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Germline findings in patients with advanced malignancies screened with paired blood–tumour testing for personalised treatment approaches

Published:December 07, 2022DOI:https://doi.org/10.1016/j.ejca.2022.11.003

      Highlights

      • Significant amount of relevant germline variants is detected by blood-tumour testing.
      • Carriers do not always fulfil clinical criteria for cancer predisposition.
      • Blood–Tumour testing identifies novel links between cancer predisposition genes and cancer types.
      • Family-specific screening strategies are required when cancer predisposition genes are found in atypical tumours.

      Abstract

      Background

      Sequencing of tumour tissue with comprehensive gene panels is increasingly used to guide treatment in precision oncology. Analysis of tumour–normal pairs allows in contrast to tumour-only assessment direct discrimination between somatic and germline alterations, which might have important implications not only for the patients but also their families.

      Methods

      We performed tumour normal sequencing with a large gene panel in 1048 patients with advanced cancer to support treatment decision. Sequencing results were correlated with clinical and family data.

      Results

      We identified 156 likely pathogenic or pathogenic (LP/P) germline variants in cancer predisposition genes (CPGs) in 144 cases (13.7%). Of all patients, 8.8% had a LP/P variant in autosomal-dominant cancer predisposition genes (AD-CPGs), most of them being genes with high or moderate penetrance (ATM, BRCA2, CHEK2 and BRCA1). In 48 cases, the P/LP variant matched the expected tumour spectrum. A second variant in tumour tissue was found in 31 patients with AD-CPG variants. Low frequency mutations in either TP53, ATM or DNMT3A in the normal sample indicated clonal haematopoiesis in five cases.

      Conclusions

      Tumour–normal testing for personalised treatment identifies germline LP/P variants in a relevant proportion of patients with cancer. The majority of them would not have been referred to genetic counselling based on family history. Indirect functional readouts of tumour–normal sequencing can provide novel links between CPGs and unexpected cancers. The interpretation of increasingly complex datasets in precision oncology is challenging and concepts of interdisciplinary personalised cancer prevention are needed to support patients and their families.

      Keywords

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      References

        • Yam C.
        • Ma B.B.Y.
        • Yap T.A.
        Global implementation of precision oncology.
        JCO Precis Oncol. 2021; 5
        • Zehir A.
        • Benayed R.
        • Shah R.H.
        • Syed A.
        • Middha S.
        • Kim H.R.
        • et al.
        Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients.
        Nat Med. 2017; 23: 703-713
        • Tsimberidou A.M.
        • Hong D.S.
        • Ye Y.
        • Cartwright C.
        • Wheler J.J.
        • Falchook G.S.
        • et al.
        Initiative for molecular profiling and advanced cancer therapy (IMPACT): an MD Anderson precision medicine study.
        JCO Precis Oncol. 2017; 2017
        • Fiala E.M.
        • Jayakumaran G.
        • Mauguen A.
        • Kennedy J.A.
        • Bouvier N.
        • Kemel Y.
        • et al.
        Prospective pan-cancer germline testing using MSK-IMPACT informs clinical translation in 751 patients with pediatric solid tumors.
        Nat Cancer. 2021; 2: 357-365
        • Le Tourneau C.
        • Delord J.P.
        • Goncalves A.
        • Gavoille C.
        • Dubot C.
        • Isambert N.
        • et al.
        Molecularly targeted therapy based on tumour molecular profiling versus conventional therapy for advanced cancer (SHIVA): a multicentre, open-label, proof-of-concept, randomised, controlled phase 2 trial.
        Lancet Oncol. 2015; 16: 1324-1334
        • Massard C.
        • Michiels S.
        • Ferte C.
        • Le Deley M.C.
        • Lacroix L.
        • Hollebecque A.
        • et al.
        High-throughput genomics and clinical outcome in hard-to-treat advanced cancers: results of the MOSCATO 01 trial.
        Cancer Discov. 2017; 7: 586-595
        • Mohrmann L.
        • Werner M.
        • Oles M.
        • Mock A.
        • Uhrig S.
        • Jahn A.
        • et al.
        Comprehensive genomic and epigenomic analysis in cancer of unknown primary guides molecularly-informed therapies despite heterogeneity.
        Nat Commun. 2022; 13: 4485
        • Huang K.L.
        • Mashl R.J.
        • Wu Y.
        • Ritter D.I.
        • Wang J.
        • Oh C.
        • et al.
        Pathogenic germline variants in 10,389 adult cancers.
        Cell. 2018; 173: 355-370 e14
        • Schrader K.A.
        • Cheng D.T.
        • Joseph V.
        • Prasad M.
        • Walsh M.
        • Zehir A.
        • et al.
        Germline variants in targeted tumor sequencing using matched normal DNA.
        JAMA Oncol. 2016; 2: 104-111
        • Grobner S.N.
        • Worst B.C.
        • Weischenfeldt J.
        • Buchhalter I.
        • Kleinheinz K.
        • Rudneva V.A.
        • et al.
        The landscape of genomic alterations across childhood cancers.
        Nature. 2018; 555: 321-327
        • Mandelker D.
        • Zhang L.
        • Kemel Y.
        • Stadler Z.K.
        • Joseph V.
        • Zehir A.
        • et al.
        Mutation detection in patients with advanced cancer by universal sequencing of cancer-related genes in tumor and normal DNA vs guideline-based germline testing.
        JAMA. 2017; 318: 825-835
        • Zhang J.
        • Walsh M.F.
        • Wu G.
        • Edmonson M.N.
        • Gruber T.A.
        • Easton J.
        • et al.
        Germline mutations in predisposition genes in pediatric cancer.
        N Engl J Med. 2015; 373: 2336-2346
        • Hampel H.
        • Bennett R.L.
        • Buchanan A.
        • Pearlman R.
        • Wiesner G.L.
        • Guideline Development Group ACoMG
        A practice guideline from the American College of medical genetics and genomics and the national society of genetic counselors: referral indications for cancer predisposition assessment.
        Genet Med. 2015; 17: 70-87
        • Mose L.E.
        • Perou C.M.
        • Parker J.S.
        Improved indel detection in DNA and RNA via realignment with ABRA2.
        Bioinformatics. 2019; 35: 2966-2973
        • Sturm M.
        • Schroeder C.
        • Bauer P.
        SeqPurge: highly-sensitive adapter trimming for paired-end NGS data.
        BMC Bioinf. 2016; 17
        • Vasimuddin M.
        • Misra S.
        • Li H.
        • Aluru S.
        Efficient architecture-aware acceleration of BWA-MEM for multicore systems.
        Int Parall Distrib P. 2019; : 314-324
        • Kim S.
        • Scheffler K.
        • Halpern A.L.
        • Bekritsky M.A.
        • Noh E.
        • Kallberg M.
        • et al.
        Strelka2: fast and accurate calling of germline and somatic variants.
        Nat Methods. 2018; 15 (-+): 591
        • Richards S.
        • Aziz N.
        • Bale S.
        • Bick D.
        • Das S.
        • Gastier-Foster J.
        • et al.
        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. 2015; 17: 405-424
        • Miller D.T.
        • Lee K.
        • Chung W.K.
        • Gordon A.S.
        • Herman G.E.
        • Klein T.E.
        • et al.
        ACMG SF v3.0 list for reporting of secondary findings in clinical exome and genome sequencing: a policy statement of the American College of Medical Genetics and Genomics (ACMG).
        Genet Med. 2021; 23: 1381-1390
        • Johnson D.B.
        • Frampton G.M.
        • Rioth M.J.
        • Yusko E.
        • Xu Y.
        • Guo X.
        • et al.
        Targeted next generation sequencing identifies markers of response to PD-1 blockade.
        Cancer Immunol Res. 2016; 4: 959-967
        • Bitzer M.
        • Ostermann L.
        • Horger M.
        • Biskup S.
        • Schulze M.
        • Ruhm K.
        • et al.
        Next-generation sequencing of advanced GI tumors reveals individual treatment options.
        JCO Precis Oncol. 2020; 4
        • Moore K.
        • Colombo N.
        • Scambia G.
        • Kim B.G.
        • Oaknin A.
        • Friedlander M.
        • et al.
        Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer.
        N Engl J Med. 2018; 379: 2495-2505
        • Robson M.
        • Im S.A.
        • Senkus E.
        • Xu B.
        • Domchek S.M.
        • Masuda N.
        • et al.
        Olaparib for metastatic breast cancer in patients with a germline BRCA mutation.
        N Engl J Med. 2017; 377: 523-533
        • Golan T.
        • Hammel P.
        • Reni M.
        • Van Cutsem E.
        • Macarulla T.
        • Hall M.J.
        • et al.
        Maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.
        N Engl J Med. 2019; 381: 317-327
        • Rhiem K.
        • Auber B.
        • Briest S.
        • Dikow N.
        • Ditsch N.
        • Dragicevic N.
        • et al.
        Consensus recommendations of the German Consortium for hereditary breast and ovarian cancer.
        Breast Care. 2021; 17: 199-207
        • Walsh M.F.
        • Ritter D.I.
        • Kesserwan C.
        • Sonkin D.
        • Chakravarty D.
        • Chao E.
        • et al.
        Integrating somatic variant data and biomarkers for germline variant classification in cancer predisposition genes.
        Hum Mutat. 2018; 39: 1542-1552
        • Huang D.S.
        • Tao H.Q.
        • He X.J.
        • Long M.
        • Yu S.
        • Xia Y.J.
        • et al.
        Prevalence of deleterious ATM germline mutations in gastric cancer patients.
        Oncotarget. 2015; 6: 40953-40958
        • Hall M.J.
        • Olopade O.I.
        • Daly M.B.
        • Kupfer S.
        Germline ATM mutations in families with early-onset and familial gastroesophageal and colorectal cancers.
        J Clin Oncol. 2017; 35: 11
        • Dalmasso B.
        • Pastorino L.
        • Nathan V.
        • Shah N.N.
        • Palmer J.M.
        • Howlie M.
        • et al.
        Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.
        Genet Med. 2021; 23: 2087-2095
        • Serracant Barrera A.
        • Serra Pla S.
        • Blazquez Mana C.M.
        • Salas R.C.
        • Garcia Monforte N.
        • Bejarano Gonzalez N.
        • et al.
        Pancreatic non-functioning neuroendocrine tumor: a new entity genetically related to Lynch syndrome.
        J Gastrointest Oncol. 2017; 8: E73-E79
        • Libby P.
        • Sidlow R.
        • Lin A.E.
        • Gupta D.
        • Jones L.W.
        • Moslehi J.
        • et al.
        Clonal hematopoiesis: crossroads of aging, cardiovascular disease, and cancer: JACC review topic of the week.
        J Am Coll Cardiol. 2019; 74: 567-577
        • Green R.C.
        • Berg J.S.
        • Grody W.W.
        • Kalia S.S.
        • Korf B.R.
        • Martin C.L.
        • et al.
        ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
        Genet Med. 2013; 15: 565-574
        • Jones S.
        • Anagnostou V.
        • Lytle K.
        • Parpart-Li S.
        • Nesselbush M.
        • Riley D.R.
        • et al.
        Personalized genomic analyses for cancer mutation discovery and interpretation.
        Sci Transl Med. 2015; 7: 283ra53
        • Mandelker D.
        • Donoghue M.
        • Talukdar S.
        • Bandlamudi C.
        • Srinivasan P.
        • Vivek M.
        • et al.
        Germline-focussed analysis of tumour-only sequencing: recommendations from the ESMO precision medicine working group.
        Ann Oncol. 2019; 30: 1221-1231
        • McLaren W.
        • Gil L.
        • Hunt S.E.
        • Riat H.S.
        • Ritchie G.R.
        • Thormann A.
        • et al.
        The Ensembl variant effect predictor.
        Genome Biol. 2016; 17: 122