dc.contributor.author | Kuzbari, Z | |
dc.contributor.author | Bandlamudi, C | |
dc.contributor.author | Loveday, C | |
dc.contributor.author | Garrett, A | |
dc.contributor.author | Mehine, M | |
dc.contributor.author | George, A | |
dc.contributor.author | Hanson, H | |
dc.contributor.author | Snape, K | |
dc.contributor.author | Kulkarni, A | |
dc.contributor.author | Allen, S | |
dc.contributor.author | Jezdic, S | |
dc.contributor.author | Ferrandino, R | |
dc.contributor.author | Westphalen, CB | |
dc.contributor.author | Castro, E | |
dc.contributor.author | Rodon, J | |
dc.contributor.author | Mateo, J | |
dc.contributor.author | Burghel, GJ | |
dc.contributor.author | Berger, MF | |
dc.contributor.author | Mandelker, D | |
dc.contributor.author | Turnbull, C | |
dc.coverage.spatial | England | |
dc.date.accessioned | 2023-03-06T10:49:44Z | |
dc.date.available | 2023-03-06T10:49:44Z | |
dc.date.issued | 2023-03-01 | |
dc.identifier | S0923-7534(22)04771-8 | |
dc.identifier.citation | Annals of Oncology, 2023, 34 (3), pp. 215 - 227 | |
dc.identifier.issn | 0923-7534 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/5708 | |
dc.identifier.eissn | 1569-8041 | |
dc.identifier.eissn | 1569-8041 | |
dc.identifier.doi | 10.1016/j.annonc.2022.12.003 | |
dc.description.abstract | BACKGROUND: The European Society for Medical Oncology Precision Medicine Working Group (ESMO PMWG) was reconvened to update its 2018/19 recommendations on follow-up of putative germline variants detected on tumour-only sequencing, which were based on an analysis of 17 152 cancers. METHODS: We analysed an expanded dataset including 49 264 paired tumour-normal samples. We applied filters to tumour-detected variants based on variant allele frequency, predicted pathogenicity and population variant frequency. For 58 cancer-susceptibility genes, we then examined the proportion of filtered tumour-detected variants of true germline origin [germline conversion rate (GCR)]. We conducted subanalyses based on the age of cancer diagnosis, specific tumour types and 'on-tumour' status (established tumour-gene association). RESULTS: Analysis of 45 472 nonhypermutated solid malignancy tumour samples yielded 21 351 filtered tumour-detected variants of which 3515 were of true germline origin. 3.1% of true germline pathogenic variants were absent from the filtered tumour-detected variants. For genes such as BRCA1, BRCA2 and PALB2, the GCR in filtered tumour-detected variants was >80%; conversely for TP53, APC and STK11 this GCR was <2%. CONCLUSION: Strategic germline-focused analysis can prioritise a subset of tumour-detected variants for which germline follow-up will produce the highest yield of most actionable true germline variants. We present updated recommendations around germline follow-up of tumour-only sequencing including (i) revision to 5% for the minimum per-gene GCR, (ii) inclusion of actionable intermediate penetrance genes ATM and CHEK2, (iii) definition of a set of seven 'most actionable' cancer-susceptibility genes (BRCA1, BRCA2, PALB2, MLH1, MSH2, MSH6 and RET) in which germline follow-up is recommended regardless of tumour type. | |
dc.format | Print-Electronic | |
dc.format.extent | 215 - 227 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | ELSEVIER | |
dc.relation.ispartof | Annals of Oncology | |
dc.rights.uri | https://creativecommons.org/licenses/by-nc-nd/4.0/ | |
dc.subject | cancer-susceptibility genes | |
dc.subject | germline | |
dc.subject | germline conversion rate | |
dc.subject | tumour-only sequencing | |
dc.subject | variants | |
dc.subject | Humans | |
dc.subject | Precision Medicine | |
dc.subject | Neoplasms | |
dc.subject | Gene Frequency | |
dc.subject | Germ-Line Mutation | |
dc.subject | Genes, BRCA2 | |
dc.subject | Genetic Predisposition to Disease | |
dc.title | Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2022-12-11 | |
dc.date.updated | 2023-03-06T10:49:20Z | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1016/j.annonc.2022.12.003 | |
rioxxterms.licenseref.startdate | 2023-03-01 | |
rioxxterms.type | Journal Article/Review | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/36529447 | |
pubs.issue | 3 | |
pubs.organisational-group | /ICR | |
pubs.publication-status | Published | |
pubs.publisher-url | http://dx.doi.org/10.1016/j.annonc.2022.12.003 | |
pubs.volume | 34 | |
icr.researchteam | Translational Genetics | |
dc.contributor.icrauthor | Turnbull, Clare | |
icr.provenance | Deposited by Mr Arek Surman on 2023-03-06. Deposit type is initial. No. of files: 1. Files: 1-s2.0-S0923753422047718-main.pdf | |