Results of a population-based screening for hereditary breast cancer in a region of North-Central Italy: contribution of BRCA1/2 germ-line mutations

Understanding of the molecular-genetic pathogenesis of hereditary cancer syndrome is extremely important for developing of personal therapeutic approaches and for improving the effectiveness of preventive measures. Today, the optimal solution for the search of causative germ-line mutations in hereditary breast cancer (BC) patients is the next-generation sequencing-based multigene mutational screening. The authors have assembled a targeted panel of 31 genes, based on their potential involvement in the cancer susceptibility and taking into account the frequency of pathogenic alleles in the Russian population. It includes the “canonical” genes of hereditary breast cancer (BRCA1, BRCA2, BRIP1, PALB2, TP53, ATM, NBN), the recently identified “novel” genes (BLM, FANCD2, POLE, FANCM, RAD51C, MRE11A, RECQL, as well as some other genes involved in DNA repair, apoptosis and genome stability maintenance. 94 patients with hereditary BC of unknown genetic etiology were subjected to targeted sequencing. As a result, causative germ-line mutations were identified in 21/94 (22.3%) patients. Importantly, 19 patients harbored rare non-founder BRCA1 and BRCA2 mutations. In the remaining two cases, the functions of the ATM (p.Glu73fs) and POLE (p.Leu1171fs) genes were disrupted. The obtained data are of evident clinical importance; they argue for the expanding of diagnostic panels for monitoring at-risk individuals and for moving the standards of routine clinical diagnostics towards the targeted next-generation sequencing of multigene panels.

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Searching for the missing genetic determinants of hereditary breast cancer risk by whole-exome sequencing of BRCA-negative patients: new candidate genes USP39, SLIT3, CREB3

Problems in oncology ◽

10.37469/0507-3758-2021-67-1-111-116 ◽

2021 ◽

Vol 67 (1) ◽

pp. 111-116

Author(s):

Kirill Zagorodnev ◽

Aleksandr Romanko ◽

Uliy Gorgul ◽

Aleksandr Ivantsov ◽

Anna Sokolenko ◽

...

Keyword(s):

Breast Cancer ◽

Exome Sequencing ◽

Candidate Genes ◽

Whole Exome Sequencing ◽

Hereditary Breast Cancer ◽

Germ Line ◽

Genetic Diagnosis ◽

Clinical Signs ◽

Causative Mutation ◽

Whole Exome

The search for the new hereditary mutations and a precise molecular genetic diagnosis that determines the causative mutation in each specific case of hereditary breast cancer (BC) is a clinically important task since it helps to define the personal therapeutic approach and increase the effectiveness of preventive measures. Using whole-exome sequencing (WES) we analyzed the full spectrum of hereditary variations in 49 Russian patients with clinical signs of a hereditary disease which allowed us to compile a list of 229 candidate probably pathogenic germ-line variants. Then, the selected candidate mutations were validated by Sanger sequencing and molecular-epidemiological studies, the predisposing roles of three oncologically relevant mutations (USP39 c.*208G>C, SLIT3 p.Arg154Cys, and CREB3 p.Lys157Glu) were confirmed. Our candidate genes are first mentioned in connection with the hereditary risk of BC. The final proofs of the causative roles of these variants could be obtained through functional tests as well as via the analysis of the mutations segregation in BC families.

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Breast cancer phenotype in women with TP53 germ-line mutations: An LFS consortium effort.

Journal of Clinical Oncology ◽

10.1200/jco.2011.29.15_suppl.1519 ◽

2011 ◽

Vol 29 (15_suppl) ◽

pp. 1519-1519 ◽

Cited By ~ 2

Author(s):

S. Masciari ◽

D. Dillon ◽

M. G. Dick ◽

M. E. Robson ◽

J. N. Weitzel ◽

...

Keyword(s):

Breast Cancer ◽

Germ Line ◽

Germ Line Mutations ◽

Cancer Phenotype

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Bilateral breast cancer in a patient with a strong family history of cancer: Analysis of p53 germ line mutations

Breast Cancer ◽

10.1007/bf02967046 ◽

1994 ◽

Vol 1 (2) ◽

pp. 151-155 ◽

Cited By ~ 1

Author(s):

Takashi Fukutomi ◽

Rie Inoue ◽

Toshikazu Ushijima ◽

Hitoshi Tsuda ◽

Isamu Adachi

Keyword(s):

Breast Cancer ◽

Family History ◽

Germ Line ◽

Bilateral Breast Cancer ◽

Strong Family History ◽

Family History Of Cancer ◽

Germ Line Mutations ◽

History Of ◽

History Of Cancer

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Population-based breast cancer survival. Mammographic screening activities in central italy

Cancer ◽

10.1002/1097-0142(19941215)74:12<3126::aid-cncr2820741211>3.0.co;2-9 ◽

1994 ◽

Vol 74 (12) ◽

pp. 3126-3134 ◽

Cited By ~ 7

Author(s):

Alessandro Barchielli ◽

Eugenio Paci ◽

Daniela Balzi ◽

Marco Geddes ◽

Daniela Giorgi ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Survival ◽

Central Italy ◽

Population Based ◽

Mammographic Screening ◽

Breast Cancer Survival

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Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil

Genetics and Molecular Biology ◽

10.1590/1678-4685-gmb-2014-0363 ◽

2016 ◽

Vol 39 (2) ◽

pp. 210-222 ◽

Cited By ~ 9

Author(s):

Edenir Inêz Palmero ◽

Bárbara Alemar ◽

Lavínia Schüler-Faccini ◽

Pierre Hainaut ◽

Carlos Alberto Moreira-Filho ◽

...

Keyword(s):

Breast Cancer ◽

At Risk ◽

Hereditary Breast Cancer ◽

Population Based ◽

Southern Brazil ◽

Population Based Study ◽

Brca1 Brca2

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Germline Mutation Analysis in Sporadic Breast Cancer Cases with Clinical Correlations

10.1101/2021.03.29.21254525 ◽

2021 ◽

Author(s):

Sadia Ajaz ◽

Sani-e-Zehra Zaidi ◽

Saleema Mehboob Ali ◽

Aisha Siddiqa ◽

Mohammad Ali Memon

Keyword(s):

Breast Cancer ◽

Sporadic Breast Cancer ◽

Ductal Carcinoma ◽

Germ Line ◽

Copy Number Variations ◽

P Value ◽

Breast Cancers ◽

Pakistani Population ◽

Germ Line Mutations ◽

Clinical Correlations

Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately in Pakistani population. In the present study, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy controls. The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The analyses were stratified on the basis of age (<40 years vs >40 years) and ethnicity. The breast cancer gene panel assay was carried out by a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 assay with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (<40 years) was higher in Sindhis (n=12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grades II and III (46.4%), tumor size 2-5cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of preventive and treatment strategies against breast cancers in Pakistani population.

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Germ-line BRCA1 mutations in women with sporadic breast cancer: clinical correlations.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.1.115 ◽

1998 ◽

Vol 16 (1) ◽

pp. 115-120 ◽

Cited By ~ 19

Author(s):

E Garcia-Patiño ◽

B Gomendio ◽

M Provencio ◽

J M Silva ◽

J M Garcia ◽

...

Keyword(s):

Breast Cancer ◽

Sporadic Breast Cancer ◽

Germ Line ◽

Late Onset ◽

Brca1 Gene ◽

Peripheral Blood Lymphocytes ◽

Missense Mutations ◽

Direct Dna Sequencing ◽

Brca1 Mutations ◽

Germ Line Mutations

PURPOSE Sporadic nonhereditary breast cancer is recognized as the most common form of this malignancy. Presence of germ-line mutations in the BRCA1 gene of these tumors is an infrequent event. We undertook the present study to evaluate the prevalence of germ-line mutations in patients diagnosed with sporadic breast cancer, and to delimit the clinical spectrum of this subgroup of patients with germ-line mutations and their differences with respect to patients with no evidence of BRCA1 gene mutations. METHODS We studied 105 patients diagnosed with breast cancer, selected from among our living patients; those with carcinoma-in-situ and those with a definite family history of breast or ovarian cancer were excluded. Genomic DNA, obtained from peripheral-blood lymphocytes, was studied for BRCA1 mutations by polymerase chain reaction/single-strand conformation polymorphism (PCR-SSCP) and direct DNA sequencing. Fourteen clinicopathologic parameters were analyzed in each patient. RESULTS Six (5.7%) frameshift mutations that corresponded to truncating proteins and three missense mutations, the functional meaning of which remains speculative, were identified. The patients with germ-line mutations were found to have a more advanced age at diagnosis, as well as a longer median survival (51 months). CONCLUSION Women with sporadic breast cancer of late onset may display a significant incidence of germline BRCA1 mutations, which occur at a rate not previously determined in this group of patients. The presence of variations in the sequence of the BRCA1 gene could influence the longer survival observed in these patients.

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