Familial clustering, twin concordance, and identification of high- and low-penetrance cancer predisposition variants support the idea that there are families that are at a high to moderate excess risk of cancer. To what extent there may be families that are protected from cancer is unknown. We wanted to test genetically whether cancer-free families share fewer breast, colorectal, and prostate cancer risk alleles than the population at large. We addressed this question by whole-genome sequencing (WGS) of 51 elderly cancer-free individuals whose numerous (ca. 1000) family members were found to be cancer-free ('cancer-free families', CFFs) based on face-to-face interviews. The average coverage of the 51 samples in the WGS was 42x. We compared cancer risk allele frequencies in cancer-free individuals with those in the general population available in public databases. The CFF members had fewer loss-of-function variants in suggested cancer predisposition genes compared to the ExAC data, and for high-risk cancer predisposition genes, no pathogenic variants were found in CFFs. For common low-penetrance breast, colorectal, and prostate cancer risk alleles, the results were not conclusive. The results suggest that, in line with twin and family studies, random environmental causes are so dominant that a clear demarcation of cancer-free populations using genetic data may not be feasible.

Bioinformatics and Omics Data Analytics German Cancer Research Center 69120 Heidelberg Germany

Cancer Gene Therapy Group Translational Immunology Research Program University of Helsinki 00290 Helsinki Finland

Comprehensive Cancer Center Helsinki University Hospital 00290 Helsinki Finland

Computational Oncology Molecular Diagnostics Program National Center for Tumor Diseases 69120 Heidelberg Germany

Department of Genetics University Medical Center Groningen University of Groningen 9700 RB Groningen The Netherlands

Department of Internal Medicine 5 University of Heidelberg 69120 Heidelberg Germany

Division of Cancer Epidemiology German Cancer Research Center 69120 Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center Im Neuenheimer Feld 580 D 69120 Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center 69120 Heidelberg Germany

Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague 30605 Pilsen Czech Republic

Hereditary Cancer Center Department of Genetics and Pathology Pomeranian Medical University 70 111 Szczecin Poland

Hopp Children's Cancer Center 69120 Heidelberg Germany

Medical Faculty University of Heidelberg 69120 Heidelberg Germany

See more in PubMed

Frank C., Sundquist J., Yu H., Hemminki A., Hemminki K. Concordant and discordant familial cancer: Familial risks, proportions and population impact. Int. J. Cancer. 2017;140:1510–1516. doi: 10.1002/ijc.30583. PubMed DOI

Lichtenstein P., Holm N.V., Verkasalo P.K., Iliadou A., Kaprio J., Koskenvuo M., Pukkala E., Skytthe A., Hemminki K. Environmental and heritable factors in the causation of cancer--analyses of cohorts of twins from sweden, denmark, and finland. N. Engl. J. Med. 2000;343:78–85. doi: 10.1056/NEJM200007133430201. PubMed DOI

Mucci L.A., Hjelmborg J.B., Harris J.R., Czene K., Havelick D.J., Scheike T., Graff R.E., Holst K., Moller S., Unger R.H., et al. Familial risk and heritability of cancer among twins in nordic countries. JAMA. 2016;315:68–76. doi: 10.1001/jama.2015.17703. PubMed DOI PMC

Artomov M., Joseph V., Tiao G., Thomas T., Schrader K., Klein R.J., Kiezun A., Gupta N., Margolin L., Stratigos A.J., et al. Case-control analysis identifies shared properties of rare germline variation in cancer predisposing genes. Eur. J. Hum. Genet. 2019;27:824–828. doi: 10.1038/s41431-019-0346-0. PubMed DOI PMC

Sampson J.N., Wheeler W.A., Yeager M., Panagiotou O., Wang Z., Berndt S.I., Lan Q., Abnet C.C., Amundadottir L.T., Figueroa J.D., et al. Analysis of heritability and shared heritability based on genome-wide association studies for thirteen cancer types. J. Natl. Cancer Inst. 2015;107:e279. doi: 10.1093/jnci/djv279. PubMed DOI PMC

Chubb D., Broderick P., Frampton M., Kinnersley B., Sherborne A., Penegar S., Lloyd A., Ma Y.P., Dobbins S.E., Houlston R.S. Genetic diagnosis of high-penetrance susceptibility for colorectal cancer (crc) is achievable for a high proportion of familial crc by exome sequencing. J. Clin. Oncol. 2015;33:426–432. doi: 10.1200/JCO.2014.56.5689. PubMed DOI

Palomaki G.E. Is it time for brca1/2 mutation screening in the general adult population?: Impact of population characteristics. Genet. Med. 2015;17:24–26. doi: 10.1038/gim.2014.167. PubMed DOI

Sud A., Kinnersley B., Houlston R.S. Genome-wide association studies of cancer: Current insights and future perspectives. Nat. Rev. Cancer. 2017;17:692–704. doi: 10.1038/nrc.2017.82. PubMed DOI

Huang K.L., Mashl R.J., Wu Y., Ritter D.I., Wang J., Oh C., Paczkowska M., Reynolds S., Wyczalkowski M.A., Oak N., et al. Pathogenic germline variants in 10,389 adult cancers. Cell. 2018;173:355–370. doi: 10.1016/j.cell.2018.03.039. PubMed DOI PMC

Michailidou K., Lindstrom S., Dennis J., Beesley J., Hui S., Kar S., Lemacon A., Soucy P., Glubb D., Rostamianfar A., et al. Association analysis identifies 65 new breast cancer risk loci. Nature. 2017;551:92–94. doi: 10.1038/nature24284. PubMed DOI PMC

Schmit S.L., Edlund C.K., Schumacher F.R., Gong J., Harrison T.A., Huyghe J.R., Qu C., Melas M., Van Den Berg D.J., Wang H., et al. Novel common genetic susceptibility loci for colorectal cancer. J. Natl. Cancer Inst. 2019;111:146–157. doi: 10.1093/jnci/djy099. PubMed DOI PMC

Yu H., Frank C., Sundquist J., Hemminki A., Hemminki K. Common cancers share familial susceptibility: Implications for cancer genetics and counselling. J. Med. Genet. 2017;54:248–253. doi: 10.1136/jmedgenet-2016-103932. PubMed DOI

Pinese M., Lacaze P., Rath E.M., Stone A., Brion M.J., Ameur A., Nagpal S., Puttick C., Husson S., Degrave D., et al. The medical genome reference bank contains whole genome and phenotype data of 2570 healthy elderly. Nat. Commun. 2020;11:e435. doi: 10.1038/s41467-019-14079-0. PubMed DOI PMC

Huyghe J.R., Bien S.A., Harrison T.A., Kang H.M., Chen S., Schmit S.L., Conti D.V., Qu C., Jeon J., Edlund C.K., et al. Discovery of common and rare genetic risk variants for colorectal cancer. Nat. Genet. 2019;51:76–87. doi: 10.1038/s41588-018-0286-6. PubMed DOI PMC

Lilyquist J., Ruddy K.J., Vachon C.M., Couch F.J. Common genetic variation and breast cancer risk-past, present, and future. Cancer. Epidemiol. Biomark. Prev. 2018;27:380–394. doi: 10.1158/1055-9965.EPI-17-1144. PubMed DOI PMC

Schumacher F.R., Al Olama A.A., Berndt S.I., Benlloch S., Ahmed M., Saunders E.J., Dadaev T., Leongamornlert D., Anokian E., Cieza-Borrella C., et al. Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci. Nat. Genet. 2018;50:928–936. doi: 10.1038/s41588-018-0142-8. PubMed DOI PMC

Rahman N. Realizing the promise of cancer predisposition genes. Nature. 2014;505:302–308. doi: 10.1038/nature12981. PubMed DOI PMC

Wei R., Yao Y., Yang W., Zheng C.H., Zhao M., Xia J. Dbcpg: A web resource for cancer predisposition genes. Oncotarget. 2016;7:37803–37811. doi: 10.18632/oncotarget.9334. PubMed DOI PMC

Kumar A., Bandapalli O.R., Paramasivam N., Giangiobbe S., Diquigiovanni C., Bonora E., Eils R., Schlesner M., Hemminki K., Forsti A. Familial cancer variant prioritization pipeline version 2 (fcvppv2) applied to a papillary thyroid cancer family. Sci. Rep. 2018;8:11635. doi: 10.1038/s41598-018-29952-z. PubMed DOI PMC

Czene K., Lichtenstein P., Hemminki K. Environmental and heritable causes of cancer among 9.6 million individuals in the swedish family-cancer database. Int. J. Cancer. 2002;99:260–266. doi: 10.1002/ijc.10332. PubMed DOI

Mitchell J.S., Li N., Weinhold N., Forsti A., Ali M., van Duin M., Thorleifsson G., Johnson D.C., Chen B., Halvarsson B.M., et al. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat. Commun. 2016;7:12050. doi: 10.1038/ncomms12050. PubMed DOI PMC

Cremers R.G., Galesloot T.E., Aben K.K., van Oort I.M., Vasen H.F., Vermeulen S.H., Kiemeney L.A. Known susceptibility snps for sporadic prostate cancer show a similar association with "hereditary" prostate cancer. Prostate. 2015;75:474–483. doi: 10.1002/pros.22933. PubMed DOI PMC

Archambault A.N., Su Y.R., Jeon J., Thomas M., Lin Y., Conti D.V., Win A.K., Sakoda L.C., Lansdorp-Vogelaar I., Peterse E.F., et al. Cumulative burden of colorectal cancer-associated genetic variants is more strongly associated with early-onset vs late-onset cancer. Gastroenterology. 2019;158:1274–1286. doi: 10.1053/j.gastro.2019.12.012. PubMed DOI PMC

Cust A.E., Drummond M., Kanetsky P.A., Mann G.J., Schmid H., Hopper J.L., Aitken J.F., Armstrong B.K., Giles G.G., Holland E., et al. Assessing the incremental contribution of common genomic variants to melanoma risk prediction in two population-based studies. J. Invest. Derm. 2018;138:2617–2624. doi: 10.1016/j.jid.2018.05.023. PubMed DOI PMC

Weigl K., Thomsen H., Balavarca Y., Hellwege J.N., Shrubsole M.J., Brenner H. Genetic risk score is associated with prevalence of advanced neoplasms in a colorectal cancer screening population. Gastroenterology. 2018;155:88–98. doi: 10.1053/j.gastro.2018.03.030. PubMed DOI PMC

Ji J., Sundquist K., Sundquist J., Hemminki K. Comparability of cancer identification among death registry, cancer registry and hospital discharge registry. Int. J. Cancer. 2012;131:2085–2093. doi: 10.1002/ijc.27462. PubMed DOI

Andersen M.M., Eriksen P.S., Morling N. Cluster analysis of european y-chromosomal str haplotypes using the discrete laplace method. Forensic Sci. Int. Genet. 2014;11:182–194. doi: 10.1016/j.fsigen.2014.03.016. PubMed DOI

Heath S.C., Gut I.G., Brennan P., McKay J.D., Bencko V., Fabianova E., Foretova L., Georges M., Janout V., Kabesch M., et al. Investigation of the fine structure of european populations with applications to disease association studies. Eur. J. Hum. Genet. 2008;16:1413–1429. doi: 10.1038/ejhg.2008.210. PubMed DOI

Mielnik-Sikorska M., Daca P., Malyarchuk B., Derenko M., Skonieczna K., Perkova M., Dobosz T., Grzybowski T. The history of slavs inferred from complete mitochondrial genome sequences. PLoS ONE. 2013;8:e54360. doi: 10.1371/journal.pone.0054360. PubMed DOI PMC

Nelis M., Esko T., Magi R., Zimprich F., Zimprich A., Toncheva D., Karachanak S., Piskackova T., Balascak I., Peltonen L., et al. Genetic structure of europeans: A view from the north-east. PLoS ONE. 2009;4:e5472. doi: 10.1371/journal.pone.0005472. PubMed DOI PMC

Guo M.H., Plummer L., Chan Y.M., Hirschhorn J.N., Lippincott M.F. Burden testing of rare variants identified through exome sequencing via publicly available control data. Am. J. Hum. Genet. 2018;103:522–534. doi: 10.1016/j.ajhg.2018.08.016. PubMed DOI PMC

Turnbull C., Sud A., Houlston R.S. Cancer genetics, precision prevention and a call to action. Nat. Genet. 2018;50:1212–1218. doi: 10.1038/s41588-018-0202-0. PubMed DOI PMC

Lek M., Karczewski K.J., Minikel E.V., Samocha K.E., Banks E., Fennell T., O’Donnell-Luria A.H., Ware J.S., Hill A.J., Cummings B.B., et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–291. doi: 10.1038/nature19057. PubMed DOI PMC

Wang K., Li M., Hakonarson H. Annovar: Functional annotation of genetic variants from high-throughput sequencing data. Nucleic. Acids. Res. 2010;38:e164. doi: 10.1093/nar/gkq603. PubMed DOI PMC

Smigielski E.M., Sirotkin K., Ward M., Sherry S.T. Dbsnp: A database of single nucleotide polymorphisms. Nucleic. Acids. Res. 2000;28:352–355. doi: 10.1093/nar/28.1.352. PubMed DOI PMC

Genomes Project C., Auton A., Brooks L.D., Durbin R.M., Garrison E.P., Kang H.M., Korbel J.O., Marchini J.L., McCarthy S., McVean G.A., et al. A global reference for human genetic variation. Nature. 2015;526:68–74. PubMed PMC

Liu X., Wu C., Li C., Boerwinkle E. Dbnsfp v3.0: A one-stop database of functional predictions and annotations for human nonsynonymous and splice-site snvs. Hum. Mutat. 2016;37:235–241. doi: 10.1002/humu.22932. PubMed DOI PMC

Kircher M., Witten D.M., Jain P., O’Roak B.J., Cooper G.M., Shendure J. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 2014;46:310–315. doi: 10.1038/ng.2892. PubMed DOI PMC

Petrovski S., Wang Q., Heinzen E.L., Allen A.S., Goldstein D.B. Genic intolerance to functional variation and the interpretation of personal genomes. PLoS Genet. 2013;9:e1003709. doi: 10.1371/annotation/32c8d343-9e1d-46c6-bfd4-b0cd3fb7a97e. PubMed DOI PMC

Cooper G.M., Stone E.A., Asimenos G., Program N.C.S., Green E.D., Batzoglou S., Sidow A. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 2005;15:901–913. doi: 10.1101/gr.3577405. PubMed DOI PMC

Siepel A., Bejerano G., Pedersen J.S., Hinrichs A.S., Hou M., Rosenbloom K., Clawson H., Spieth J., Hillier L.W., Richards S., et al. Evolutionarily conserved elements in vertebrate, insect, worm, and yeast genomes. Genome Res. 2005;15:1034–1050. doi: 10.1101/gr.3715005. PubMed DOI PMC

Pollard K.S., Hubisz M.J., Rosenbloom K.R., Siepel A. Detection of nonneutral substitution rates on mammalian phylogenies. Genome Res. 2010;20:110–121. doi: 10.1101/gr.097857.109. PubMed DOI PMC

Kumar P., Henikoff S., Ng P.C. Predicting the effects of coding non-synonymous variants on protein function using the sift algorithm. Nat. Protoc. 2009;4:1073–1081. doi: 10.1038/nprot.2009.86. PubMed DOI

Adzhubei I., Jordan D.M., Sunyaev S.R. Predicting functional effect of human missense mutations using polyphen-2. Curr. Protoc. Hum. Genet. 2013;7:e20. doi: 10.1002/0471142905.hg0720s76. PubMed DOI PMC

Chun S., Fay J.C. Identification of deleterious mutations within three human genomes. Genome Res. 2009;19:1553–1561. doi: 10.1101/gr.092619.109. PubMed DOI PMC

Schwarz J.M., Rodelsperger C., Schuelke M., Seelow D. Mutationtaster evaluates disease-causing potential of sequence alterations. Nat. Methods. 2010;7:575–576. doi: 10.1038/nmeth0810-575. PubMed DOI

Reva B., Antipin Y., Sander C. Predicting the functional impact of protein mutations: Application to cancer genomics. Nucleic. Acids. Res. 2011;39:e118. doi: 10.1093/nar/gkr407. PubMed DOI PMC

Shihab H.A., Gough J., Cooper D.N., Stenson P.D., Barker G.L., Edwards K.J., Day I.N., Gaunt T.R. Predicting the functional, molecular, and phenotypic consequences of amino acid substitutions using hidden markov models. Hum. Mutat. 2013;34:57–65. doi: 10.1002/humu.22225. PubMed DOI PMC

Choi Y., Sims G.E., Murphy S., Miller J.R., Chan A.P. Predicting the functional effect of amino acid substitutions and indels. PLoS ONE. 2012;7:e46688. doi: 10.1371/journal.pone.0046688. PubMed DOI PMC

Castera L., Harter V., Muller E., Krieger S., Goardon N., Ricou A., Rousselin A., Paimparay G., Legros A., Bruet O., et al. Landscape of pathogenic variations in a panel of 34 genes and cancer risk estimation from 5131 hboc families. Genet. Med. 2018;20:1677–1686. doi: 10.1038/s41436-018-0005-9. PubMed DOI

Haukoos J.S., Lewis R.J. Advanced statistics: Bootstrapping confidence intervals for statistics with "difficult" distributions. Acad. Emerg. Med. 2005;12:360–365. doi: 10.1197/j.aem.2004.11.018. PubMed DOI