Frequency of Pathogenic Germline Variants in <i>CDH1, BRCA2, CHEK2, PALB2, BRCA1</i>, and <i>TP53</i> in Sporadic Lobular Breast Cancer

Petridis, Christos; Arora, Iteeka; Shah, Vandna; Moss, Charlotte; Mera, Anca; Clifford, Angela; Gillett, Cheryl; Pinder, Sarah; Tomlinson, Ian; Roylance, Rebecca; Simpson, Michael A.; Sawyer, Elinor J.

doi:10.1158/1055-9965.epi-18-1102

Cited by 27 publications

(26 citation statements)

References 40 publications

(51 reference statements)

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“…Increasing researches reported that CDH1, BRCA2, and BRCA1 were susceptibility genes for BC ( Petridis et al, 2019 ) and around 60–70% of women with BRCA1 or BRCA2 gene mutations would be suffered with BC in her lifetime ( Antoniou et al, 2003 ). Besides, BRCA2 mutation carriers were more likely to develop brain metastases than non-carriers ( Song et al, 2020 ).…”

Section: Discussionmentioning

confidence: 99%

A Novel Gene Prognostic Signature Based on Differential DNA Methylation in Breast Cancer

et al. 2021

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Background: DNA methylation played essential roles in regulating gene expression. The impact of DNA methylation status on the occurrence and development of cancers has been well demonstrated. However, little is known about its prognostic role in breast cancer (BC).Materials: The Illumina Human Methylation450 array (450k array) data of BC was downloaded from the UCSC xena database. Transcriptomic data of BC was downloaded from the Cancer Genome Atlas (TCGA) database. Firstly, we used univariate and multivariate Cox regression analysis to screen out independent prognostic CpGs, and then we identified methylation-associated prognosis subgroups by consensus clustering. Next, a methylation prognostic model was developed using multivariate Cox analysis and was validated with the Illumina Human Methylation27 array (27k array) dataset of BC. We then screened out differentially expressed genes (DEGs) between methylation high-risk and low-risk groups and constructed a methylation-based gene prognostic signature. Further, we validated the gene signature with three subgroups of the TCGA-BRCA dataset and an external dataset GSE146558 from the Gene Expression Omnibus (GEO) database.Results: We established a methylation prognostic signature and a methylation-based gene prognostic signature, and there was a close positive correlation between them. The gene prognostic signature involved six genes: IRF2, KCNJ11, ZDHHC9, LRP11, PCMT1, and TMEM70. We verified their expression in mRNA and protein levels in BC. Both methylation and methylation-based gene prognostic signatures showed good prognostic stratification ability. The AUC values of 3-years, 5-years overall survival (OS) were 0.737, 0.744 in the methylation signature and 0.725, 0.715 in the gene signature, respectively. In the validation groups, high-risk patients were confirmed to have poorer OS. The AUC values of 3 years were 0.757, 0.735, 0.733 in the three subgroups of TCGA dataset and 0.635 in GSE146558 dataset.Conclusion: This study revealed the DNA methylation landscape and established promising methylation and methylation-based gene prognostic signatures that could serve as potential prognostic biomarkers and therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

A Novel Gene Prognostic Signature Based on Differential DNA Methylation in Breast Cancer

et al. 2021

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“…Thus many commercial gene panels for breast cancer hereditary predisposition include, in addition to TP53, the CDH1 tumour suppressor gene. Whilst germline CDH1 mutations have been described in 0.34% of lobular breast cancer cases [22], they are more commonly associated with diffuse gastric cancer, a diagnosis with a dismal prognosis and prophylactic gastrectomy being the main preventable measure. In view of the uncertainties around true penetrance in breast cancer and the real potential for psychological harm, CDH1 is not included in NHS England hereditary breast cancer panel testing, as was determined by the UK Cancer Genetics Group [23].…”

Section: Breast Cancer Gene Panel Testing and The Need For A Refined mentioning

confidence: 99%

New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer

Evans

Woodward

2020

Familial Cancer

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“…BRCA1, BRCA2, PALB2 confer a high risk of developing breast cancer and are enriched in familial cases. Notably, lobular breast cancer (LBC) is less common as a proportion of breast cancers in women with BRCA1 PGVs compared to women without BRCA1 PGVs [3][4][5][6] As the main pathway to breast cancer is from basal progenitor cells leading to the predominant ductal triple negative breast cancer, this route excludes the predominantly estrogen receptor positive lobular cancer. However, individuals with BRCA2 PGVs have a similar proportion of LBC to women without BRCA2 PGVs.…”

Section: Introductionmentioning

confidence: 99%

“…Several studies have reported the association for the diffuse gastric cancer predisposition gene, CDH1, in lobular, rather than ductal breast cancer [9][10][11][12]. Petridis et al screened six genes for an association with LBC and found that variants in BRCA2, CHEK2, and PALB2 in addition to CDH1 were all enriched in women with lobular compared to ductal cancer [5].…”

Section: Introductionmentioning

confidence: 99%

Extended gene panel testing in lobular breast cancer

et al. 2021

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Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53.Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

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Frequency of Pathogenic Germline Variants in CDH1, BRCA2, CHEK2, PALB2, BRCA1, and TP53 in Sporadic Lobular Breast Cancer

Cited by 27 publications

References 40 publications

A Novel Gene Prognostic Signature Based on Differential DNA Methylation in Breast Cancer

A Novel Gene Prognostic Signature Based on Differential DNA Methylation in Breast Cancer

New surveillance guidelines for Li-Fraumeni and hereditary TP53 related cancer syndrome: implications for germline TP53 testing in breast cancer

Extended gene panel testing in lobular breast cancer

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