Low risk of invasive lobular carcinoma of the breast in carriers of
            <i>BRCA1</i>
            (hereditary breast and ovarian cancer) and
            <i>TP53</i>
            (Li‐Fraumeni syndrome) germline mutations

Ditchi, Yoan; Broudin, Chloé; Dakdouki, Yolla El; Müller, Marie; Lavaud, Pernelle; Caron, Olivier; Lejri, Donia; Baynes, Caroline; Mathieu, Marie‐Christine; Salleron, Julia; Benusiglio, Patrick R.

doi:10.1111/tbj.13154

Cited by 8 publications

(9 citation statements)

References 20 publications

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“…In addition, the risk of ILC among carriers of PVs in other genes from multigene hereditary cancer testing panels has not been adequately defined. Some studies have reported that PVs in BRCA1 and TP53 do not predispose to ILC, 5,6 whereas PVs in BRCA2 7 and the CHEK2 I157T missense variant have been associated with ILC. [8][9][10] Furthermore, previous studies have primarily evaluated the frequency of germline PVs in CDH1 and other genes among high-risk women with family history of breast cancer or young age at diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Yadav

Nathanson

et al. 2021

JCO

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PURPOSE To determine the contribution of germline pathogenic variants (PVs) in hereditary cancer testing panel genes to invasive lobular carcinoma (ILC) of the breast. MATERIALS AND METHODS The study included 2,999 women with ILC from a population-based cohort and 3,796 women with ILC undergoing clinical multigene panel testing (clinical cohort). Frequencies of germline PVs in breast cancer predisposition genes ( ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, PALB2, PTEN, RAD51C, RAD51D, and TP53) were compared between women with ILC and unaffected female controls and between women with ILC and infiltrating ductal carcinoma (IDC). RESULTS The frequency of PVs in breast cancer predisposition genes among women with ILC was 6.5% in the clinical cohort and 5.2% in the population-based cohort. In case-control analysis, CDH1 and BRCA2 PVs were associated with high risks of ILC (odds ratio [OR] > 4) and CHEK2, ATM, and PALB2 PVs were associated with moderate (OR = 2-4) risks. BRCA1 PVs and CHEK2 p.Ile157Thr were not associated with clinically relevant risks (OR < 2) of ILC. Compared with IDC, CDH1 PVs were > 10-fold enriched, whereas PVs in BRCA1 were substantially reduced in ILC. CONCLUSION The study establishes that PVs in ATM, BRCA2, CDH1, CHEK2, and PALB2 are associated with an increased risk of ILC, whereas BRCA1 PVs are not. The similar overall PV frequencies for ILC and IDC suggest that cancer histology should not influence the decision to proceed with genetic testing. Similar to IDC, multigene panel testing may be appropriate for women with ILC, but CDH1 should be specifically discussed because of low prevalence and gastric cancer risk.

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Section: Introductionmentioning

confidence: 99%

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Yadav

Nathanson

et al. 2021

JCO

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“…This almost certainly indicates that even the current reduction in score for lobular breast cancer of -2 is insufficient to reflect BRCA1 risk. The absence of an association of LBC with BRCA1 has already been noted by ourselves and others [ 6 ], with only 2/342 (0.58%) LBCs in BRCA1 breast cancer patients in one study [ 6 ]. The higher odds ratio for BRCA1 in our study is therefore likely to be explained by the strong family history of breast and/or ovarian cancer in relatives rather than a true association with BRCA1 .…”

Section: Discussionmentioning

confidence: 59%

“…This is in contrast to Petridis et al who did not identify any TP53 PGVs in an unselected series of 1434 lobular cancers [ 5 ]. A lack of association with lobular cancer and germline TP53 was also suggested by Ditchi et al in 2019 [ 6 ] but this is based on one case in only 57 carriers and the 95% CI do not exclude a 10% rate. One of our women was diagnosed with very early onset, bilateral breast cancer (the contralateral tumour was reported as invasive ductal carcinoma histologically).…”

Section: Discussionmentioning

confidence: 81%

“…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%

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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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“…[ 21 ] 0/1434 NA NA NA Ditchi et al . [ 22 ] 1/3469 * * ILC Le AN et al . [ 23 ] 3/94 * * MDLC Kuba et al .…”

Section: Discussionmentioning

confidence: 99%

Li–Fraumeni syndrome in Tunisian carriers with different and rare tumor phenotype: genotype–phenotype correlation

et al. 2022

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Background Li–Fraumeni syndrome (LFS) is a rare autosomal hereditary predisposition to multiples cancers, mainly affecting young individuals. It is characterized by a broad tumor spectrum. To our best knowledge, only one Tunisian study with a confirmed LFS was published. Methods Our study focused on the clinical, histopathological and genetic results of two patients with rare tumor phenotype and tried to establish genotype–phenotype correlation. The clinical diagnosis was based on Chompret-Bonaiti criteria relative to LFS. Molecular study was assessed using Sanger sequencing of the hotspot germline variants of TP53 gene. Results We report 2 Tunisian families fulfilling the clinical criteria of Chompret-Bonaiti. The tumor phenotype was bilateral breast cancer (BC) in 27-year-old woman and multiple tumors for the second proband, with an onset age of 14, 35 and 36 yo for osteosarcoma, BC and esophageal cancer respectively. Each of them had a rare histological type of breast cancer associated with LFS, phyllode tumor and intralobular carcinoma. Both patients had cancer family history. The molecular study showed deleterious heterozygous germline TP53 variants in each index case: The first had a well-known hotspot missense variation c.742C>T p.(R248W) with a rare histological association, explaining genotype phenotype correlation. The second case had a nonsense variation c.159G>A p.(W53*), rare worldwide, extending the phenotype spectrum in LFS. Immunohistochemistry study in tumor samples confirmed the lack of p53 protein expression. Conclusions Conclusively, germline TP53 testing is primordial in patients with a family history suggestive of LFS for clinical practice avoiding genotoxic treatments and adapting the surveillance. National database in LFS listing clinical and mutational data is important to set, particularly for variants rarely reported worldwide. Experience from different countries must be integrated to harmonize global protocols for cancer surveillance in LFS.

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Low risk of invasive lobular carcinoma of the breast in carriers of BRCA1 (hereditary breast and ovarian cancer) and TP53 (Li‐Fraumeni syndrome) germline mutations

Cited by 8 publications

References 20 publications

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Germline Pathogenic Variants in Cancer Predisposition Genes Among Women With Invasive Lobular Carcinoma of the Breast

Extended gene panel testing in lobular breast cancer

Li–Fraumeni syndrome in Tunisian carriers with different and rare tumor phenotype: genotype–phenotype correlation

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