Background Hereditary cancers are the consequence of inherited genetic variants that increase the risk of cancer development. The susceptibility to hereditary cancers can be increased by a combination of variable genes with different penetrance, such as BRCA1/2, which are common genes involved in several types of familial cancers. The current study aims to analyze the genetic outcomes of genes linked to hereditary cancer, focusing on identifying pathogenic variants and their allele frequencies to improve risk assessment, genetic counseling, and targeted screening efforts in hereditary cancer management.
Method A group of 298 patients (278 females and 20 males) were chosen for the comprehensive hereditary cancer panel based on their clinical presentation, family history of cancer, and eligibility criteria for hereditary cancer testing. The panel included a custom target enrichment of 52 genes linked to an inherited predisposition to cancer. All therapeutically relevant observations were verified by Sanger sequencing.
Result Among the 298 individuals tested, 78.52 % tested negative for hereditary cancer-associated genes, while 21.48 % tested positive, with a higher proportion amongst females (89.06 %). A majority of those testing positive for hereditary cancer-associated pathogenic variants had a family history of cancer (71.88 %). Consanguinity was absent in most cases (81.90 %). Breast cancer was the most prevalent cancer (246 cases). Genes detected with L/LP variants include BRCA2, BRCA1, ATM, MSH2, MUTYH, and PALB2, with other genes detected at lower frequencies. Notably, BRCA1:c.1444_1447delATAA>A, p.(Ile482fs) variant occurred at the most high frequency (57 %).
Conclusion This study identified key pathogenic variants in hereditary cancer genes, with BRCA1 and BRCA2 mutations being the most prevalent. The findings reinforce the strong association between family history and hereditary cancer risk while indicating that consanguinity plays a limited role. This highlights the importance of comprehensive genetic screening and personalized counseling to improve hereditary cancer risk assessment and early detection strategies.
Authors contribution
Conceived and designed the analysis: P.O., O.D., M.S.B.A., K.D.E., I.O.O., M.C.E; Collected the data: M.S.B.A., K.D.E., I.O.O., M.C.E; Contributed data or analysis tools: M.S.B.A., K.D.E., I.O.O., M.C.E; Performed the analysis: M.C.E.; Wrote the paper: M.S.B.A., P.O., O.D., K.D.E., I.O.O., M.C.E; revised the paper: M.S.B.A., P.O., O.D., K.D.E., I.O.O., M.C.E; supervised the project: M.C.E.
Funding
There is no funding for this study.
Data availability
The data is available upon request.
Conflict of Interest
The authors do not have any conflict of interest to declare.
| [1] |
H. Sung, J. Ferlay, R.L. Siegel, M. Laversanne, I. Soerjomataram, A. Jemal, F. Bray, Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 Countries, CA: A Cancer J. Clin. 71 (3) (2021) 209-249.
|
| [2] |
S. Hodgson, Mechanisms of inherited cancer susceptibility, J. Zhejiang Univ. Sci. B 9 (1) (2008) 1-4.
|
| [3] |
N. Rahman, Realizing the promise of cancer predisposition genes, Nature 505 (7483) (2014) 302-308.
|
| [4] |
C.M. Phelan, K.B. Kuchenbaecker, J.P. Tyrer, S.P. Kar, K. Lawrenson, S.J. Winham, C.A. Haiman, Identification of 12 new susceptibility loci for different histotypes of epithelial ovarian cancer, Nat. Genet. 49 (5) (2017) 680-691.
|
| [5] |
E.Y. Lee, W.J. Muller, Oncogenes and tumor suppressor genes, Cold Spring Harb. Perspect. Biol. 2 (10) (2010) a003236.
|
| [6] |
L. Yin, J.J. Duan, X.W. Bian, S.C. Yu, Triple-negative breast cancer molecular subtyping and treatment progress, Breast Cancer Res. 22 (2020) 1-13.
|
| [7] |
X. Yang, G. Leslie, A. Doroszuk, S. Schneider, J. Allen, B. Decker, M. Tischkowitz, Cancer risks associated with germline PALB2 pathogenic variants: an international study of 524 families, J. Clin. Oncol. 38 (7) (2020) 674-685.
|
| [8] |
E. Castro, C. Goh, D. Olmos, E. Saunders, D. Leongamornlert, M. Tymrakiewicz, R. Eeles, Germline BRCA mutations are associated with higher risk of nodal involvement, distant metastasis, and poor survival outcomes in prostate cancer, J. Clin. Oncol. 31 (14) (2013) 1748-1757.
|
| [9] |
T.R. Rebbeck, T.M. Friebel, E. Friedman, U. Hamann, D. Huo, A. Kwong, A. Meindl, Mutational spectrum in a worldwide study of 29,700 families with BRCA1 or BRCA2 mutations, Hum. Mutat. 39 (5) (2018) 593-620.
|
| [10] |
F.J. Couch, H. Shimelis, C. Hu, S.N. Hart, E.C. Polley, J. Na, J.S. Dolinsky, Associations between cancer predisposition testing panel genes and breast cancer, JAMA Oncol. 3 (9) (2017) 1190-1196.
|
| [11] |
C.C. Pritchard, J. Mateo, M.F. Walsh, N. De Sarkar, W. Abida, H. Beltran, P.S. Nelson, Inherited DNA-repair gene mutations in men with metastatic prostate cancer, N. Engl. J. Med. 375 (5) (2016) 443-453.
|
| [12] |
A. Germani, S. Petrucci, L. De Marchis, F. Libi, C. Savio, C. Amanti, M. Piane, Beyond BRCA1 and BRCA2: deleterious variants in DNA repair pathway genes in Italian families with breast/ovarian and pancreatic cancers, J. Clin. Med. 9 (9) (2020) 3003.
|
| [13] |
H. Satam, K. Joshi, U. Mangrolia, S. Waghoo, G. Zaidi, S. Rawool, S.K. Malonia, Next-generation sequencing technology: current trends and advancements, Biology 12 (7) (2023) 997.
|
| [14] |
G.N. Tsaousis, E. Papadopoulou, A. Apessos, K. Agiannitopoulos, G. Pepe, S. Kampouri, G. Nasioulas, Analysis of hereditary cancer syndromes by using a panel of genes: novel and multiple pathogenic mutations, BMC Cancer 19 (2019) 1-19.
|
| [15] |
S. Richards, N. Aziz, S. Bale, D. Bick, S. Das, J. Gastier-Foster, H.L. Rehm, Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American college of medical genetics and genomics and the association for molecular pathology, Genet. Med. 17 (5) (2015) 405-423.
|
| [16] |
D.H. Brewster, J.W. Coebergh, H.H. Storm, Population-based cancer registries: the invisible key to cancer control, Lancet Oncol. 6 (4) (2005) 193-195.
|
| [17] |
Caliebe A., Tekola‐Ayele F., Darst B.F., Wang X., Song Y.E., Gui J., … & I.G.E.S. ELSI Committee. (2022). Including diverse and admixed populations in genetic epidemiology research. Genetic epidemiology, 46(7), 347-371.
|
| [18] |
Raby B., & Hartzfeld D. (Kohlmann, W., 2019). Genetic counseling: Family history interpretation and risk assessment.
|
| [19] |
E.D.F. Manna, D. Serrano, L. Cazzaniga, S. Mannucci, C. Zanzottera, F. Fava, M. Lazzeroni, Hereditary Breast cancer: comprehensive risk assessment and prevention strategies, Genes 16 (1) (2025) 82.
|
| [20] |
F.S. AlHarthi, A. Qari, A. Edress, M. Abedalthagafi, Familial/inherited cancer syndrome: a focus on the highly consanguineous Arab population, NPJ Genom. Med. 5 (1) (2020) 3.
|
| [21] |
S.A. Jeon, J.L. Park, S.J. Park, J.H. Kim, S.H. Goh, J.Y. Han, S.Y. Kim, Comparison between MGI and Illumina sequencing platforms for whole genome sequencing, Genes Genom. 43 (2021) 713-724.
|
| [22] |
Zheng-Bradley X., Streeter I., Fairley S., Richardson D., Clarke L., Flicek P., &1000 Genomes Project Consortium (2017). Alignment of 1000 Genomes Project reads to reference assembly GRCh38. GigaScience, 6(7), 1-8. https://doi.org/10.1093/gigascience/gix038.
|
| [23] |
B.M. Crossley, J. Bai, A. Glaser, R. Maes, E. Porter, M.L. Killian, K. Toohey-Kurth, Guidelines for sanger sequencing and molecular assay monitoring, J. Vet. Diagn. Investig. 32 (6) (2020) 767-775.
|
| [24] |
G. Povysil, A. Tzika, J. Vogt, V. Haunschmid, L. Messiaen, J. Zschocke, G. Klambauer, S. Hochreiter, K. Wimmer, Panelcn. MOPS: copy-number detection in targeted NGS panel data for clinical diagnostics, Hum. Mutat. 38 (7) (2017 Jul)889-897 doi: 10.1002/humu.23237. Epub 2017 May 16. PMID: 28449315; PMCID: PMC5518446.
|
| [25] |
M.A. Unger, K.L. Nathanson, K. Calzone, D. Antin-Ozerkis, H.A. Shih, A.M. Martin, G.M. Lenoir, S. Mazoyer, B.L. Weber, Screening for genomic rearrangements in families with breast and ovarian cancer identifies BRCA1 mutations previously missed by conformation-sensitive gel electrophoresis or sequencing, Am. J. Hum. Genet. 67 (4) (2000) 841-850, https://doi.org/10.1086/303076.
|
| [26] |
V. Valentini, A. Bucalo, G. Conti, L. Celli, V. Porzio, C. Capalbo, L. Ottini, Gender-specific genetic predisposition to breast cancer: BRCA genes and beyond, Cancers 16 (3) (2024) 579.
|
| [27] |
M.H. Belanger, L. Dolman, S.L. Arcand, Z. Shen, G. Chong, A.M. Mes-Masson, P.N. Tonin, A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population, J. ovarian Res. 8 (2015) 1-10.
|
| [28] |
K.K. Childers, M. Maggard-Gibbons, J. Macinko, C.P. Childers, National distribution of cancer genetic testing in the United States: evidence for a gender disparity in hereditary breast and ovarian cancer, JAMA Oncol. 4 (6) (2018) 876-879.
|
| [29] |
P. Rofes, C. Castillo-Manzano, M. Menéndez, Á. Teulé, S. Iglesias, E. Munté, C. Lázaro, TP 53 germline testing and hereditary cancer: how somatic events and clinical criteria affect variant detection rate, Genome Med. 17 (1) (2025) 3.
|
| [30] |
M.A. Trujillo-Rojas, M.D.L.L. Ayala-Madrigal, M. Gutiérrez-Angulo, A. González-Mercado, J.M. Moreno-Ortiz, Diagnosis of patients with lynch syndrome lacking the Amsterdam II or bethesda criteria, Hered. Cancer Clin. Pract. 21 (1) (2023) 21.
|
| [31] |
S.M. Fung, R.R. Wu, R.A. Myers, J. Goh, G.S. Ginsburg, D. Matchar, J. Ngeow, Clinical implementation of an oncology‐specific family health history risk assessment tool, Hered. Cancer Clin. Pract. 19 (2021) 1-12.
|
| [32] |
S. Aslam, Shabana, M. Ahmed, Implications of ACMG guidelines to identify high-risk acute lymphoblastic leukemia patients with hereditary cancer susceptibility syndromes (HCSS) in a highly consanguineous population, BMC Pediatr. 21 (1) (2021) 282.
|
| [33] |
L. Castéra, S. Krieger, A. Rousselin, A. Legros, J.J. Baumann, O. Bruet, D. Vaur, Next-generation sequencing for the diagnosis of hereditary breast and ovarian cancer using genomic capture targeting multiple candidate genes, Eur. J. Hum. Genet. 22 (11) (2014) 1305-1313.
|
| [34] |
V. Rocca, E. Lo Feudo, F. Dinatolo, S.M. Lavano, A. Bilotta, R. Amato, R. Iuliano, Germline variant spectrum in southern Italian high-risk hereditary breast cancer patients: insights from multi-gene panel testing, Curr. Issues Mol. Biol. 46 (11) (2024) 13003-13020.
|
| [35] |
J. Cheng, J. Peng, J. Fu, M.A. Khan, P. Tan, C. Wei, J. Fu, Identification of a novel germline BRCA2 variant in a Chinese breast cancer family, J. Cell. Mol. Med. 24 (2) (2020) 1676-1683.
|
| [36] |
A.K. Siraj, R. Bu, K. Iqbal, N. Siraj, W. Al‐Haqawi, I.A. Al‐Badawi, K.S. Al‐Kuraya, Prevalence, spectrum, and founder effect of BRCA1 and BRCA2 mutations in epithelial ovarian cancer from the Middle East, Hum. Mutat. 40 (6) (2019) 729-733.
|
| [37] |
Y. Ghazwani, M. AlBalwi, I. Al-Abdulkareem, M. Al-Dress, T. Alharbi, R. Alsudairy, A. Alsultan, Clinical characteristics and genetic subtypes of fanconi anemia in Saudi patients, Cancer Genet. 209 (4) (2016) 171-176.
|
| [38] |
S. Di Rado, R. Giansante, M. Cicirelli, L. Pilenzi, A. Dell’Elice, F. Anaclerio, I. Antonucci, Detection of germline mutations in a cohort of250 relatives of mutation carriers in multigene panel: impact of pathogenic variants in other genes beyond BRCA1/2, Cancers 15 (24) (2023) 5730.
|
| [39] |
E. Machackova, L. Foretova, M. Lukesova, P. Vasickova, M. Navratilova, I. Coene, K. Claes, Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer, BMC Cancer 8 (2008) 1-11.
|
| [40] |
Y. Laitman, T.M. Friebel, D. Yannoukakos, F. Fostira, I. Konstantopoulou, G. Figlioli, E. Friedman, The spectrum of BRCA1 and BRCA2 pathogenic sequence variants in Middle Eastern, North African, and South European countries, Hum. Mutat. 40 (11) (2019) e1-e23.
|
| [41] |
Chapla A., John A., Singh A., Yadav P., Joel A., Thumaty D., … & Titus R. (2023). BRCA1 and BRCA2 gene mutation spectrum and high frequency of BRCA 1 185delAG among breast and ovarian cancer patients from Southern India.
|
| [42] |
T.P. McVeigh, F. Lalloo, K.J. Monahan, A. Latchford, M. Durkie, R. Mein, H. Hanson, Carrier testing for partners of MUTYH variant carriers: UK cancer genetics group recommendations, J. Med. Genet. (2024).
|
| [43] |
M.T. Ricci, S. Miccoli, D. Turchetti, D. Bondavalli, A. Viel, M. Quaia, L. Varesco, Type and frequency of MUTYH variants in Italian patients with suspected MAP: a retrospective multicenter study, J. Hum. Genet. 62 (2) (2017) 309-315.
|
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