precisely. The RAD51D variants enriched in our cohort may serve as therapeutic targets and guide precision treatment of TNBC.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description
RAD51D	E157*	nonsense	loss of function - predicted	RAD51D E157* results in a premature truncation of the Rad51d protein at amino acid 157 of 328 (UniProt.org). E157* has not been characterized however, due to the effects of other truncation mutations downstream of E157 (PMID: 33151324), is predicted to lead to a loss of Rad51d protein function.
RAD51D	K91fs	frameshift	loss of function	RAD51D K91fs results in a change in the amino acid sequence of the Rad51d protein beginning at aa 91 of 328, likely resulting in premature truncation of the functional protein (UniProt.org). K91fs results in decreased Rad51d protein stability, impaired DNA homologous recombination activity and DNA damage response, and increased sensitivity to PARP inhibitors in culture (PMID: 33151324).
RAD51D	V200*	nonsense	loss of function	RAD51D V200* results in a premature truncation of the Rad51d protein at amino acid 200 of 328 (UniProt.org). V200* results in decreased Rad51d protein stability, impaired DNA homologous recombination activity and DNA damage response, and increased sensitivity to PARP inhibitors in culture (PMID: 33151324).

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
RAD51D K91fs	triple-receptor negative breast cancer	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of triple-negative breast cancer cells expressing RAD51D K91fs in culture (PMID: 33151324).	33151324
RAD51D V200*	triple-receptor negative breast cancer	sensitive	Olaparib	Preclinical - Cell culture	Actionable	In a preclinical study, Lynparza (olaparib) treatment inhibited viability of triple-negative breast cancer cells expressing RAD51D V200* in culture (PMID: 33151324).	33151324