Loss-of-function variants in CTNNA1 detected on multigene panel testing in individuals with gastric or breast cancer

Purpose Most existing literature describes Lynch syndrome (LS) as a hereditary syndrome leading to high risks of colorectal cancer (CRC) and endometrial cancer mainly as a result of mutations in MLH1 and MSH2. Most of these studies were performed on cohorts with disease suggestive of hereditary CRC and population-based CRC and endometrial cancer cohorts, possibly biasing results. We aimed to describe a large cohort of mismatch repair (MMR) mutation carriers ascertained through multigene panel testing, evaluate their phenotype, and compare the results with those of previous studies. Methods We retrospectively reviewed clinical histories of patients who had multigene panel testing, including the MMR and EPCAM genes, between March 2012 and June 2015 (N = 34,981) and performed a series of statistical comparisons. Results Overall, MSH6 mutations were most frequent, followed by PMS2, MSH2, MLH1, and EPCAM mutations, respectively. Of 528 patients who had MMR mutations, 63 (11.9%) had breast cancer only and 144 (27.3%) had CRC only. When comparing those with breast cancer only to those with CRC only, MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations ( P = 2.3 × 10−5). Of the 528 patients, 22.2% met BRCA1 and BRCA2 ( BRCA1/2) testing criteria and not LS criteria, and 5.1% met neither BRCA1/2 nor LS testing criteria. MSH6 and PMS2 mutations were more frequent than MLH1 and MSH2 mutations among patients who met BRCA1/2 testing criteria but did not meet LS testing criteria ( P = 4.3 × 10−7). Conclusion These results provide a new perspective on LS and suggest that individuals with MSH6 and PMS2 mutations may present with a hereditary breast and ovarian cancer phenotype. These data also highlight the limitations of current testing criteria in identifying these patients, as well as the need for further investigation of cancer risks in patients with MMR mutations.

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Abstract 1236: Insight into genetic susceptibility toBRCA-negative male breast cancer by multigene panel testing: Results from a multicenter study in Italy

10.1158/1538-7445.am2018-1236 ◽

2018 ◽

Cited By ~ 1

Author(s):

Piera Rizzolo ◽

Veronica Zelli ◽

Valentina Silvestri ◽

Virginia Valentini ◽

Alessandro Spinelli ◽

...

Keyword(s):

Breast Cancer ◽

Genetic Susceptibility ◽

Male Breast Cancer ◽

Multicenter Study ◽

Male Breast ◽

Panel Testing ◽

Multigene Panel Testing ◽

Insight Into ◽

Multigene Panel

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Multigene Panel Testing Increases the Number of Loci Associated with Gastric Cancer Predisposition

Cancers ◽

10.3390/cancers11091340 ◽

2019 ◽

Vol 11 (9) ◽

pp. 1340 ◽

Cited By ~ 3

Author(s):

Gianluca Tedaldi ◽

Francesca Pirini ◽

Michela Tebaldi ◽

Valentina Zampiga ◽

Ilaria Cangini ◽

...

Keyword(s):

Breast Cancer ◽

Gastric Cancer ◽

Susceptibility Genes ◽

Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Cancer Susceptibility Genes ◽

Number Of Patients ◽

Multigene Panel Testing ◽

Multigene Panel

The main gene involved in gastric cancer (GC) predisposition is CDH1, the pathogenic variants of which are associated with diffuse-type gastric cancer (DGC) and lobular breast cancer (LBC). CDH1 only explains a fraction (10–50%) of patients suspected of DGC/LBC genetic predisposition. To identify novel susceptibility genes, thus improving the management of families at risk, we performed a multigene panel testing on selected patients. We searched for germline pathogenic variants in 94 cancer-related genes in 96 GC or LBC Italian patients with early-onset and/or family history of GC. We found CDH1 pathogenic variants in 10.4% of patients. In 11.5% of cases, we identified loss-of-function variants in BRCA1, BRCA2, PALB2, and ATM breast/ovarian cancer susceptibility genes, as well as in MSH2, PMS2, BMPR1A, PRF1, and BLM genes. In 78.1% of patients, we did not find any variants with clear-cut clinical significance; however, 37.3% of these cases harbored rare missense variants predicted to be damaging by bioinformatics tools. Multigene panel testing decreased the number of patients that would have otherwise remained genetically unexplained. Besides CDH1, our results demonstrated that GC pathogenic variants are distributed across a number of susceptibility genes and reinforced the emerging link between gastric and breast cancer predisposition.

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New insights into the performance of multigene panel testing: Two novel nonsense variants in BRIP1 and TP53 in a young woman with breast cancer

Cancer Genetics ◽

10.1016/j.cancergen.2018.06.002 ◽

2018 ◽

Vol 228-229 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Verónica Castillo-Guardiola ◽

M Desamparados Sarabia-Meseguer ◽

Miguel Marín-Vera ◽

Ana Isabel Sánchez-Bermúdez ◽

José Luis Alonso-Romero ◽

...

Keyword(s):

Breast Cancer ◽

Young Woman ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Impact of pre-surgical germline multigene panel testing on choice of surgery for breast cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.15_suppl.1579 ◽

2018 ◽

Vol 36 (15_suppl) ◽

pp. 1579-1579

Author(s):

Elena Zarcaro ◽

Leif W. Ellisen ◽

Kristen M Shannon ◽

Erica Blouch ◽

Steven J. Isakoff

Keyword(s):

Breast Cancer ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Acceptability and outcomes of multigene panel testing among young Black breast cancer survivors

The Breast Journal ◽

10.1111/tbj.13848 ◽

2020 ◽

Vol 26 (10) ◽

pp. 2112-2114

Author(s):

Claire C. Conley ◽

Jennifer D. Garcia ◽

Cristi Radford ◽

Richard R. Reich ◽

Alvaro N. Monteiro ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Survivors ◽

Breast Cancer Survivors ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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“Decoding hereditary breast cancer” benefits and questions from multigene panel testing

The Breast ◽

10.1016/j.breast.2019.01.002 ◽

2019 ◽

Vol 45 ◽

pp. 29-35 ◽

Cited By ~ 9

Author(s):

Chrystelle Colas ◽

Lisa Golmard ◽

Antoine de Pauw ◽

Sandrine M. Caputo ◽

Dominique Stoppa-Lyonnet

Keyword(s):

Breast Cancer ◽

Hereditary Breast Cancer ◽

Panel Testing ◽

Multigene Panel Testing ◽

Multigene Panel

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Germline pathogenic variants in cancer predisposition genes among women with invasive lobular cancer of breast.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10581 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10581-10581

Author(s):

Siddhartha Yadav ◽

Chunling Hu ◽

Susan M. Domchek ◽

Jeffrey N. Weitzel ◽

David Goldgar ◽

...

Keyword(s):

Breast Cancer ◽

Population Based ◽

Cancer Predisposition ◽

Clinical Cohort ◽

Breast Cancer Predisposition ◽

Panel Testing ◽

Pathogenic Variants ◽

Predisposition Genes ◽

Multigene Panel Testing ◽

Multigene Panel

10581 Background: The prevalence of germline pathogenic variants (PVs) in cancer predisposition genes among women with invasive lobular breast cancer (ILC) and the risk of ILC in PV carriers is not well-defined. Methods: The study included 2,999 women with ILC and 32,544 unaffected controls from a population-based cohort; 3,796 women with ILC and 20,323 women with invasive ductal carcinoma (IDC) undergoing clinical multigene panel testing (clinical cohort); and 125,748 exome sequences from unrelated women without a cancer diagnosis in the gnomAD 3.0 dataset. 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 controls in both cohorts and between women with ILC and IDC in the clinical cohort. 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 analyses, 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. PV frequencies in these genes in ILC and IDC were similar except for PV frequencies in BRCA1 and CDH1. Conclusions: 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. While, multigene panel testing may be appropriate for women with ILC, CDH1 should be specifically discussed in the context of low prevalence and attendant gastric cancer risk.

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