The context-specific role of germline pathogenicity in tumorigenesis.
Journal
Nature genetics
ISSN: 1546-1718
Titre abrégé: Nat Genet
Pays: United States
ID NLM: 9216904
Informations de publication
Date de publication:
11 2021
11 2021
Historique:
received:
16
11
2020
accepted:
09
09
2021
entrez:
6
11
2021
pubmed:
7
11
2021
medline:
28
12
2021
Statut:
ppublish
Résumé
Human cancers arise from environmental, heritable and somatic factors, but how these mechanisms interact in tumorigenesis is poorly understood. Studying 17,152 prospectively sequenced patients with cancer, we identified pathogenic germline variants in cancer predisposition genes, and assessed their zygosity and co-occurring somatic alterations in the concomitant tumors. Two major routes to tumorigenesis were apparent. In carriers of pathogenic germline variants in high-penetrance genes (5.1% overall), lineage-dependent patterns of biallelic inactivation led to tumors exhibiting mechanism-specific somatic phenotypes and fewer additional somatic oncogenic drivers. Nevertheless, 27% of cancers in these patients, and most tumors in patients with pathogenic germline variants in lower-penetrance genes, lacked particular hallmarks of tumorigenesis associated with the germline allele. The dependence of tumors on pathogenic germline variants is variable and often dictated by both penetrance and lineage, a finding with implications for clinical management.
Identifiants
pubmed: 34741162
doi: 10.1038/s41588-021-00949-1
pii: 10.1038/s41588-021-00949-1
pmc: PMC8957388
mid: NIHMS1739905
doi:
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1577-1585Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221745
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA227534
Pays : United States
Organisme : NCI NIH HHS
ID : R25 CA233208
Pays : United States
Commentaires et corrections
Type : CommentIn
Informations de copyright
© 2021. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Garber, J. E. & Offit, K. Hereditary cancer predisposition syndromes. J. Clin. Oncol. 23, 276–292 (2005).
pubmed: 15637391
doi: 10.1200/JCO.2005.10.042
Rahman, N. Realizing the promise of cancer predisposition genes. Nature 505, 302–308 (2014).
pubmed: 24429628
pmcid: 4975511
doi: 10.1038/nature12981
Knudson, A. G. Mutation and cancer: statistical study of retinoblastoma. Proc. Natl Acad. Sci. USA 68, 820–823 (1971).
pubmed: 5279523
pmcid: 389051
doi: 10.1073/pnas.68.4.820
Nichols, K. E., Malkin, D., Garber, J. E., Fraumeni, J. F. & Li, F. P. Germ-line p53 mutations predispose to a wide spectrum of early-onset cancers. Cancer Epidemiol. Biomark. Prev. 10, 83–87 (2001).
Chandrasekharappa, S. C. et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science 276, 404–407 (1997).
pubmed: 9103196
doi: 10.1126/science.276.5311.404
Moore, K. et al. Maintenance olaparib in patients with newly diagnosed advanced ovarian cancer. N. Engl. J. Med. 379, 2495–2505 (2018).
pubmed: 30345884
doi: 10.1056/NEJMoa1810858
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
pubmed: 26028255
pmcid: 4481136
doi: 10.1056/NEJMoa1500596
Fong, P. C. et al. Inhibition of poly(ADP-ribose) polymerase in tumors from BRCA mutation carriers. N. Engl. J. Med. 361, 123–134 (2009).
pubmed: 19553641
doi: 10.1056/NEJMoa0900212
Stadler, Z. K., Schrader, K. A., Vijai, J., Robson, M. E. & Offit, K. Cancer genomics and inherited risk. J. Clin. Oncol. 32, 687–698 (2014).
pubmed: 24449244
pmcid: 5795694
doi: 10.1200/JCO.2013.49.7271
Tung, N. et al. Counselling framework for moderate-penetrance cancer-susceptibility mutations. Nat. Rev. Clin. Oncol. 13, 581–588 (2016).
pubmed: 27296296
pmcid: 5513673
doi: 10.1038/nrclinonc.2016.90
Jasperson, K. W., Tuohy, T. M., Neklason, D. W. & Burt, R. W. Hereditary and familial colon cancer. Gastroenterology 138, 2044–2058 (2010).
pubmed: 20420945
doi: 10.1053/j.gastro.2010.01.054
Hampel, H. & Peltomaki, P. Hereditary colorectal cancer: risk assessment and management. Clin. Genet. 58, 89–97 (2000).
pubmed: 11005140
doi: 10.1034/j.1399-0004.2000.580201.x
Couch, F. J. et al. Associations between cancer predisposition testing panel genes and breast cancer. JAMA Oncol. 3, 1190–1196 (2017).
pubmed: 28418444
pmcid: 5599323
doi: 10.1001/jamaoncol.2017.0424
Thavaneswaran, S. et al. Therapeutic implications of germline genetic findings in cancer. Nat. Rev. Clin. Oncol. 16, 386–396 (2019).
pubmed: 30783251
doi: 10.1038/s41571-019-0179-3
Zhang, J. et al. Germline mutations in predisposition genes in pediatric cancer. N. Engl. J. Med. 373, 2336–2346 (2015).
pubmed: 26580448
pmcid: 4734119
doi: 10.1056/NEJMoa1508054
Huang, K.-L. et al. Pathogenic germline variants in 10,389 adult cancers. Cell 173, 355–370.e14 (2018).
pubmed: 29625052
pmcid: 5949147
doi: 10.1016/j.cell.2018.03.039
Lu, C. et al. Patterns and functional implications of rare germline variants across 12 cancer types. Nat. Commun. 6, 10086 (2015).
pubmed: 26689913
doi: 10.1038/ncomms10086
Mandelker, D. 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 318, 825–835 (2017).
pubmed: 28873162
pmcid: 5611881
doi: 10.1001/jama.2017.11137
Jonsson, P. et al. Tumour lineage shapes BRCA-mediated phenotypes. Nature 571, 576–579 (2019).
pubmed: 31292550
pmcid: 7048239
doi: 10.1038/s41586-019-1382-1
Cheng, D. T. et al. Comprehensive detection of germline variants by MSK-IMPACT, a clinical diagnostic platform for solid tumor molecular oncology and concurrent cancer predisposition testing. BMC Med. Genom. 10, 33 (2017).
doi: 10.1186/s12920-017-0271-4
Richards, S. 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. 17, 405–424 (2015).
pubmed: 25741868
pmcid: 4544753
doi: 10.1038/gim.2015.30
Gryfe, R., Di Nicola, N., Gallinger, S. & Redston, M. Somatic instability of the APC I1307K allele in colorectal neoplasia. Cancer Res. 58, 4040–4043 (1998).
pubmed: 9751605
Win, A. K., Hopper, J. L. & Jenkins, M. A. Association between monoallelic MUTYH mutation and colorectal cancer risk: a meta-regression analysis. Fam. Cancer 10, 1–9 (2011).
pubmed: 21061173
pmcid: 3228836
doi: 10.1007/s10689-010-9399-5
Knudson, A. G. Two genetic hits (more or less) to cancer. Nat. Rev. Cancer 1, 157–162 (2001).
pubmed: 11905807
doi: 10.1038/35101031
Nickerson, M. L. et al. Mutations in a novel gene lead to kidney tumors, lung wall defects, and benign tumors of the hair follicle in patients with the Birt–Hogg–Dubé syndrome. Cancer Cell 2, 157–164 (2002).
pubmed: 12204536
doi: 10.1016/S1535-6108(02)00104-6
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
pubmed: 23945592
pmcid: 3776390
doi: 10.1038/nature12477
Polak, P. et al. A mutational signature reveals alterations underlying deficient homologous recombination repair in breast cancer. Nat. Genet. 49, 1476–1486 (2017).
pubmed: 28825726
pmcid: 7376751
doi: 10.1038/ng.3934
Pilati, C. et al. Mutational signature analysis identifies MUTYH deficiency in colorectal cancers and adrenocortical carcinomas. J. Pathol. 242, 10–15 (2017).
pubmed: 28127763
doi: 10.1002/path.4880
Viel, A. et al. A specific mutational signature associated with DNA 8-oxoguanine persistence in MUTYH-defective colorectal cancer. eBioMedicine 20, 39–49 (2017).
pubmed: 28551381
pmcid: 5478212
doi: 10.1016/j.ebiom.2017.04.022
Scarpa, A. et al. Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543, 65–71 (2017).
pubmed: 28199314
doi: 10.1038/nature21063
Chakravarty, D. et al. Oncokb: a precision oncology knowledge base. JCO Precis. Oncol. https://doi.org/10.1200/PO.17.00011 (2017).
Le, D. T. et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 357, 409–413 (2017).
pubmed: 28596308
pmcid: 5576142
doi: 10.1126/science.aan6733
Lynch, H. T., Shaw, M. W., Magnuson, C. W., Larsen, A. L. & Krush, A. J. Hereditary factors in cancer. Study of two large midwestern kindreds. Arch. Intern. Med. 117, 206–212 (1966).
pubmed: 5901552
doi: 10.1001/archinte.1966.03870080050009
Lynch, H. T. & Krush, A. J. Cancer family ‘G’ revisited: 1895–1970. Cancer 27, 1505–1511 (1971).
pubmed: 5088221
doi: 10.1002/1097-0142(197106)27:6<1505::AID-CNCR2820270635>3.0.CO;2-L
Latham, A. et al. Microsatellite instability is associated with the presence of Lynch syndrome pan-cancer. J. Clin. Oncol. 37, 286–295 (2019).
pubmed: 30376427
doi: 10.1200/JCO.18.00283
Møller, P. et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75 years of age: a report from the Prospective Lynch Syndrome Database. Gut 67, 1306–1316 (2018).
pubmed: 28754778
doi: 10.1136/gutjnl-2017-314057
Kinzler, K. W. & Vogelstein, B. Landscaping the cancer terrain. Science 280, 1036–1037 (1998).
pubmed: 9616081
doi: 10.1126/science.280.5366.1036
Kinzler, K. W. & Vogelstein, B. Cancer-susceptibility genes. Gatekeepers and caretakers. Nature 386, 761–763 (1997).
pubmed: 9126728
doi: 10.1038/386761a0
Baysal, B. E. et al. Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma. Science 287, 848–851 (2000).
pubmed: 10657297
doi: 10.1126/science.287.5454.848
Karaayvaz-Yildirim, M. et al. Aneuploidy and a deregulated DNA damage response suggest haploinsufficiency in breast tissues of BRCA2 mutation carriers. Sci. Adv. 6, eaay2611 (2020).
pubmed: 32064343
pmcid: 6989139
doi: 10.1126/sciadv.aay2611
Cheng, D. T. et al. Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT): a hybridization capture-based next-generation sequencing clinical assay for solid tumor molecular oncology. J. Mol. Diagn. 17, 251–264 (2015).
pubmed: 25801821
pmcid: 5808190
doi: 10.1016/j.jmoldx.2014.12.006
Won, H. H., Scott, S. N., Brannon, A. R., Shah, R. H. & Berger, M. F. Detecting somatic genetic alterations in tumor specimens by exon capture and massively parallel sequencing. J. Vis. Exp. 80, e50710 (2013).
Xin, J. et al. High-performance web services for querying gene and variant annotation. Genome Biol. 17, 91 (2016).
pubmed: 27154141
pmcid: 4858870
doi: 10.1186/s13059-016-0953-9
Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020).
pubmed: 32461654
pmcid: 7334197
doi: 10.1038/s41586-020-2308-7
Landrum, M. J. et al. ClinVar: public archive of interpretations of clinically relevant variants. Nucleic Acids Res. 44, D862–D868 (2016).
pubmed: 26582918
doi: 10.1093/nar/gkv1222
Nakagawa, H. et al. Mismatch repair gene PMS2: disease-causing germline mutations are frequent in patients whose tumors stain negative for PMS2 protein, but paralogous genes obscure mutation detection and interpretation. Cancer Res. 64, 4721–4727 (2004).
pubmed: 15256438
doi: 10.1158/0008-5472.CAN-03-2879
Hayward, B. E. et al. Extensive gene conversion at the PMS2 DNA mismatch repair locus. Hum. Mutat. 28, 424–430 (2007).
pubmed: 17253626
doi: 10.1002/humu.20457
Kilpivaara, O., Alhopuro, P., Vahteristo, P., Aaltonen, L. A. & Nevanlinna, H. CHEK2 I157T associates with familial and sporadic colorectal cancer. J. Med. Genet. 43, e34 (2006).
pubmed: 16816021
pmcid: 2564563
doi: 10.1136/jmg.2005.038331
Kilpivaara, O. et al. CHEK2 variant I157T may be associated with increased breast cancer risk. Int. J. Cancer 111, 543–547 (2004).
pubmed: 15239132
doi: 10.1002/ijc.20299
Apostolou, P. & Papasotiriou, I. Current perspectives on CHEK2 mutations in breast cancer. Breast Cancer 9, 331–335 (2017).
pubmed: 28553140
pmcid: 5439543
Zhang, L. et al. Fumarate hydratase FH c.1431_1433dupAAA (p.Lys477dup) variant is not associated with cancer including renal cell carcinoma. Hum. Mutat. 41, 103–109 (2020).
pubmed: 31444830
doi: 10.1002/humu.23900
Alam, N. A. et al. Genetic and functional analyses of FH mutations in multiple cutaneous and uterine leiomyomatosis, hereditary leiomyomatosis and renal cancer, and fumarate hydratase deficiency. Hum. Mol. Genet. 12, 1241–1252 (2003).
pubmed: 12761039
doi: 10.1093/hmg/ddg148
Gossage, L., Cartwright, E., Eisen, T. & Bycroft, M. A detailed analysis of von Hippel Lindau (VHL) mutations in sporadic clear cell renal carcinoma (ccRCC), VHL syndrome, and Chuvash polycythaemia. J. Clin. Oncol. 28, e15024–e15024 (2010).
doi: 10.1200/jco.2010.28.15_suppl.e15024
Liang, J. et al. APC polymorphisms and the risk of colorectal neoplasia: a HuGE review and meta-analysis. Am. J. Epidemiol. 177, 1169–1179 (2013).
pubmed: 23576677
doi: 10.1093/aje/kws382
Benjamini, Y. & Hochberg, Y. Controlling the false discovery rate: a practical and powerful approach to multiple testing. J. R. Statist. Soc. B Methodol. 57, 289–300 (1995).
Bielski, C. M. et al. Widespread selection for oncogenic mutant allele imbalance in cancer. Cancer Cell 34, 852–862.e4 (2018).
pubmed: 30393068
pmcid: 6234065
doi: 10.1016/j.ccell.2018.10.003
Zehir, A. et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequencing of 10,000 patients. Nat. Med. 23, 703–713 (2017).
pubmed: 28481359
pmcid: 5461196
doi: 10.1038/nm.4333
Chang, M. T. et al. Accelerating discovery of functional mutant alleles in cancer. Cancer Discov. 8, 174–183 (2018).
pubmed: 29247016
doi: 10.1158/2159-8290.CD-17-0321
Vogelstein, B. et al. Cancer genome landscapes. Science 339, 1546–1558 (2013).
pubmed: 23539594
pmcid: 3749880
doi: 10.1126/science.1235122