A study of over 35,000 women with breast cancer tested with a 25-gene panel of hereditary cancer genes

ImportanceGenetic testing of hereditary cancer using comprehensive gene panels can identify patients with more than one pathogenic mutation in high and/or moderate-risk-associated cancer genes. This phenomenon is known as multilocus inherited neoplasia alleles syndrome (MINAS), which has been potentially linked to more severe clinical manifestations.ObjectiveTo determine the prevalence and clinical features of MINAS in a large cohort of adult patients with hereditary cancer homogeneously tested with the same gene panel.Patients and methodsA cohort of 1023 unrelated patients with suspicion of hereditary cancer was screened using a validated panel including up to 135 genes associated with hereditary cancer and phakomatoses.ResultsThirteen (1.37%) patients harbouring two pathogenic mutations in dominant cancer-predisposing genes were identified, representing 5.7% (13/226) of patients with pathogenic mutations. Most (10/13) of these cases presented clinical manifestations associated with only one of the mutations identified. One case showed mutations in MEN1 and MLH1 and developed tumours associated with both cancer syndromes. Interestingly, three of the double mutants had a young age of onset or severe breast cancer phenotype and carried mutations in moderate to low-risk DNA damage repair-associated genes; two of them presented biallelic inactivation of CHEK2. We included these two patients for the sake of their clinical interest although we are aware that they do not exactly fulfil the definition of MINAS since both mutations are in the same gene.Conclusions and relevanceGenetic analysis of a broad cancer gene panel identified the largest series of patients with MINAS described in a single study. Overall, our data do not support the existence of more severe manifestations in double mutants at the time of diagnosis although they do confirm previous evidence of severe phenotype in biallelic CHEK2 and other DNA repair cancer-predisposing genes.

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Frequency of germline patghogenic mutation in breast cancer patients at high risk hereditary cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e13110 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e13110-e13110 ◽

Cited By ~ 1

Author(s):

Hee-Chul Shin ◽

Wonshik Han ◽

Han-Byoel Lee ◽

Hyeong-Gon Moon ◽

Eunshin Lee ◽

...

Keyword(s):

Breast Cancer ◽

High Risk ◽

Cancer Patients ◽

Hereditary Cancer ◽

Gene Panel ◽

Breast Cancer Patients ◽

Sequencing Technology ◽

Next Generation Sequencing Technology ◽

Pathogenic Mutations ◽

Generation Sequencing

e13110 Background: Next-generation sequencing technology allows the simultaneous sequencing of multiple target genes. We developed a gene panel containing 64 genes which were associated with various hereditary cancers. This study was performed to evaluate the frequency of pathogenic mutations associated with hereditary cancer among Korean patients at high risk hereditary breast cancer using multi-gene sequencing panel. Methods: A total of 252 breast cancer patients with high-risk hereditary cancer were included. Among them, 179 patients (71.0%) had multiple primary cancers including breast cancer, 27 patients (10.7%) were diagnosed with bilateral breast cancer at age 40 or younger. Thirty-five patients (13.9%) had breast cancer family history of more than 2 relatives. With the 64 gene panel, sequence variants were detected by next-generation sequencing technology. Results: Sixty seven patients (26.8%) were found to have 77 germline pathogenic mutations, 12 in BRCA1, 13 in BRCA2, 9 in CDH1, 3 in FH, 5 in MSH2, 2 in MSH6, 4 in NAT1, 6 in PTCH1, 3 in RAD51, 7 in RET, 4 in SPINK1, 3 in TP53 and one each in ALK, BRIP1, CHEK2, MLH2, MUTYH, and PTEN. In 20 patients (4.0%), 2 (n = 9) or 3 (n = 1) pathogenic mutations were detected. In 227 patients with BRCA1/2 negative, CDH1 (n = 7), RET (n = 7), PTCH1 (n = 5), and MSH2 (n = 5) were the most prevalent pathogenic mutations. Conclusions: The 64 gene panel detected germline pathogenic mutations in 26.8% of Korean breast cancer patients with feature of hereditary cancer. Mutations of BRCA1, BRCA2, CDH1, RET, and PTCH1 were the most prevalent variants.Mutation carriers were considered as high risk to develop malignancy and recommended to receive genetic counseling and intensive cancer screening.

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A study of ovarian cancer patients tested with a 25-gene panel of hereditary cancer genes.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.15_suppl.1511 ◽

2014 ◽

Vol 32 (15_suppl) ◽

pp. 1511-1511 ◽

Cited By ~ 1

Author(s):

Lucy R. Langer ◽

Heidi McCoy ◽

Kelsey Moyes ◽

Jennifer Saam ◽

Brian Abbott ◽

...

Keyword(s):

Ovarian Cancer ◽

Cancer Patients ◽

Hereditary Cancer ◽

Gene Panel ◽

Cancer Genes

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Patients with pathogenic variants for breast cancer other than BRCA1 and BRCA2: qualitative interviews about health care experiences

Hereditary Cancer in Clinical Practice ◽

10.1186/s13053-019-0132-6 ◽

2019 ◽

Vol 17 (1) ◽

Author(s):

Kristin E. Clift ◽

Sarah K. Macklin ◽

Stephanie L. Hines

Keyword(s):

Breast Cancer ◽

Health Care ◽

Hereditary Cancer ◽

Qualitative Interviews ◽

Clinical Effects ◽

Test Results ◽

Cancer Genes ◽

Care Providers ◽

Pathogenic Variants ◽

Health Care Experiences

Abstract Background Genetic testing for hereditary cancer syndromes has been revolutionized by next-generation sequencing, which allows for simultaneous review of numerous genes. Multigene panels are regularly offered to patients because of their scope and decreased cost and turnaround time. However, many genes included on larger panels have not been studied as extensively as BRCA1 and BRCA2 (BRCA1/2), and their clinical effects are often not as well established. Methods We identified patients who received positive test results for pathogenic variants of breast cancer genes from January 2012 through May 2018. We mailed a survey and conducted qualitative interviews to explore the personal and health care experiences of patients with pathogenic variants of BRCA1/2 and patients with “other” (ie, non-BRCA1/2 or PALB2; PTEN; ATM; TP53; NBM, RAD51C; MSH6) variants. We compared the experiences of these patients. Results Fifty-nine out of 128 individuals responded to the survey (46%). Thirty-two patients had BRCA1/2 variants, and 27 had other variants. (49 women and 10 men; median [range] age, 63 [34–87] years). We interviewed 21 patients (17 women and 4 men; median [range] age, 59.6 [34–82] years). Of the interview participants, ten patients had BRCA1/2 variants, and 11 had non-BRCA1/2 variants. Patients reported receiving poor information about their genetic test results, and they often educated their physicians about their results. Some patients believed that they had been ignored or “brushed off” by health care professionals because non-BRCA1/2 genes are less understood outside the genetics research community. Patients with BRCA1/2 variants had similar problems with health care providers, despite increased awareness and established guidelines about BRCA1/2. Conclusions Research is required to understand the clinical significance and proper management of diseases attributable to newly characterized hereditary cancer genes. Additional evaluation of patient and provider education should be at the forefront of efforts to improve patient care.

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Exploring the Role of Mutations in Fanconi Anemia Genes in Hereditary Cancer Patients

Cancers ◽

10.3390/cancers12040829 ◽

2020 ◽

Vol 12 (4) ◽

pp. 829 ◽

Cited By ~ 2

Author(s):

Jesús del Valle ◽

Paula Rofes ◽

José Marcos Moreno-Cabrera ◽

Adriana López-Dóriga ◽

Sami Belhadj ◽

...

Keyword(s):

Breast Cancer ◽

Ovarian Cancer ◽

Cancer Patients ◽

Fanconi Anemia ◽

Hereditary Cancer ◽

Tumor Development ◽

Clinical Diagnostics ◽

Cancer Genes ◽

Cancer Breast ◽

Biallelic Mutations

Fanconi anemia (FA) is caused by biallelic mutations in FA genes. Monoallelic mutations in five of these genes (BRCA1, BRCA2, PALB2, BRIP1 and RAD51C) increase the susceptibility to breast/ovarian cancer and are used in clinical diagnostics as bona-fide hereditary cancer genes. Increasing evidence suggests that monoallelic mutations in other FA genes could predispose to tumor development, especially breast cancer. The objective of this study is to assess the mutational spectrum of 14 additional FA genes (FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, FANCP, FANCQ, FANCR and FANCU) in a cohort of hereditary cancer patients, to compare with local cancer-free controls as well as GnomAD. A total of 1021 hereditary cancer patients and 194 controls were analyzed using our next generation custom sequencing panel. We identified 35 pathogenic variants in eight genes. A significant association with the risk of breast cancer/breast and ovarian cancer was found for carriers of FANCA mutations (odds ratio (OR) = 3.14 95% confidence interval (CI) 1.4–6.17, p = 0.003). Two patients with early-onset cancer showed a pathogenic FA variant in addition to another germline mutation, suggesting a modifier role for FA variants. Our results encourage a comprehensive analysis of FA genes in larger studies to better assess their role in cancer risk.

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Clinically Relevant Germline Mutations in a Cohort of Young Women with Breast Cancer: A Comprehensive Analysis of Hereditary-Cancer Genes from Whole-Exome Sequencing

10.20944/preprints202008.0718.v1 ◽

2020 ◽

Author(s):

Liliana Gomez-Flores-Ramos ◽

Micheal Dean ◽

Kristine Jones ◽

Mingyi Wang ◽

Cynthia Villarreal-Garza ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Young Women ◽

Hereditary Cancer ◽

Germline Mutations ◽

Age At Diagnosis ◽

Cancer Genes ◽

Mutational Status ◽

Whole Exome

Young women with breast cancer represent 15% of cancer cases in Latin America. Genomic studies have found that early-onset breast-cancer cases exhibit a higher genetic susceptibility and a specific genomic signature as compared to their older counterparts. The aim of this study was to describe clinically relevant germline mutations in a cohort of young women with breast cancer. To achieve this, we analyzed hereditary-cancer genes from whole-exome sequencing data in 108 unrelated women with an extreme phenotype of breast cancer (≤40 years of age), diagnosed and treated at the National Cancer Institute of Mexico; 11% of the patients carried a pathogenic variant. BRCA2 comprised 46% of the mutations, followed by BRCA1 with 23%; PALB2 with 15%; and TP53 and RAD51C with 8 % each. This article describes a novel pathogenic mutation in RAD51C c.519dupT. The median age at diagnosis was 35 years overall; however, it was six years younger in patients with mutations. Age at diagnosis (OR=0.82, CI 95% 0.71-0.94; P= 0.008) and first-degree family history of cancer (OR=8.26, CI95% 1.35-50; P= 0.022) were the only epidemiological variables associated with mutational status. We found no differences in disease-free survival (p=0.403) or overall survival (p=0.735) among mutational status subgroups.

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Statistical Genetic Methods for Localizing Multiple Breast Cancer Genes.

10.21236/ada301699 ◽

1995 ◽

Author(s):

Jurg Ott

Keyword(s):

Breast Cancer ◽

Cancer Genes ◽

Breast Cancer Genes

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Statistical Genetics Methods for Localizing Multiple Breast Cancer Genes.

10.21236/ada337861 ◽

1997 ◽

Author(s):

Jurg Ott

Keyword(s):

Breast Cancer ◽

Statistical Genetics ◽

Cancer Genes ◽

Breast Cancer Genes

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High likelihood of actionable pathogenic variant detection in breast cancer genes in women with very early onset breast cancer

Journal of Medical Genetics ◽

10.1136/jmedgenet-2020-107347 ◽

2021 ◽

pp. jmedgenet-2020-107347

Author(s):

D Gareth Evans ◽

Elke Maria van Veen ◽

Helen J Byers ◽

Sarah J Evans ◽

George J Burghel ◽

...

Keyword(s):

Breast Cancer ◽

Early Onset ◽

Ductal Carcinoma ◽

Cancer Genes ◽

Early Onset Breast Cancer ◽

Younger Women ◽

Pathogenic Variants ◽

Younger Age ◽

Predisposition Genes

BackgroundWhile the likelihood of identifying constitutional breast cancer-associated BRCA1, BRCA2 and TP53 pathogenic variants (PVs) increases with earlier diagnosis age, little is known about the correlation with age at diagnosis in other predisposition genes. Here, we assessed the contribution of known breast cancer-associated genes to very early onset disease.MethodsSequencing of BRCA1, BRCA2, TP53 and CHEK2 c.1100delC was undertaken in women with breast cancer diagnosed ≤30 years. Those testing negative were screened for PVs in a minimum of eight additional breast cancer-associated genes. Rates of PVs were compared with cases ≤30 years from the Prospective study of Outcomes in Sporadic vs Hereditary breast cancer (POSH) study.ResultsTesting 379 women with breast cancer aged ≤30 years identified 75 PVs (19.7%) in BRCA1, 35 (9.2%) in BRCA2, 22 (5.8%) in TP53 and 2 (0.5%) CHEK2 c.1100delC. Extended screening of 184 PV negative women only identified eight additional actionable PVs. BRCA1/2 PVs were more common in women aged 26–30 years than in younger women (p=0.0083) although the younger age group had rates more similar to those in the POSH cohort. Out of 26 women with ductal carcinoma in situ (DCIS) alone, most were high-grade and 11/26 (42.3%) had a PV (TP53=6, BRCA2=2, BRCA1=2, PALB2=1). This PV yield is similar to the 61 (48.8%) BRCA1/2 PVs identified in 125 women with triple-negative breast cancer. The POSH cohort specifically excluded pure DCIS which may explain lower TP53 PV rates in this group (1.7%).ConclusionThe rates of BRCA1, BRCA2 and TP53 PVs are high in very early onset breast cancer, with limited benefit from testing of additional breast cancer-associated genes.

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