Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations Guidelines

  

Authors:	Kuzbari, Z.; Bandlamudi, C.; Loveday, C.; Garrett, A.; Mehine, M.; George, A.; Hanson, H.; Snape, K.; Kulkarni, A.; Allen, S.; Jezdic, S.; Ferrandino, R.; Westphalen, C. B.; Castro, E.; Rodon, J.; Mateo, J.; Burghel, G. J.; Berger, M. F.; Mandelker, D.; Turnbull, C.
Title:	Germline-focused analysis of tumour-detected variants in 49,264 cancer patients: ESMO Precision Medicine Working Group recommendations
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. © 2022 The Authors
Keywords:	germline; variants; cancer-susceptibility genes; germline conversion rate; tumour-only sequencing
Journal Title:	Annals of Oncology
Volume:	34
Issue:	3
ISSN:	0923-7534
Publisher:	Oxford University Press
Date Published:	2023-03-01
Start Page:	215
End Page:	227
Language:	English
DOI:	10.1016/j.annonc.2022.12.003
PUBMED:	36529447
PROVIDER:	scopus
DOI/URL:	https://www.scopus.com/inward/record.uri?eid=2-s2.0-85146581639&doi=10.1016%2fj.annonc.2022.12.003&partnerID=40&md5=d8e45b743a9146c22165d95adbeb447e
Notes:	Article -- Export Date: 1 March 2023 -- Source: Scopus

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