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Molecular Genetics of Breast and Ovary Cancer

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A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Molecular Cancer Biology".

Deadline for manuscript submissions: closed (31 October 2020) | Viewed by 50077

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Special Issue Editors

Prof. Giuseppe Giannini

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Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy Pasteur Institute-Cenci Bolognetti Foundation, 00161 Rome, Italy

Prof. Dr. Laura Ottini

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Department of Molecular Medicine, University La Sapienza, 00161 Rome, Italy
Interests: hereditary cancer; breast cancer; prostate cancer; gastrointestinal cancer; melanoma; cancer genetics and genomics; cancer risk assessment; molecular epidemiology
Special Issues, Collections and Topics in MDPI journals

Dr. Anna Coppa

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Department of Experimental Medicine, University La Sapienza, 00161 Rome, Italy

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Dear Colleague,

The discovery of the first two breast cancer genes, BRCA1 and BRCA2, dates back to more than two decades. Since then, a number of additional susceptibility genes were shown to differentially impact on the lifetime risk of developing breast or ovarian cancer. Much has been accomplished due to the continuously expanding use of high-throughput technologies and, particularly, next-generation sequencing (NGS), both in research settings and in clinical screenings for breast/ovary cancer inheritance. High-to-moderate penetrance alleles with clinical validity have been identified, mainly for genes involved in homologous recombination (HR) repair of DNA double-strand breaks. Moreover, genetic variations in low-penetrance susceptibility loci were shown to affect breast and ovarian cancer genetic predisposition and/or to contribute as genetic risk modifiers, particularly through a polygenic inheritance model. While we expect that further exploitation of this and similar information will have a strong impact in the field of molecular genetics of breast and ovarian cancer, clear guidelines on how to use it for risk-reducing purposes in mutation carriers is still lagging behind.

BRCA1/BRCA2 mutation status has recently become a predictive biomarker for the treatment of breast and ovarian cancer patients with PARP inhibitors, in routine clinical settings. Additional genetic defects in HR and other DNA repair pathways may also account for constitutional or acquired resistance/sensitivity to PARP inhibitors.

Thus, on one hand, expanded knowledge on the genetic factors contributing to breast and ovarian cancer genetics will be essential for a more efficient risk prediction and control in a larger fraction of familial cases. On the other hand, at least some of these genetic alterations may surge as predictive biomarkers for molecularly targeted therapy. For this Special Issue of Cancers, we will welcome manuscripts describing novel data, methods, collaborative initiatives, editorials, and reviews related to these topics.

Prof. Giuseppe Giannini
Prof. Laura Ottini
Dr. Anna Coppa
Guest Editors

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Keywords

Genetic predisposition to breast and ovarian cancer
breast and ovarian cancer risk estimate
NGS of gene panels
HR genes
HR deficiency
targeted therapy

Published Papers (13 papers)

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Research

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12 pages, 269 KiB

Open AccessArticle

BRCA1/2 Variants and Metabolic Factors: Results From a Cohort of Italian Female Carriers

by Andreina Oliverio, Eleonora Bruno, Mara Colombo, Angelo Paradiso, Stefania Tommasi, Antonella Daniele, Daniela Andreina Terribile, Stefano Magno, Donatella Guarino, Siranoush Manoukian, Bernard Peissel, Paolo Radice and Patrizia Pasanisi

Cancers 2020, 12(12), 3584; https://doi.org/10.3390/cancers12123584 - 30 Nov 2020

Cited by 3 | Viewed by 1986

Abstract

Women carriers of pathogenic variants (mutations) in the BRCA1/2 genes face a high lifetime risk of developing breast cancer (BC) and/or ovarian cancer (OC). However, metabolic factors may influence BRCA penetrance. We studied the association of metabolic factors with BRCA1/2 variants and the risk effect of metabolic exposures in relation to the position of the mutations within the BRCA1/2. Overall, 438 women carriers of BRCA1/2 mutations, aged 18–70, with or without a previous diagnosis of BC/OC and without metastases, who joined our randomized dietary trial, were included in the study. The pathogenic variants were divided, according to their predicted effect, into loss of function (LOF) and nonsynonymous variants. The association between metabolic exposures and variants were analyzed by a logistic regression model. LOF variant carriers showed higher levels of metabolic parameters compared to carriers of nonsynonymous variants. LOF variant carriers had significantly higher levels of plasma glucose and serum insulin than nonsynonymous variant carriers (p = 0.03 and p < 0.001, respectively). This study suggests that higher insulin levels are significantly associated with LOF variants. Further investigations are required to explore the association of metabolic factors with LOF variants and the mechanisms by which these factors may affect BRCA-related cancer risk. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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22 pages, 2882 KiB

Open AccessArticle

The 40bp Indel Polymorphism rs150550023 in the MDM2 Promoter is Associated with Intriguing Shifts in Gene Expression in the p53-MDM2 Regulatory Hub

by Heidi Miedl, Bianca Dietrich, Klaus Kaserer and Martin Schreiber

Cancers 2020, 12(11), 3363; https://doi.org/10.3390/cancers12113363 - 13 Nov 2020

Cited by 3 | Viewed by 2141

Abstract

Most low-penetrance genetic risk factors for cancer are located in noncoding regions, presumably altering the regulation of neighboring genes. The poorly characterized Indel polymorphism rs150550023 (rs3730485; del1518) in the promoter of MDM2 (human homolog of mouse double minute 2) is a biologically plausible candidate genetic risk factor, which might influence the expression of MDM2, a key negative regulator of the central tumor suppressor p53. Here, we genotyped rs150550023 in a Central European hospital-based case–control study of 407 breast cancer patients and 254 female controls. mRNA levels of MDM2, p53, and the p53 target genes p21, BAX, and PERP were quantified with qRT-PCR, and p53 protein was assessed with immune histochemistry in ≈100 primary breast tumors with ascertained rs150550023 genotype. We found no evidence for an association of rs150550023 with the risk, age at onset, or prognosis of breast cancer. A possible synergism was observed with SNP309 in promoter P2 of MDM2. Mean mRNA levels of MDM2, p53, p21, and BAX were ≈1.5–3 fold elevated in TP53 wildtype tumors with the minor homozygous Del/Del genotype. However, systematic shifts in p53 protein levels or mutation rates were not observed, suggesting that the elevated p53 mRNA levels are due to regulatory feedback loops that compensate for the effects of rs150550023 on MDM2 expression. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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11 pages, 728 KiB

Open AccessArticle

NGS Panel Testing of Triple-Negative Breast Cancer Patients in Cyprus: A Study of BRCA-Negative Cases

by Maria Zanti, Maria A. Loizidou, Kyriaki Michailidou, Panagiota Pirpa, Christina Machattou, Yiola Marcou, Flora Kyriakou, Eleni Kakouri, George A. Tanteles, Elena Spanou, George M. Spyrou, Kyriacos Kyriacou and Andreas Hadjisavvas

Cancers 2020, 12(11), 3140; https://doi.org/10.3390/cancers12113140 - 27 Oct 2020

Cited by 8 | Viewed by 3011

Abstract

In Cyprus, approximately 9% of triple-negative (estrogen receptor-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative) breast cancer (TNBC) patients are positive for germline pathogenic variants (PVs) in BRCA1/2. However, the contribution of other genes has not yet been determined. To this end, we aimed to investigate the prevalence of germline PVs in BRCA1/2-negative TNBC patients in Cyprus, unselected for family history of cancer or age of diagnosis. A comprehensive 94-cancer-gene panel was implemented for 163 germline DNA samples, extracted from the peripheral blood of TNBC patients. Identified variants of uncertain clinical significance were evaluated, using extensive in silico investigation. Eight PVs (4.9%) were identified in two high-penetrance TNBC susceptibility genes. Of these, seven occurred in PALB2 (87.5%) and one occurred in TP53 (12.5%). Interestingly, 50% of the patients carrying PVs were diagnosed over the age of 60 years. The frequency of non-BRCA PVs (4.9%) and especially PALB2 PVs (4.3%) in TNBC patients in Cyprus appears to be higher compared to other populations. Based on these results, we believe that PALB2 and TP53 along with BRCA1/2 genetic testing could be beneficial for a large proportion of TNBC patients in Cyprus, irrespective of their age of diagnosis. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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16 pages, 1302 KiB

Open AccessArticle

Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

by Ana Barbosa, Pedro Pinto, Ana Peixoto, Joana Guerra, Carla Pinto, Catarina Santos, Manuela Pinheiro, Carla Escudeiro, Carla Bartosch, João Silva and Manuel R. Teixeira

Cancers 2020, 12(10), 2834; https://doi.org/10.3390/cancers12102834 - 30 Sep 2020

Cited by 7 | Viewed by 3081

Abstract

Since the approval of PARP inhibitors for the treatment of high-grade serous ovarian cancer, in addition to cancer risk assessment, BRCA1 and BRCA2 genetic testing also has therapeutic implications (germline and somatic variants) and should be offered to these patients at diagnosis, irrespective of family history. However, variants in other genes besides BRCA1 and BRCA2 are associated with ovarian cancer predisposition, which would be missed by a genetic testing aimed only at indication for PARP inhibitor treatment. In this study, we aimed to evaluate the yield of clinically actionable germline variants using next-generation sequencing of a customized panel of 10 genes for the analysis of formalin-fixed paraffin-embedded samples from 96 ovarian carcinomas, a strategy that allows the detection of both somatic and germline variants in a single test. In addition to 13.7% of deleterious germline BRCA1/BRCA2 carriers, we identified 7.4% additional patients with pathogenic germline variants in other genes predisposing for ovarian cancer, namely RAD51C, RAD51D, and MSH6, representing 35% of all pathogenic germline variants. We conclude that the strategy of reflex gene-panel tumor testing enables the identification of clinically actionable germline variants in a significantly higher proportion of ovarian cancer patients, which may be valuable information in patients with advanced disease that have run out of approved therapeutic options. Furthermore, this approach increases the chance to make available genetic counseling, presymptomatic genetic testing, and gynecological cancer prophylaxis to female relatives who turn out to be healthy carriers of deleterious germline variants. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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15 pages, 1694 KiB

Open AccessArticle

Beneficial Molecular Adaptations in BRCA-Mutation Carriers by Combined HIT/HIRT Intervention: Results from a Pilot Study

by Daniel A. Bizjak, Sebastian V. W. Schulz, Uwe Schumann, Stephanie Otto, Johannes Kirsten, Florian Ebner, Elena Leinert, Jens Huober, Wolfgang Janni and Jürgen Michael Steinacker

Cancers 2020, 12(6), 1526; https://doi.org/10.3390/cancers12061526 - 10 Jun 2020

Cited by 5 | Viewed by 3102

Abstract

Based on growing evidence that breast cancer (BRCA) also plays a pivotal role in the regulation of skeletal muscle metabolism and the response to anti-oxidative stress, we examined the influence of regular exercise in human BRCA mutation carriers on their BRCA1 gene/protein expression and inflammatory/oxidative response. Sixteen BRCA-mutation carriers were assigned to an intervention (IG) or control group (CG). IG received a combination of high-intensity interval endurance (HIT) and strength training (HIRT) for six weeks, whereas CG received a low-intensity activity program. Before (T0) and at the end of the intervention (T1), muscle biopsy, physiological performance, blood withdrawal and anthropometry were obtained. Parameters included: Muscle BRCA1 gene/protein expression, inflammatory/oxidative stress, anti-oxidative capacity, peak oxygen capacity (VO₂peak) and 1-repetition maximum (1-RM) at six different training machines. VO₂peak and 1-RM of IG were increased at T1 compared to T0, whereas CG performance, physiological and molecular parameters remained unchanged. IG showed increased BRCA1 protein concentration as well as anti-oxidative capacity, whereas gene expression was unaltered. IG inflammatory and oxidative damage did not differ between time points. Combined HIT/HIRT increases aerobic and strength performance of BRCA-mutation carriers with up regulated BRCA1 protein expression and improved anti-oxidative status without showing an increased inflammatory response. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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14 pages, 1244 KiB

Open AccessArticle

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

by Klara Lhotova, Lenka Stolarova, Petra Zemankova, Michal Vocka, Marketa Janatova, Marianna Borecka, Marta Cerna, Sandra Jelinkova, Jan Kral, Zuzana Volkova, Marketa Urbanova, Petra Kleiblova, Eva Machackova, Lenka Foretova, Jana Hazova, Petra Vasickova, Filip Lhota, Monika Koudova, Leona Cerna, Spiros Tavandzis, Jana Indrakova, Lucie Hruskova, Marcela Kosarova, Radek Vrtel, Viktor Stranecky, Stanislav Kmoch, Michal Zikan, Libor Macurek, Zdenek Kleibl and Jana Soukupova Show full author list Hide full author list

Cancers 2020, 12(4), 956; https://doi.org/10.3390/cancers12040956 - 13 Apr 2020

Cited by 24 | Viewed by 5359

Abstract

Ovarian cancer (OC) is the deadliest gynecologic malignancy with a substantial proportion of hereditary cases and a frequent association with breast cancer (BC). Genetic testing facilitates treatment and preventive strategies reducing OC mortality in mutation carriers. However, the prevalence of germline mutations varies among populations and many rarely mutated OC predisposition genes remain to be identified. We aimed to analyze 219 genes in 1333 Czech OC patients and 2278 population-matched controls using next-generation sequencing. We revealed germline mutations in 18 OC/BC predisposition genes in 32.0% of patients and in 2.5% of controls. Mutations in BRCA1/BRCA2, RAD51C/RAD51D, BARD1, and mismatch repair genes conferred high OC risk (OR > 5). Mutations in BRIP1 and NBN were associated with moderate risk (both OR = 3.5). BRCA1/2 mutations dominated in almost all clinicopathological subgroups including sporadic borderline tumors of ovary (BTO). Analysis of remaining 201 genes revealed somatic mosaics in PPM1D and germline mutations in SHPRH and NAT1 associating with a high/moderate OC risk significantly; however, further studies are warranted to delineate their contribution to OC development in other populations. Our findings demonstrate the high proportion of patients with hereditary OC in Slavic population justifying genetic testing in all patients with OC, including BTO. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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8 pages, 410 KiB

Open AccessFeature PaperArticle

Analysis of BRCA1 and RAD51C Promoter Methylation in Italian Families at High-Risk of Breast and Ovarian Cancer

by Silvia Tabano, Jacopo Azzollini, Chiara Pesenti, Sara Lovati, Jole Costanza, Laura Fontana, Bernard Peissel, Monica Miozzo and Siranoush Manoukian

Cancers 2020, 12(4), 910; https://doi.org/10.3390/cancers12040910 - 8 Apr 2020

Cited by 12 | Viewed by 3494

Abstract

Previous studies on breast and ovarian carcinoma (BC and OC) revealed constitutional BRCA1 and RAD51C promoter hypermethylation as epigenetic alterations leading to tumor predisposition. Nevertheless, the impact of epimutations at these genes is still debated. One hundred and eight women affected by BC, OC, or both and considered at very high risk of carrying BRCA1 germline mutations were studied. All samples were negative for pathogenic variants or variants of uncertain significance at BRCA testing. Quantitative BRCA1 and RAD51C promoter methylation analyses were performed by Epityper mass spectrometry on peripheral blood samples and results were compared with those in controls. All the 108 analyzed cases showed methylation levels at the BRCA1/RAD51C promoter comparable with controls. Mean methylation levels (± stdev) at the BRCA1 promoter were 4.3% (± 1.4%) and 4.4% (± 1.4%) in controls and patients, respectively (p > 0.05; t-test); mean methylation levels (± stdev) at the RAD51C promoter were 4.3% (± 0.9%) and 3.7% (± 0.9%) in controls and patients, respectively (p > 0.05; t-test). Based on these observations; the analysis of constitutional methylation at promoters of these genes does not seem to substantially improve the definition of cancer risks in patients. These data support the idea that epimutations represent a very rare event in high-risk BC/OC populations. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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10 pages, 748 KiB

Open AccessArticle

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

by Jesús del Valle, Paula Rofes, José Marcos Moreno-Cabrera, Adriana López-Dóriga, Sami Belhadj, Gardenia Vargas-Parra, Àlex Teulé, Raquel Cuesta, Xavier Muñoz, Olga Campos, Mónica Salinas, Rafael de Cid, Joan Brunet, Sara González, Gabriel Capellá, Marta Pineda, Lídia Feliubadaló and Conxi Lázaro

Cancers 2020, 12(4), 829; https://doi.org/10.3390/cancers12040829 - 30 Mar 2020

Cited by 47 | Viewed by 7344

Abstract

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. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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10 pages, 1203 KiB

Open AccessArticle

The Spectrum of FANCM Protein Truncating Variants in European Breast Cancer Cases

by Gisella Figlioli, Anders Kvist, Emma Tham, Jana Soukupova, Petra Kleiblova, Taru A Muranen, Nadine Andrieu, Jacopo Azzollini, Judith Balmaña, Alicia Barroso, Javier Benítez, Birgitte Bertelsen, Ana Blanco, Bernardo Bonanni, Åke Borg, Joan Brunet, Daniele Calistri, Mariarosaria Calvello, Stepan Chvojka, Laura Cortesi, Esther Darder, Jesús Del Valle, Orland Diez, ENIGMA Consortium, Séverine Eon-Marchais, Florentia Fostira, GENESIS Study Collaborators, Francesca Gensini, Claude Houdayer, Marketa Janatova, Johanna I Kiiski, Irene Konstantopoulou, Katerina Kubelka-Sabit, Conxi Lázaro, Fabienne Lesueur, Siranoush Manoukian, Ruta Marcinkute, Ugnius Mickys, Virginie Moncoutier, SWE-BRCA Group, Aleksander Myszka, Tu Nguyen-Dumont, Finn Cilius Nielsen, Rimvydas Norvilas, Edith Olah, Ana Osorio, Laura Papi, Bernard Peissel, Ana Peixoto, Dijana Plaseska-Karanfilska, Timea Pócza, Maria Rossing, Vilius Rudaitis, Marta Santamariña, Catarina Santos, Snezhana Smichkoska, Melissa C Southey, Dominique Stoppa-Lyonnet, Manuel Teixeira, Therese Törngren, Angela Toss, Miguel Urioste, Ana Vega, Zdenka Vlckova, Drakoulis Yannoukakos, Valentina Zampiga, Zdenek Kleibl, Paolo Radice, Heli Nevanlinna, Hans Ehrencrona, Ramunas Janavicius and Paolo Peterlongo Show full author list Hide full author list

Cancers 2020, 12(2), 292; https://doi.org/10.3390/cancers12020292 - 26 Jan 2020

Cited by 12 | Viewed by 4578

Abstract

Germline protein truncating variants (PTVs) in the FANCM gene have been associated with a 2–4-fold increased breast cancer risk in case-control studies conducted in different European populations. However, the distribution and the frequency of FANCM PTVs in Europe have never been investigated. In the present study, we collected the data of 114 European female breast cancer cases with FANCM PTVs ascertained in 20 centers from 13 European countries. We identified 27 different FANCM PTVs. The p.Gln1701* PTV is the most common PTV in Northern Europe with a maximum frequency in Finland and a lower relative frequency in Southern Europe. On the contrary, p.Arg1931* seems to be the most common PTV in Southern Europe. We also showed that p.Arg658*, the third most common PTV, is more frequent in Central Europe, and p.Gln498Thrfs*7 is probably a founder variant from Lithuania. Of the 23 rare or unique FANCM PTVs, 15 have not been previously reported. We provide here the initial spectrum of FANCM PTVs in European breast cancer cases. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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12 pages, 665 KiB

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The Association of IL-1 and HRAS Gene Polymorphisms with Breast Cancer Susceptibility in a Jordanian Population of Arab Descent: A Genotype–Phenotype Study

by Laith N. AL-Eitan, Bashar H. Al-Ahmad and Fouad A. Almomani

Cancers 2020, 12(2), 283; https://doi.org/10.3390/cancers12020283 - 23 Jan 2020

Cited by 12 | Viewed by 3439

Abstract

Breast cancer (BC) pathogenesis is poorly understood and not yet completely determined. BC susceptibility genes are responsible for 20% to 25% of breast cancer risk. The main objective of this study is to identify the genetic polymorphisms within the Harvey rat sarcoma viral oncogene homolog (HRAS1) and interleukin-1 receptor antagonist (IL1-Ra) genes in Jordanian BC female patients and to investigate the genetic association of these polymorphisms with BC. Samples were collected from 150 Jordanian BC patients and 187 healthy age-matched controls. PCR and PCR-RFLP techniques were used to identify genetic polymorphisms within these candidate genes. The single nucleotide polymorphism single nucleotide polymorphism (SNP) association web tool SNPStats (v. 3.6) was used to investigate the allelic and genotypic association with BC. Different statistical analyses were used to study the correlation between the investigated genetic variants and several prognosis factors of BC. A genetic association between BC susceptibility and Il-1β rs1143634 was found specifically at the allelic level of E1 as a risk allele (72% in the cases vs. 64.2% in the controls). Another genetic association was found in the IL-Ra gene (86-VNTR (variable number tandem repeat)), which presented one repeat allele (24.1% in cases vs. 15.59% in controls) and could be considered as a risk allele in Jordanian women. In contrast, this study found that there is no genetic association between Il-1β SNP rs16944 and BC. In addition, a significant association was found between the allelic level of the HRAS1 gene and BC susceptibility. Since this study is the first to be conducted on the genetic susceptibility of these genes to BC in the Jordanian population, more investigations on the link between BC and these variants are recommended to determine the impact of these polymorphisms on other ethnic groups. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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14 pages, 536 KiB

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Germline Variants in Driver Genes of Breast Cancer and Their Association with Familial and Early-Onset Breast Cancer Risk in a Chilean Population

by Alejandro Fernandez-Moya, Sebastian Morales, Trinidad Arancibia, Patricio Gonzalez-Hormazabal, Julio C. Tapia, Raul Godoy-Herrera, Jose Miguel Reyes, Fernando Gomez, Enrique Waugh and Lilian Jara

Cancers 2020, 12(1), 249; https://doi.org/10.3390/cancers12010249 - 20 Jan 2020

Cited by 6 | Viewed by 3439

Abstract

The genetic variations responsible for tumorigenesis are called driver mutations. In breast cancer (BC), two studies have demonstrated that germline mutations in driver genes linked to sporadic tumors may also influence BC risk. The present study evaluates the association between SNPs and SNP-SNP interaction in driver genes TTN (rs10497520), TBX3 (rs2242442), KMT2D (rs11168827), and MAP3K1 (rs702688 and rs702689) with BC risk in BRCA1/2-negative Chilean families. The SNPs were genotyped in 489 BC cases and 1078 controls by TaqMan Assay. Our data do not support an association between rs702688: A>G or rs702689: G>A and BC risk. The rs10497520-T allele was associated with a decreased risk in patients with family history of BC or early-onset BC (OR = 0.6, p < 0.0001 and OR = 0.7, p = 0.05, respectively). rs2242442-G was associated with a protective effect and rs11168827-C was associated with increased BC risk in families with a strong history of BC (OR = 0.6, p = 0.02 and OR = 1.4, p = 0.05, respectively). As rs10497520-T and rs2242442-G seemed to protect against BC risk, we then evaluated their combined effect. Familial BC risk decreased in a dose-dependent manner with the protective allele count, reflecting an additive effect (p-trend < 10⁻⁴). To our knowledge, this is the first association study of BC driver gene germline variations in a Chilean population. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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27 pages, 406 KiB

Open AccessReview

Resistance to Neoadjuvant Treatment in Breast Cancer: Clinicopathological and Molecular Predictors

by María Rosario Chica-Parrado, Ana Godoy-Ortiz, Begoña Jiménez, Nuria Ribelles, Isabel Barragan and Emilio Alba

Cancers 2020, 12(8), 2012; https://doi.org/10.3390/cancers12082012 - 22 Jul 2020

Cited by 13 | Viewed by 3255

Abstract

Neoadjuvant Chemotherapy (NAC) in Breast Cancer (BC) has proved useful for the reduction in tumor burden prior to surgery, allowing for a more extensive breast preservation and the eradication of subjacent micrometastases. However, the impact on prognosis is highly dependent on the establishment of Pathological Complete Response (pCR), in particular for Triple Negative (TN) and Hormonal Receptor negative/Human Epidermal growth factor Receptor 2 positive (HR−/HER2+) subtypes. Several pCR predictors, such as PAM50, Integrative Cluster (IntClust), mutations in PI3KCA, or the Trastuzumab Risk model (TRAR), are useful molecular tools for estimating response to treatment and are prognostic. Major evolution events during BC NAC that feature the Residual Disease (RD) are the loss of HR and HER2, which are prognostic of bad outcome, and stemness and immune depletion-related gene expression aberrations. This dynamic nature of the determinants of response to BC NAC, together with the extensive heterogeneity of BC, raises the need to discern the individual and subtype-specific determinants of resistance. Moreover, refining the current approaches for a comprehensive monitoring of tumor evolution during treatment, RD, and eventual recurrences is essential for identifying new actionable alterations and the integral best management of the disease. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

30 pages, 2397 KiB

Open AccessReview

An Overview of Candidate Therapeutic Target Genes in Ovarian Cancer

by Elena Alexandrova, Giovanni Pecoraro, Assunta Sellitto, Viola Melone, Carlo Ferravante, Teresa Rocco, Anna Guacci, Giorgio Giurato, Giovanni Nassa, Francesca Rizzo, Alessandro Weisz and Roberta Tarallo

Cancers 2020, 12(6), 1470; https://doi.org/10.3390/cancers12061470 - 4 Jun 2020

Cited by 22 | Viewed by 4812

Abstract

Ovarian cancer (OC) shows the highest mortality rate among gynecological malignancies and, because of the absence of specific symptoms, it is frequently diagnosed at an advanced stage, mainly due to the lack of specific and early biomarkers, such as those based on cancer molecular signature identification. Indeed, although significant progress has been made toward improving the clinical outcome of other cancers, rates of mortality for OC are essentially unchanged since 1980, suggesting the need of new approaches to identify and characterize the molecular mechanisms underlying pathogenesis and progression of these malignancies. In addition, due to the low response rate and the high frequency of resistance to current treatments, emerging therapeutic strategies against OC focus on targeting single factors and pathways specifically involved in tumor growth and metastasis. To date, loss-of-function screenings are extensively applied to identify key drug targets in cancer, seeking for more effective, disease-tailored treatments to overcome lack of response or resistance to current therapies. We review here the information relative to essential genes and functional pathways recently discovered in OC, often strictly interconnected with each other and representing promising biomarkers and molecular targets to treat these malignancies. Full article

(This article belongs to the Special Issue Molecular Genetics of Breast and Ovary Cancer)

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