Paula Rofes

Institut Català d'Oncologia

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Trends

Author Order

Document Type

Co-Authors

Joan Brunet

Institut Català d'Oncologia

Jesús Del Valle

Institut Català d'Oncologia

Conxi Lázaro

Institut d'Investigació Biomédica de Bellvitge

Gabriel Capellá

Institut Català d'Oncologia

Marta Pineda

Institut Català d'Oncologia

Sara González

Institut Català d'Oncologia

Lídia Feliubadaló

Institut Català d'Oncologia

ÀT

Àlex Teulé

Institut Català d'Oncologia

Gardenia Vargas‐Parra

Hospital Del Mar

Rafael de Cid

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

Cooperative Institutions

Institut Català d'Oncologia

Institut d'Investigació Biomédica de Bellvitge

Centro de Investigación Biomédica en Red de Cáncer

Instituto de Salud Carlos III

Institut d'Investigació Biomèdica de Girona

Inserm

Bellvitge University Hospital

Heidelberg University

Istituti di Ricovero e Cura a Carattere Scientifico

Baylor College of Medicine

Author Statistics

Papers

Citation

H-Index

i-10 index

Research Field

Comprehensive analysis and ACMG-based classification of CHEK2 variants in Spanish hereditary cancer patients

Authorea (Authorea) (2020)

Gardenia Vargas Parra Jesús Del Valle Paula Rofes Mireia Gausachs Agostina Stradella

Background: CHEK2 variants are associated with intermediate breast cancer risk among other cancers. We aimed to comprehensively describe CHEK2 variants in a Spanish hereditary cancer (HC) cohort and adjust American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for their classification. Methods: First, three CHEK2 frequent variants were screened in a retrospective Hereditary Breast and Ovarian Cancer cohort of 516 patients. After, the whole CHEK2 coding region was analyzed by next-generation sequencing in 1,848 prospective patients with HC suspicion. We refined ACMGAMP criteria and applied different combinatorial rules to classify CHEK2 variants and define risk alleles. Results: We identified 10 CHEK2 null variants, 6 missense variants with discordant interpretation in ClinVar database, and 35 additional variants of unknown significance. Twelve variants were classified as (likely)-pathogenic; 2 can also be considered “established risk-alleles” and one as “likely risk-allele”. The prevalence of (likely)-pathogenic variants in the HC cohort was 0.8% (1.3% in breast cancer patients and 1.0% in hereditary non-polyposis colorectal cancer patients). Conclusions: Here we provide ACMG adjustment guidelines to classify CHEK2 variants. We hope that this work would be useful for variant classification of other genes with low effect variants

CHEK2

Medical genetics

10.22541/au.159050458.86704879

Cite

Citations (0)

TP53 germline testing and hereditary cancer: how somatic events and clinical criteria affect variant detection rate

Genome Medicine (2025)

Paula Rofes Carmen Castillo-Manzano Mireia Menéndez Àlex Teulé Sílvia Iglesias

Li–Fraumeni syndrome

Penetrance

Proband

10.1186/s13073-025-01429-5

Cite

Citations (0)

Novel genetic mutations detected by multigene panel are associated with hereditary colorectal cancer predisposition

PLoS ONE (2018)

Lorena Martín-Morales Paula Rofes Eduardo Díaz‐Rubio Patricia Llovet Víctor Lorca

Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening methods. The aim of this study is the use of a Next Generation Sequencing panel in order to find the genes involved in the cancer predisposition of these families. For this study, 98 patients from these unexplained families were tested with a multigene panel targeting 94 genes involved in cancer predisposition. The mutations found were validated by Sanger sequencing and the segregation was studied when possible. We identified 19 likely pathogenic variants in 18 patients. Out of these, 8 were found in MMR genes (5 in MLH1, 1 in MSH6 and 2 in PMS2). In addition, 11 mutations were detected in other genes, including high penetrance genes (APC, SMAD4 and TP53) and moderate penetrance genes (BRIP1, CHEK2, MUTYH, HNF1A and XPC). Mutations c.1194G>A in SMAD4, c.714_720dup in PMS2, c.2050T>G in MLH1 and c.1635_1636del in MSH6 were novel. In conclusion, the detection of new pathogenic mutations in high and moderate penetrance genes could contribute to the explanation of the heritability of colorectal cancer, changing the individual clinical management. Multigene panel testing is a more effective method to identify germline variants in cancer patients compared to single-gene approaches and should be therefore included in clinical laboratories.

MUTYH

MSH6

MLH1

Penetrance

Lynch Syndrome

CHEK2

MSH2

PMS2

10.1371/journal.pone.0203885

Cite

Citations (21)

Large scale multifactorial likelihood quantitative analysis of BRCA1 and BRCA2 variants: An ENIGMA resource to support clinical variant classification

Human Mutation (2019)

Michael T. Parsons Emma Tudini Hongyan Li Eric Hahnen Barbara Wappenschmidt

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co-segregation, family cancer history profile, co-occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case-control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene-specific calibration of evidence types used for variant classification.

10.1002/humu.23818

Cite

Citations (124)

Issue Information

Human Mutation (2020)

Adam M. Tobias Edward S. Tobias Elizabeth Mccormick Marie Lo Ma Dulik

FREQMAX provides an alterna ve approach for determining

10.1002/humu.23816

Cite

Citations (0)

Biological basis of extensive pleiotropy between blood traits and cancer risk

Genome Medicine (2024)

Miguel Ángel Pardo-Cea Xavier Farré Anna Esteve‐Codina Joanna Palade Roderic Espín

Abstract Background The immune system has a central role in preventing carcinogenesis. Alteration of systemic immune cell levels may increase cancer risk. However, the extent to which common genetic variation influences blood traits and cancer risk remains largely undetermined. Here, we identify pleiotropic variants and predict their underlying molecular and cellular alterations. Methods Multivariate Cox regression was used to evaluate associations between blood traits and cancer diagnosis in cases in the UK Biobank. Shared genetic variants were identified from the summary statistics of the genome-wide association studies of 27 blood traits and 27 cancer types and subtypes, applying the conditional/conjunctional false-discovery rate approach. Analysis of genomic positions, expression quantitative trait loci, enhancers, regulatory marks, functionally defined gene sets, and bulk- and single-cell expression profiles predicted the biological impact of pleiotropic variants. Plasma small RNAs were sequenced to assess association with cancer diagnosis. Results The study identified 4093 common genetic variants, involving 1248 gene loci, that contributed to blood–cancer pleiotropism. Genomic hotspots of pleiotropism include chromosomal regions 5p15- TERT and 6p21- HLA . Genes whose products are involved in regulating telomere length are found to be enriched in pleiotropic variants. Pleiotropic gene candidates are frequently linked to transcriptional programs that regulate hematopoiesis and define progenitor cell states of immune system development. Perturbation of the myeloid lineage is indicated by pleiotropic associations with defined master regulators and cell alterations. Eosinophil count is inversely associated with cancer risk. A high frequency of pleiotropic associations is also centered on the regulation of small noncoding Y-RNAs. Predicted pleiotropic Y-RNAs show specific regulatory marks and are overabundant in the normal tissue and blood of cancer patients. Analysis of plasma small RNAs in women who developed breast cancer indicates there is an overabundance of Y-RNA preceding neoplasm diagnosis. Conclusions This study reveals extensive pleiotropism between blood traits and cancer risk. Pleiotropism is linked to factors and processes involved in hematopoietic development and immune system function, including components of the major histocompatibility complexes, and regulators of telomere length and myeloid lineage. Deregulation of Y-RNAs is also associated with pleiotropism. Overexpression of these elements might indicate increased cancer risk.

Genome-wide Association Study

Pleiotropy

Genetic Association

Human genetics

10.1186/s13073-024-01294-8

Cite

Citations (2)

BARD1 Pathogenic Variants Are Associated with Triple-Negative Breast Cancer in a Spanish Hereditary Breast and Ovarian Cancer Cohort

Genes (2021)

Paula Rofes Jesús Del Valle Sara Torres‐Esquius Lídia Feliubadaló Agostina Stradella

Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (BRCA1 and BRCA2). BRCA1-associated ring domain 1 (BARD1), nuclear partner of BRCA1, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of BARD1 truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive BARD1 screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous BARD1 truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating BARD1 variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10-6.48; p = 1.16 × 10-5). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10-7.70; p = 5.45 × 10-5). Furthermore, deleterious BARD1 variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77-18.15; p = 0.001) compared to other BC subtypes. Our results support the role of BARD1 as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.

Triple-negative breast cancer

10.3390/genes12020150

Cite

Citations (11)

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

Cancers (2020)

Jesús Del Valle Paula Rofes José Marcos Moreno-Cabrera Adriana López‐Doriga Sami Belhadj

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.

PALB2

FANCA

CHEK2

FANCD2

MLH1

10.3390/cancers12040829

Cite

Citations (68)

RNA assay identifies a previous misclassification of BARD1 c.1977A>G variant

Scientific Reports (2021)

Paula Rofes Marta Pineda Lídia Feliubadaló Mireia Menéndez Rafael de Cid

Abstract Case–control studies have shown an association of BARD1 with hereditary breast and/or ovarian cancer (HBOC) predisposition. BARD1 alternatively spliced isoforms are abundant and some are highly expressed in different cancer types. In addition, a number of BARD1 germline pathogenic variants have been reported among HBOC patients. In previous reports, BARD1 c.1977A>G variant has been classified as pathogenic since it produces a frameshift transcript lacking exons 2 to 9. In the present study, we sought to validate the mRNA splicing results previously published and to contribute with new evidence to refine the classification of this substitution according to ACMG/AMP guidelines. The presence of the variant was screened in patients and controls. RT-PCR was performed in order to compare the transcriptional profiles of two variant carriers and ten non-carrier controls. In addition, allele-specific expression was assessed. No differences in variant frequency were detected between patients and controls. The RNA assay confirmed the presence of the shorter transcript lacking exons 2–9, but it was detected both in carriers and non-carriers. Furthermore, allelic imbalance was discarded and no significant differences in the proportion of full-length and shorter transcript were detected between carriers and controls. The shorter transcript detected corresponds to BARD1 isoform η, constituted by exons 1, 10 and 11. Our results support that this transcript is a constitutive splicing product rather than an aberrant transcript caused by BARD1 c.1977A>G variant, and for this reason this variant should be considered as likely benign following ACMG/AMP guidelines.

10.1038/s41598-021-02465-y

Cite

Citations (0)

Improving Genetic Testing in Hereditary Cancer by RNA Analysis

Journal of Molecular Diagnostics (2020)

Paula Rofes Mireia Menéndez Sara González Eva Tornero Carolina de la Torre

Sanger sequencing

Medical genetics

10.1016/j.jmoldx.2020.09.007

Cite

Citations (12)