Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer

Koivuluoma, Susanna; Tervasmäki, Anna; Kauppila, Saila; Winqvist, Robert; Kumpula, Timo; Kuismin, Outi; Moilanen, Jukka S.; Pylkäs, Katri

doi:10.1016/j.ejca.2020.10.033

Cited by 13 publications

(9 citation statements)

References 29 publications

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“…Two cases from the hereditary cohort were identified as CHEK2 p.(Asp438Tyr) carriers (2/281, 0.7%, P = 1.00, odds ratio [OR] = 0.92, 95% confidence interval [CI] = 0.20-4.21, Table 1), and the presence of other germline CHEK2 variants in them was ruled out [14]. One carrier was diagnosed with breast cancer at the age of 47 and the other had bilateral disease (at the age of 45 and 48, respectively).…”

Section: Resultsmentioning

confidence: 99%

Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

et al. 2023

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CHEK2 is a well-established breast cancer susceptibility gene. The most frequent pathogenic CHEK2 variant is 1100delC, a loss-of-function mutation conferring 2-fold risk for breast cancer. This gene also harbors other rare variants encountered in the clinical gene panels for hereditary cancer. One of these is CHEK2 c.1312 G > T, p.(Asp438Tyr) in the kinase domain of the protein, but due to its rarity its clinical significance for breast cancer predisposition has remained unclear. Here, we tested the prevalence of CHEK2 p.(Asp438Tyr) allele showing enrichment in the Northern Finnish population, in a total of 2284 breast cancer patients from this geographical region. Genotyping was performed for DNA samples extracted from peripheral blood using high-resolution melt analysis. Fourteen CHEK2 p.(Asp438Tyr) carriers were identified (14/2284, 0.6%, P = 0.67): two in the cohort of breast cancer cases with the indication of inherited disease susceptibility (2/281, 0.7%, P = 1.00) and twelve in the breast cancer cohort unselected for the family history of disease and age at disease onset (12/2003, 0.6%, P = 0.66). This frequency did not differ from the frequency in the general population (10/1299, 0.8%). No CHEK2 p.(Asp438Tyr) homozygotes were identified. Our results indicate that CHEK2 p.(Asp438Tyr) carriers do not have an increased risk for breast cancer and the classification of the CHEK2 p.(Asp438Tyr) variant can be changed from the variant of uncertain significance (VUS) to likely benign for breast cancer.

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Section: Resultsmentioning

confidence: 99%

Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

et al. 2023

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“…This was a 64 kb duplication covering the exons 1–7 detected in two cases, which matched in size and position to that previously reported [ 17 ]. The presence of other known susceptibility alleles was investigated in these nine CNV carriers using the SNV calls from whole-exome sequencing [ 18 ]. One case with RAD51C duplication was found to carry the ATM c.7570G>C (p.Ala2524Pro) allele, recently established to confer a high-risk for breast cancer [ 19 ], whereas the rest had no other known moderate-to-high risk predisposing alleles.…”

Section: Resultsmentioning

confidence: 99%

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility

Kumpula,

Vorimo,

Mattila

et al. 2023

PLoS Genet

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Copy number variants (CNVs) are a major source of genetic variation and can disrupt genes or affect gene dosage. They are known to be causal or underlie predisposition to various diseases. However, the role of CNVs in inherited breast cancer susceptibility has not been thoroughly investigated. To address this, we performed whole-exome sequencing based analysis of rare CNVs in 98 high-risk Northern Finnish breast cancer cases. After filtering, selected candidate alleles were validated and characterized with a combination of orthogonal methods, including PCR-based approaches, optical genome mapping and long-read sequencing. This revealed three recurrent alterations: a 31 kb deletion co-occurring with a retrotransposon insertion (delins) in RAD52, a 13.4 kb deletion in HSD17B14 and a 64 kb partial duplication of RAD51C. Notably, all these genes encode proteins involved in pathways previously identified as essential for breast cancer development. Variants were genotyped in geographically matched cases and controls (altogether 278 hereditary and 1983 unselected breast cancer cases, and 1229 controls). The RAD52 delins and HSD17B14 deletion both showed significant enrichment among cases with indications of hereditary disease susceptibility. RAD52 delins was identified in 7/278 cases (2.5%, P = 0.034, OR = 2.86, 95% CI = 1.10–7.45) and HSD17B14 deletion in 8/278 cases (2.9%, P = 0.014, OR = 3.28, 95% CI = 1.31–8.23), the frequency of both variants in the controls being 11/1229 (0.9%). This suggests a role for RAD52 and HSD17B14 in hereditary breast cancer susceptibility. The RAD51C duplication was very rare, identified only in 2/278 of hereditary cases and 2/1229 controls (P = 0.157, OR = 4.45, 95% CI = 0.62–31.70). The identification of recurrent CNVs in these genes, and especially the relatively high frequency of RAD52 and HSD17B14 alterations in the Finnish population, highlights the importance of studying CNVs alongside single nucleotide variants when searching for genetic factors underlying hereditary disease predisposition.

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“…SERPINA3 has been reported to principally works as an inhibitor in maintaining cellular homeostasis; it is a matricellular acute-phase glycoprotein that appears to be the sole nuclear-binding secretory serpin [ 22 ]. Several studies have emerged in recent years demonstrating its link to cancer biology [ 23 , 24 , 25 , 26 ]. As a typical acute-phase protein, SERPINA3 is regulated by inflammatory cytokines so that its expression is increased in the inflammatory response; overexpression of SERPINA3 predicts that damage tends to occur in the body contributing to decreased cell adhesion ability and inhibition of apoptosis.…”

Section: Resultsmentioning

confidence: 99%

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis

Zhang

et al. 2022

Molecules

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Proteomic profiling of extracellular vesicles (EVs) represents a promising approach for early detection and therapeutic monitoring of diseases such as cancer. The focus of this study was to apply robust EV isolation and subsequent data-independent acquisition mass spectrometry (DIA-MS) for urinary EV proteomics of prostate cancer and prostate inflammation patients. Urinary EVs were isolated by functionalized magnetic beads through chemical affinity on an automatic station, and EV proteins were analyzed by integrating three library-base analyses (Direct-DIA, GPF-DIA, and Fractionated DDA-base DIA) to improve the coverage and quantitation. We assessed the levels of urinary EV-associated proteins based on 40 samples consisting of 20 cases and 20 controls, where 18 EV proteins were identified to be differentiated in prostate cancer outcome, of which three (i.e., SERPINA3, LRG1, and SCGB3A1) were shown to be consistently upregulated. We also observed 6 out of the 18 (33%) EV proteins that had been developed as drug targets, while some of them showed protein-protein interactions. Moreover, the potential mechanistic pathways of 18 significantly different EV proteins were enriched in metabolic, immune, and inflammatory activities. These results showed consistency in an independent cohort with 20 participants. Using a random forest algorithm for classification assessment, including the identified EV proteins, we found that SERPINA3, LRG1, or SCGB3A1 add predictable value in addition to age, prostate size, body mass index (BMI), and prostate-specific antigen (PSA). In summary, the current study demonstrates a translational workflow to identify EV proteins as molecular markers to improve the clinical diagnosis of prostate cancer.

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Exome sequencing identifies a recurrent variant in SERPINA3 associating with hereditary susceptibility to breast cancer

Cited by 13 publications

References 29 publications

Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

Evaluating the role of CHEK2 p.(Asp438Tyr) allele in inherited breast cancer predisposition

Exome sequencing identified rare recurrent copy number variants and hereditary breast cancer susceptibility

High Throughput Isolation and Data Independent Acquisition Mass Spectrometry (DIA-MS) of Urinary Extracellular Vesicles to Improve Prostate Cancer Diagnosis

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