Abstract P3-07-05: Genetic profile of germline mutations in unselected women with breast cancer in a Colombian population
Authors: Sierra-Díaz Diana Carolina , Morel Adrien , Fonseca Dora Janeth , Contreras Nora , Angulo-Aguado Mariana , Balaguera Valentina , Llinás-Caballero Kevin , Munevar Isabel , Borras Mariana , Lema Mauricio , Idrobo Henry , Trujillo Daniela , Serrano Norma , Orduz Ana Isabel , Lopera Diego , Gonzalez Jaime , Rojas Gustavo , Londoño Paula , Manneh Ray , Quintero Catalina , Laissue Paul , Cabrera Rodrigo , Restrepo Carlos M , Mantilla William 
Published: March 2022

Abstract
Introduction In Colombia Breast cancer (BC), is the most frequent and has the highest mortality rate among all types of cancer. There are few studies of the genomic profile in unselected affected population by BC in Colombia. Some of these studies have only tested the presence of variants reported as founders named “Colombian Profile”.We conducted a large-scale genomic analysis using Whole Exome Sequencing (WES) to evaluate germline mutations in unselected BC patients. Methods This trial included 299 unselected BC female patients aged over 18 years old, without personal and family history of germline BC risk mutations.The protocol was approved by the IRC and EC of Fundación Cardioinfantil (FCI). All patients signed informed consent before recruitment.Genomic DNA was extracted from peripheral blood samples and was used to WES (Novogene Inc. Beijing, China). The variants were filtered using VarSeq v2.1.1 software, following the criteria: missense, non-sense, frameshift, and intronic variants, we additionally considered a MAF ≤0.01 for ATM, CHEK2, and PALB2 genes.Clinical significance of each variant was annotated according to the ACMG/AMP and ENIGMA guidelines.MLPA was assessed using the commercial kit SALSA MLPA Probemix P002-D1 for BRCA1 and P090-C1 for BRCA2 (MRC-Holland, Amsterdam).This study was financially supported by an unrestricted grant from Pfizer. Results This abstract is the first report from 299 patients. To determine the presence of germline variants in the patients a WES was performed. Here we describe the pathogenic and probably pathogenic mutations in BRCA1, BRCA2, ATM, CHEK2, PALB2. We found BRCA1/2 alterations were found in 3.7% of the patients (11 patients, IC 95% 1.7-5.6%), 5 patients in BRCA1 and 6 patients in BRCA2 (1.7% IC 95% 0.7-4%, and 2% IC 95% 0.9-4.4% respectively). We found 29 patients had mutations unrelated to BRCA1/2 (9.5% IC 95% 5.8-11.7%). The most frequently affected gene was ATM (17 patients, 5.7% IC95% 3.6-9%). Discussion and conclusion We found that 12.2% of the population of the study were carriers of a pathogenic/likely pathogenic variant in the evaluated genes, and interestingly 9.5% of them corresponded to non-BRCA1/2 genes. ATM variants have a prevalence of 5.7% in the whole population and represent 42% of all the variants. Other mutations in genes like BRCA2, ATM and CHEK2 were exclusive in non-TNBC. Meanwhile, BRCA1 and PALB2 mutations had higher frequencies in TNBC. We identified five novel mutations.We demonstrate that LGRs are not an important molecular cause in non-hereditary cases of BC.27% of the carriers of mutations in BRCA1/2 did not fulfilled NCCN criteria and 82% of the mutations are not described in “Colombian Profile”. These findings demonstrate the particular genetic profile in an unselected population with breast cancer, and this highlights the importance of WES as a molecular diagnostic tool. We think that universal germline testing in cancer should be considered.
Baseline demographic and clinical characteristics
Demographic and clinical characteristics of patients with pathogenic and likely pathogenic mutationsVariableBRCA1 n (%, IC 95%)BRCA2 n (%, IC 95%)ATM n (%, IC 95%)PALB2 n (%, IC 95%)CHEK2 n (%, IC 95%)Median age37.4 (22.4 – 54.3)45.5 (36.2 – 54.7)53.1 (45.4 – 60.7)55.8 (27.9 – 83.5)NA*Age≤ 50 years4 (80, 11.1 – 99.2%)4 (66.7, 14.8 – 95.8%)8 (47.1, 23.5 – 80%)2 (50, 24.7 – 97.5)NA*&gt; 50 years1 (20, 0.7 – 88.9%)2 (33.3, 4 – 85%)9 (52.9, 28 – 76.5%)2 (50, 24.7 – 97.5)OverweightYes4 (80, 11 – 99-2%)(33.3, 4 – 85%)9 (52.9, 28 – 76.5%) 3 (75, 0.4 – 99.5%)NA*No1 (20, 0.8 – 88.9%)(66.7, 14.9 – 94.8%)8 (47, 23.5 – 80%)1 (25, 0.4 – 95.9%)Estrogen receptor(+)2 (0.9%, 0.2 – 3.5%)5 (2.2%, 0.9 – 5.3%)16 (7.1%, 4.4 – 11.3%)3 (1.3%, 0.4 – 4.1%)3 (1.3%, 0.4 – 4.1%)(-)3 (4.3%, 1.4 – 12.6%)1 (1.4%, 0.2 – 9.6%)1 (1.4%, 0,2 – 9.6%)1 (1.4%, 0.2 – 9.6%)1 (1.4%, 0.2 – 9.6%)Progesterone receptor(+)2 (0.9%, 0.2 – 3.5%)5 (2.2%, 0.9 – 5.3%)13 (6%, 3.7 – 10.5%)3 (1.3%, 0.4 – 4.1%)4 (1.9%, 0.7 – 5%)(-)3 (4.3%, 1.4 – 12.6%)1 (1.4%, 0,2 – 9.6%)4 (4%, 1.7 – 11.7%)1 (1.4%, 0.2 – 9.6%)0HER-2 3+Yes1 (1.3%, 0.2 – 8.5%)1 (1.3%, 0.2 – 8.5%)4 (5%, 1.9 – 12.7%)1 (1.3%, 0.2 – 8.5%)2 (2.5%, 0.6 – 9.6%)No4 (1.9%, 0.7 – 4.9%)5 (2.3, 0.1 – 5.5%)13 (6%, 3.5- 10.2%)3 (1.4%, 0.4 – 4.3%)2 (0.9%, 0.2 – 3.7%)ER/Pgr y HER-2 negativeYes2 (5.1, 1.3 – 18.7%)001 (2.5%, 0-3 – 16.5%)0No3 (1.2%, 0.4 – 3.6%)6 (2.3%, 1 – 5.1%)17 (6.6%, 4-2 – 10.4%)3 (1.2%, 0.4 – 3.6%)4 (1.6%, 0.6 – 4.1%)Ki67&lt;20%0 1 (16.7, 0.9 – 81%) 5 (29.4, 11.5 – 57.1)0NA*≥20%5 (100%)5 (83.3, 18.6 – 99%)12 (70.6, 42.8 – 88.5%)4 (100%)Median tumoral size mm (min-max)24 (19.6 – 47.8)21 (12.5 – 29.5)24.9 (19.6 – 30.3)27.6 (0 – 59)NA* Lymph nodes involvementYes1 (0.7%, 0.1 – 4.6%)2 (1.3%, 0.3 – 5.2%)10 (6.7%, 3.6 – 12.1%)3 (2%, 0.6 – 6.1%)4 (2.7%, 1 – 7%)1No4 (2.7%, 1 – 7%)4 (2.7%, 1 – 7%)7 (4.7%, 2.2 – 9.5%)1 (0.7%, 0.1 – 4.6%)0MetastasisYes00001 (9%, 1.1 – 46.6%)2No5 (1.9%, 0.8 – 4.5%)6 (2.3%, 1 – 5%)17 (5.7%, 3.5 – 9.3%)4 (1.5 – 0.5 – 4%)3 (1.1%, 0.4 – 3.5%)Clinical stage (AJCC)I2 (40, 3.7 – 91.9%)1 (16.7, 0.9 – 81.3%)4 (23.5, 81 – 51.8%)0NA*II2(40 3.7 – 91.9%)4 (66.7, 14.8 – 95.8%)7 (41.2, 19.3 – 67.3%)4 (100%)III1 (20, 0.7 – 88.9%)1 (16.7, 0.9 – 81.3%)6 (23-3, 15.2 – 62.3%)0IV0000Family history for cancerYes4 (80, 11.1 – 99.2%)5 (83.3, 9 – 81.4%)13 (76.5 – 48.2 – 91.9%)2 (50, 2- 97.5%)NA*No1 (20, 0.7 – 88-9)1 (16.7, 0.9 – 81.4%)4 (23, 8 – 51.8%)2 (50, 2- 97.5%)NCCN criteriaYes4 (2.4%, 0.9 – 6.3%)4 (2.4%, 0.9 – 6.3%)NA*NA*NA*No1 (0.8%, 0.1 – 5.9%)2 (1.7%, 0.4 – 6.6%)Colombian profileYes1 (50%, 19 – 98%)31(50%, 19 – 98%)3NA*NA*NA*No4 (13.5%, 5 – 35.5%)5 (17%, 7 – 40%)
Citation Format: Diana Carolina Sierra-Díaz, Adrien Morel, Dora Janeth Fonseca, Nora Contreras, Mariana Angulo-Aguado, Valentina Balaguera, Kevin Llinás-Caballero, Isabel Munevar, Mariana Borras, Mauricio Lema, Henry Idrobo, Daniela Trujillo, Norma Serrano, Ana Isabel Orduz, Diego Lopera, Jaime Gonzalez, Gustavo Rojas, Paula Londoño, Ray Manneh, Catalina Quintero, Paul Laissue, Rodrigo Cabrera, Carlos M Restrepo, William Mantilla. Genetic profile of germline mutations in unselected women with breast cancer in a Colombian population [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-07-05.