Dataset Information

Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

ABSTRACT: FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe. In contrast, p.Gly1906Alafs*12 was the most common PTV in Southern Europe with decreasing frequencies in Central and Northern Europe. We verified that p.Arg658* was prevalent in Central Europe and had highest frequencies in Eastern Europe. We also confirmed that the fourth most common PTV, p.Gln498Thrfs*7, might be a founder variant from Lithuania. Based on the frequency distribution of the carriers of rare PTVs, we showed that the FANCM PTVs spectra in Southwestern and Central Europe were much more heterogeneous than those from Northeastern Europe. These findings will inform the development of more efficient FANCM genetic testing strategies for breast cancer cases from specific European populations.

SUBMITTER: Figlioli G

PROVIDER: S-EPMC10340689 | biostudies-literature | 2023 Jun

REPOSITORIES: biostudies-literature

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Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

Figlioli Gisella G Billaud Amandine A Wang Qin Q Bolla Manjeet K MK Dennis Joe J Lush Michael M Kvist Anders A Adank Muriel A MA Ahearn Thomas U TU Antonenkova Natalia N NN Auvinen Päivi P Behrens Sabine S Bermisheva Marina M Bogdanova Natalia V NV Bojesen Stig E SE Bonanni Bernardo B Brüning Thomas T Camp Nicola J NJ Campbell Archie A Castelao Jose E JE Cessna Melissa H MH Nbcs Collaborators Czene Kamila K Devilee Peter P Dörk Thilo T Eriksson Mikael M Fasching Peter A PA Flyger Henrik H Gabrielson Marike M Gago-Dominguez Manuela M García-Closas Montserrat M Glendon Gord G Gómez Garcia Encarna B EB González-Neira Anna A Grassmann Felix F Guénel Pascal P Hahnen Eric E Hamann Ute U Hillemanns Peter P Hooning Maartje J MJ Hoppe Reiner R Howell Anthony A Humphreys Keith K kConFab Investigators Jakubowska Anna A Khusnutdinova Elza K EK Kristensen Vessela N VN Lindblom Annika A Loizidou Maria A MA Lubiński Jan J Mannermaa Arto A Maurer Tabea T Mavroudis Dimitrios D Newman William G WG Obi Nadia N Panayiotidis Mihalis I MI Radice Paolo P Rashid Muhammad U MU Rhenius Valerie V Ruebner Matthias M Saloustros Emmanouil E Sawyer Elinor J EJ Schmidt Marjanka K MK Schmutzler Rita K RK Shah Mitul M Southey Melissa C MC Tomlinson Ian I Truong Thérèse T van Veen Elke M EM Wendt Camilla C Yang Xiaohong R XR Michailidou Kyriaki K Dunning Alison M AM Pharoah Paul D P PDP Easton Douglas F DF Andrulis Irene L IL Evans D Gareth DG Hollestelle Antoinette A Chang-Claude Jenny J Milne Roger L RL Peterlongo Paolo P

Cancers 20230623 13

FANCM germline protein truncating variants (PTVs) are moderate-risk factors for ER-negative breast cancer. We previously described the spectrum of FANCM PTVs in 114 European breast cancer cases. In the present, larger cohort, we report the spectrum and frequency of four common and 62 rare FANCM PTVs found in 274 carriers detected among 44,803 breast cancer cases. We confirmed that p.Gln1701* was the most common PTV in Northern Europe with lower frequencies in Southern Europe ...[more]

PMID: 37444426

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Project description:BackgroundInterpreting genetic variants remains a challenge in prostate cancer (PCa). Although many annotation tools are available for prioritizing causal variants, the clinical relevance of these variants is rarely studied.MethodsWe collected a cohort study that included 274 PCa patients from June 2017 to December 2020 and sequenced 19 DNA damage repair (DDR) genes in these patients and explored the clinical consequence of these different approaches. We also examined all-cause and PCa-specific survival in DDR gene mutation carriers compared to non-carriers after androgen receptor (AR)-directed therapy.ResultsWe identified 13 variants from 19 DDR genes in a total of 14 (5.1%) patients who had at least one presumed pathogenic mutation using different annotation methods. Four variants were annotated as pathogenic, 11 variants were predicted as protein-truncating variants (PTVs), four variants received proxy-deleterious (Combined Annotation-Dependent Depletion scores of > 30), and only one variant was identified as a pathogenic variant or as having a functional effect by all three methods. PCa patients with PTVs were significantly associated with early onset, high cancer stage, and a worse response to AR-directed treatment. However, patients carrying a proxy-deleterious variant were only associated with a higher T (tumor) stage and N (node) stage than those without such a variant, but not associated with other clinical characteristics. In patients treated with AR-directed therapy, patients with a PTV showed an increased risk of all-cause death (adjusted hazard ratio (aHR) = 3.51, 95% confidence interval (CI): 1.06 ~ 11.56) and PCa-specific death (aHR = 4.49, 95% CI: 1.87 ~ 10.77) compared to non-PTV carriers after adjustment. We were unable to examine gene-specific risks due to the small number of patients.ConclusionsPTVs may assist in guiding treatment and early screening in PCa, while population-specific data for pathogenic variants are still being amassed.

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Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

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Spectrum and Frequency of Germline <i>FANCM</i> Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

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Spectrum and Frequency of Germline FANCM Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

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Spectrum and Frequency of Germline &lt;i&gt;FANCM&lt;/i&gt; Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.

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OmicsDI is part of the ELIXIR infrastructure

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Spectrum and Frequency of Germline <i>FANCM</i> Protein-Truncating Variants in 44,803 European Female Breast Cancer Cases.