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Germline; Tumour-only sequencing Línia germinal; Seqüenciació només de tumors Línea germinal; Secuenciación solo de tumors 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

Tumor-only sequencing, implemented for the identification of somatic variants, is oftentimes used for the detection of actionable germline variants. We sought to determine whether tumor-only sequencing assays are suitable for detection of actionable germline variants, given their importance for the delivery of targeted therapies and risk-reducing measures.The detection of germline variants affecting moderate- and high-penetrance cancer susceptibility genes (CSGs) by tumor-only sequencing was compared to clinical germline testing in 21 333 cancer patients who underwent tumor and germline testing using the Food and Drug Administration (FDA)-authorized Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Targets (MSK-IMPACT) assay. Seven homologous recombination deficiency (HRD), two DNA damage response (DDR) and four mismatch repair (MMR) genes, as well as NF1, RB1 and TP53 were included in the analysis. FDA-authorized and New York State Department of Health-approved sequencing methods for germline, tumor/normal and tumor-only sequencing assays and analytical pipelines were employed.In patients who underwent tumor and germline sequencing, as compared to clinical genetic testing, tumor-only sequencing failed to detect 10.5% of clinically actionable pathogenic germline variants in CSGs, including 18.8%, 12.8% and 7.3% of germline variants in MMR, DDR and HRD genes, respectively. The sensitivity for detection of pathogenic germline variants by tumor-only sequencing was 89.5%. Whilst the vast majority of pathogenic germline exonic single-nucleotide variants (SNVs) and small indels were detected by tumor-only sequencing, large percentages of germline copy number variants, intronic variants and repetitive element insertions were not detected.Tumor-only sequencing is adequate for the detection of clinically actionable germline variants, particularly for SNVs and small indels; however, a small subset of alterations affecting HRD, DDR and MMR genes may not be detected optimally. Therefore, for high-risk patients with negative tumor-only sequencing results, clinical genetic testing could be considered given the impact of these variants on therapy and genetic counseling.

Introduction: Checkpoint kinase 2 (CHEK2) is a tumor suppressor gene, which regulates cell cycle in response to DNA damage response. Selected CHEK2 germline mutations have been shown to confer an increased risk of breast cancer development. Multiple founder mutations in CHEK2 have been identified, and meta analyses have shown that CHEK2 truncating variants confer a higher breast cancer risk than missense variants. Here, we assessed the phenotype and repertoire of genetic alterations of breast cancers from 33 patients with CHEK2 pathogenic germline variants. Materials and methods: We performed targeted capture massively parallel sequencing (≥410 genes) of tumor and normal samples from 13 patients with CHEK2 pathogenic germline variants, and retrieved whole exome sequencing (WES) data (BAM files) of tumor and normal samples from 20 patients with CHEK2 germline pathogenic variants included in the TCGA breast cancer study. In addition, we retrieved WES data of BRCA1, BRCA2 and ATM associated breast cancers from TCGA and Weigelt et al. (JNCI 2018). Somatic mutations, copy number alterations, mutational signatures and large-scale transitions (LSTs) were defined using state-of-the-art bioinformatics algorithms. Results: Of the 33 CHEK2-associated breast cancers included in this study, 21 had missense and 12 had loss-of-function (LoF) germline mutations, and 81% were ER-positive and 12% HER2-positive. CHEK2-associated breast cancers statistically significantly less frequently displayed an ER-negative/HER2-negative phenotype (0%) than BRCA1- (80%) or BRCA2-associated (33%) breast cancers (BRCA1, p Conclusion:CHEK2-associated breast cancers are phenotypically and genetically distinct from BRCA1- and BRCA2-associated breast cancers, but similar to ATM-associated breast cancers. Akin to ATM-associated breast cancers, CHEK2-associated breast cancers are preferentially ER-positive, lack genomics features consistent with defective HR, and have a repertoire of somatic genetic alterations similar to those of non-BRCA1/2 ER-positive breast cancers. Our results suggest that either CHEK2 germline mutations contribute to an increased risk of breast cancer independently of the HR DNA repair defects or that the mutational signatures caused by CHEK2 pathogenic germline mutations differ from those caused by pathogenic germline mutations affecting bona fide HR-related genes (e.g. BRCA1, BRCA2 and PALB2). Citation Format: Kumar R, Pei X, Selenica P, Wen HY, Powell S, Robson M, Riaz N, Reis-Filho JS, Weigelt B, Mandelker D. The landscape of somatic genetic alterations in breast cancers from CHEK2 germline mutation carriers [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P4-04-01.