bims-lifras 2019-11-24 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2019–11–24
eleven papers selected by
Joanna Zawacka-Pankau

Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome).
A Pediatric Case of Glioblastoma Multiforme Associated With a Novel Germline p.His112CysfsTer9 Mutation in the MLH1 Gene Accompanied by a p.Arg283Cys Mutation in the TP53 Gene: A Case Report.
Estimated number of adult survivors of childhood cancer in United States with cancer-predisposing germline variants.
Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil.
Incorporating Colorectal Cancer Genetic Risk Assessment into Gastroenterology Practice.
Prevalence of hereditary breast and ovarian cancer predisposition gene mutations among 882 HBOC high-risk Chinese individuals.
Clinicopathological features of women with epithelial ovarian cancer and double heterozygosity for BRCA1 and BRCA2: A systematic review and case report analysis.
MLH1 promoter hypermethylation: are you absolutely sure about the absence of MLH1 germline mutation? About a new case.
Identification of novel BRCA1 large genomic rearrangements by a computational algorithm of amplicon-based Next-Generation Sequencing data.
Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39.
Current Approaches to Germline Cancer Genetic Testing.

Fam Cancer. 2019 Nov 20.

Radiotherapy-induced malignancies in breast cancer patients with TP53 pathogenic germline variants (Li-Fraumeni syndrome).

Vanessa Petry, Renata Colombo Bonadio, Allyne Queiroz Carneiro Cagnacci, Luiz Antonio Leite Senna, Roberta do Nascimento Galvão Campos, Guilherme Cutait Cotti, Paulo M Hoff, Maria Candida Barisson Villares Fragoso, Maria Del Pilar Estevez-Diz.

  The risk of radiotherapy-induced malignancies (RIMs) is a concern when treating Li-Fraumeni syndrome (LFS) or Li-Fraumeni Like (LFL) patients. However, the type of TP53 pathogenic germline variant may possibly influence this risk. TP53 p.R337H mutation is particularly prevalent in Brazil. We aimed to evaluate the outcomes of patients with pathogenic TP53 variants treated for localized breast cancer in a Brazilian cohort. We evaluated retrospectively a cohort of patients with germline TP53 pathogenic variants treated for localized breast cancer between December 1999 and October 2017. All patients were followed by the Hereditary Cancer Group of an academic cancer center. Our primary objective was to evaluate the occurrence of RIMs after adjuvant radiotherapy. Sixteen patients were evaluated; 10 (62.5%) had a germline TP53 p.R337H pathogenic variant. Median age was 39.8 years. Thirteen patients had invasive ductal carcinoma: 8 (61.5%) were hormone receptor-positive; 6 (46.1%), human epithelial growth factor receptor 2 (HER2)-amplified. Three patients had ductal carcinoma in situ. Most patients (N = 12/16, 75%) received adjuvant radiotherapy. After a median follow-up of 52.5 months, 2 patients (2/12, 16.6%) had RIMs. One had a fibrosarcoma and the other, a low-grade leiomyosarcoma. In the group treated with radiotherapy, one distant recurrence was diagnosed (1/12), and no loco-regional recurrence occurred. Among 4 patients who did not receive radiotherapy, 2 presented with loco-regional recurrence. In this cohort of patients with LFS enriched in TP53 p.R337H pathogenic variant, the incidence of RIMs after treatment of localized breast cancer was lower than previous literature. Nevertheless, rates of RIMs were still alarming. Early molecular diagnosis and careful evaluation of treatment risks and benefits are essential for these patients.

Keywords:  Breast cancer; Li–Fraumeni; Radiotherapy; Radiotherapy-induced malignancies; TP53

DOI:  https://doi.org/10.1007/s10689-019-00153-5
Front Genet. 2019 ;10 952

A Pediatric Case of Glioblastoma Multiforme Associated With a Novel Germline p.His112CysfsTer9 Mutation in the MLH1 Gene Accompanied by a p.Arg283Cys Mutation in the TP53 Gene: A Case Report.

Aleksandra Stajkovska, Sanja Mehandziska, Rodney Rosalia, Margarita Stavrevska, Marija Janevska, Martina Markovska, Ivan Kungulovski, Zan Mitrev, Goran Kungulovski.

  Targeted gene panel testing has the power to interrogate hundreds of genes and evaluate the genetic risk for many types of hereditary cancers simultaneously. We screened a 13-year-old male patient diagnosed with glioblastoma multiforme with the aim to get further insights into the biology of his condition. Herein, we applied gene panel sequencing and identified a heterozygous frameshift mutation c.333_334delTC; p.His112CysfsTer9 in the MLH1 gene in blood and tumor tissue accompanied by a known heterozygous missense variant of unknown significance c.847C > T; p.Arg283Cys in the TP53 gene. Parental screening revealed the presence of the same TP53 variant in the father and the same MLH1 variant in the mother, who was in fact undergoing treatment for early-stage breast cancer at the time of her son's unfortunate diagnosis. This case reports for the first time the co-occurrence of a genetic mutation in the MLH1 gene of the mismatch repair pathway, commonly associated with the Lynch syndrome, accompanied by a rare variant in the TP53 gene. This report underlines the need for broad panel gene testing in lieu of single-gene or syndrome-focused gene screening and evaluation of the effects of multiple pathogenic or modifier variants on the phenotypic spectrum of the disease.

Keywords:  Li-Fraumeni; Lynch syndrome; MLH1; North Macedonia; TP53; case report; hereditary cancer syndromes; next-generation sequencing

DOI:  https://doi.org/10.3389/fgene.2019.00952
Pediatr Blood Cancer. 2019 Nov 17. e28047

Estimated number of adult survivors of childhood cancer in United States with cancer-predisposing germline variants.

Carmen L Wilson, Zhaoming Wang, Qi Liu, Matthew J Ehrhardt, Roya Mostafavi, John Easton, Heather Mulder, Dale J Hedges, Shuoguo Wang, Michael Rusch, Michael Edmonson, Shawn Levy, Jennifer Q Lanctot, Kelsey Currie, Matthew Lear, Aman Patel, Yadav Sapkota, Russell J Brooke, Wonjong Moon, Ti-Cheng Chang, Wenan Chen, Chimene A Kesserwan, Gang Wu, Kim E Nichols, Melissa M Hudson, Jinghui Zhang, Leslie L Robison, Yutaka Yasui.

   PURPOSE: To estimate the absolute number of adult survivors of childhood cancer in the U.S. population who carry a pathogenic or likely pathogenic variant in a cancer predisposition gene.
METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated the number of childhood cancer survivors on December 31, 2016 for each childhood cancer diagnosis, multiplied this by the proportion of carriers of pathogenic/likely pathogenic variants in the St. Jude Lifetime Cohort (SJLIFE) study, and projected the resulting number onto the U.S.
POPULATION:
RESULTS: Based on genome sequence data, 11.8% of 2450 SJLIFE participants carry a pathogenic/likely pathogenic variant in one of 156 cancer predisposition genes. Given this information, we estimate that 21 800 adult survivors of childhood cancer in the United States carry a pathogenic/likely pathogenic variant in one of these genes. The highest estimated absolute number of variant carriers are among survivors of central nervous system tumors (n = 4300), particularly astrocytoma (n = 1800) and other gliomas (n = 1700), acute lymphoblastic leukemia (n = 4300), and retinoblastoma (n = 3500). The most frequently mutated genes are RB1 (n = 3000), NF1 (n = 2300), and BRCA2 (n = 800).
CONCLUSION: Given the increasing number of childhood cancer survivors in the United States, clinicians should counsel survivors regarding their potential genetic risk, consider referral for genetic counseling and testing, and, as appropriate, implement syndrome-specific cancer surveillance or risk-reducing measures.

Keywords:  cancer genetics; epidemiology; oncogenes; pediatric oncology

DOI:  https://doi.org/10.1002/pbc.28047
Cancers (Basel). 2019 Nov 16. pii: E1804. [Epub ahead of print]11(11):

Penetrance of the TP53 R337H Mutation and Pediatric Adrenocortical Carcinoma Incidence Associated with Environmental Influences in a 12-Year Observational Cohort in Southern Brazil.

Tatiana E J Costa, Viviane K Q Gerber, Humberto C Ibañez, Viviane S Melanda, Ivy Z S Parise, Flora M Watanabe, Mara A D Pianovski, Carmem M C M Fiori, Ana L M R Fabro, Denise B da Silva, Diancarlos P Andrade, Heloisa Komechen, Monalisa C Mendes, Edna Carboni, Ana Paula Kuczynski, Emanuelle N Souza, Mariana M Paraizo, Marilea V C Ibañez, Laura M Castilho, Amanda F Cruz, Thuila F da Maia, Cleber Machado-Souza, Roberto Rosati, Claudia S Oliveira, Guilherme A Parise, Jaqueline D C Passos, José R S Barbosa, Mirna M O Figueiredo, Leniza Lima, Tiago Tormen, Cesar C Sabbaga, Sylvio G A Ávilla, Leila Grisa, Airton Aranha, Karina C F Tosin, Karin R P Ogradowski, Geneci Lima, Edith F Legal, Tania H Anegawa, Tânia L Mazzuco, André L Grion, José H G Balbinotti, Karin L Dammski, Rosiane G Melo, Nilton Kiesel Filho, Gislaine Custódio, Bonald C Figueiredo.

  The TP53 R337H mutation is associated with increased incidence of pediatric adrenocortical tumor (ACT). The different environmental conditions where R337H carriers live have not been systematically analyzed. Here, the R337H frequencies, ACT incidences, and R337H penetrance for ACT were calculated using the 2006 cohort with 4165 R337H carriers living in Paraná state (PR) subregions. The effectiveness of a second surveillance for R337H probands selected from 42,438 tested newborns in PR (2016 cohort) was tested to detect early stage I tumor among educated families without periodical exams. Estimation of R337H frequencies and ACT incidence in Santa Catarina state (SC) used data from 50,115 tested newborns without surveillance, ACT cases from a SC hospital, and a public cancer registry. R337H carrier frequencies in the population were 0.245% (SC) and 0.306% (PR), and 87% and 95% in ACTs, respectively. The ACT incidence was calculated as ~6.4/million children younger than 10 years per year in PR (95% CI: 5.28; 7.65) and 4.15/million in SC (CI 95%: 2.95; 5.67). The ACT penetrance in PR for probands followed from birth to 12 years was 3.9%. R337H carriers living in an agricultural subregion (C1) had a lower risk of developing pediatric ACT than those living in industrial and large urban subregion (relative risk = 2.4). One small ACT (21g) without recurrence (1/112) was detected by the parents in the 2016 cohort. ACT incidence follows R337H frequency in each population, but remarkably environmental factors modify these rates.

Keywords:  Li–Fraumeni syndrome; R337H; TP53; adrenocortical carcinoma; children; environmental modifiers

DOI:  https://doi.org/10.3390/cancers11111804
Curr Treat Options Gastroenterol. 2019 Nov 18.

Incorporating Colorectal Cancer Genetic Risk Assessment into Gastroenterology Practice.

Benjamin Stern, Thomas McGarrity, Maria Baker.

   PURPOSE OF REVIEW: Decades have passed since the underlying molecular etiologies of the most common hereditary forms of colorectal cancer (CRC), Lynch syndrome, and familial adenomatous polyposis (FAP) were first described. With the advent of next-generation sequencing (NGS) panels, the landscape of hereditary CRC testing has changed dramatically. We review available screening strategies, novel CRC predisposition genes, and challenges and opportunities in this field.
RECENT FINDINGS: Improved sensitivity and availability of NGS panel testing have greatly expanded our understanding regarding the number of CRC syndromes and their phenotypic expression. A variety of screening strategies are available to identify heritable CRC syndromes, potentially decreasing morbidity and mortality in this population. However, these screening strategies remain imperfect and present challenges regarding their implementation in clinical practice. Screening strategies include universal screening of CRC tumors for Lynch syndrome, clinical prediction algorithms, and risk assessment questionnaires. Additionally, there remains a gap in our understanding of the clinical implications of novel gene mutations of variable penetrance and unexpected NGS panel test results. Incorporation of single nucleotide polymorphisms (SNPs) may help to further refine cancer risk assessment, and the clinical introduction of RNA analysis may allow us to clarify variants of unknown significance (VUSs) and identify deep intronic mutations that would otherwise be missed. Recognition of genetic predisposition to CRC is critical for the practicing gastroenterologist. The evolving field of cancer genetics offers great challenges and opportunities for improved CRC management.

Keywords:  Cancer genetic testing; Cancer risk assessment; Genetic counseling; Hereditary colorectal cancer; Next-generation sequencing panel; Polyposis

DOI:  https://doi.org/10.1007/s11938-019-00267-w
Cancer Sci. 2019 Nov 19.

Prevalence of hereditary breast and ovarian cancer predisposition gene mutations among 882 HBOC high-risk Chinese individuals.

Di Shao, Shaomin Cheng, Fengming Guo, Changbin Zhu, Yuying Yuan, Kunling Hu, Zhe Wang, Xuan Meng, Xin Jin, Yun Xiong, Xianghua Chai, Hong Li, Yu Zhang, Hongyun Zhang, Jihong Liu, Mingzhi Ye.

  Identification of deleterious variants in HBOC susceptibility genes allows for increased clinical surveillance and early detection, and could predict the response to PARP inhibitor in patient with advanced ovarian carcinomas. To determine the prevalence and clinical prediction factors for hereditary breast and ovarian carcinoma syndrome, 882 selected individuals underwent multigene panel testing for hereditary breast and ovarian cancer (HBOC) risk assessment at the period from January 2015 to March 2018. Overall, 176 deleterious mutations were observed in 19.50% (n = 172) individuals. 26 of 176 mutations were not previously as well as archived in public database. Among patients with ovarian cancer, 115 deleterious mutations were identified in 429 patients (48.6%) with significant enrichment for a family history of breast or ovarian cancer syndrome (p < 0.05). In breast cancer subgroup, 31 deleterious mutations were identified in 261 patients. Besides BRCA1 (8; 25.8%) and BRCA2 (11; 35.5%), most occurred genes, an additional 12 deleterious mutations (38.7%) were found in 7 other susceptibility genes. Higher mutation incidence (57.9%) was observed in subjects with histories of breast and ovarian cancer. Our results highlighted the genetic heterogeneity of HBOC and the efficiency of multigene panel in performing risk assessment.

Keywords:  BRCA1; BRCA2; HBOC; Mutation; NGS

DOI:  https://doi.org/10.1111/cas.14242
Gynecol Oncol. 2019 Nov 18. pii: S0090-8258(19)31670-1. [Epub ahead of print]

Clinicopathological features of women with epithelial ovarian cancer and double heterozygosity for BRCA1 and BRCA2: A systematic review and case report analysis.

Cécile Le Page, Kurosh Rahimi, Manuel Rodrigues, Viola Heinzelmann-Schwarz, Neil Recio, Stefania Tommasi, Guillaume Bataillon, Lise Portelance, Lisa Golmard, Liliane Meunier, Patricia N Tonin, Walter Gotlieb, Amber Yasmeen, Isabelle Ray-Coquard, S Intidhar Labidi-Galy, Diane Provencher, Anne-Marie Mes-Masson.

   BACKGROUND: Carriers of pathogenic variants in both BRCA1 and BRCA2 genes as a double mutation (BRCA1/2 DM) have been rarely reported in women with epithelial ovarian cancer (EOC).
METHODS: We reviewed the English literature and interrogated three repositories reporting EOC patients carrying BRCA1/2 DM. The clinicopathological parameters of 36 EOC patients carrying germline BRCA1/2 DM were compared to high-grade serous EOC women of the COEUR cohort with known germline BRCA1/BRCA2 mutation carrier status (n = 376 non-carriers, n = 65 BRCA1 and n = 38 BRCA2). Clinicopathological parameters evaluated were age at diagnosis, stage of disease, loss of heterozygosity, type of mutation, immunohistochemistry profile, progression occurrence and survival.
RESULTS: Median age at diagnosis of BRCA1/2 DM patients was 51.9 years, similar to BRCA1 mutation carriers (49.7 years, p = .58) and younger than BRCA2 mutation carriers (58.1 years, p = .02). Most patients were diagnosed at advanced stage (III-IV; 82%) and were carriers of founder/frequent mutations (69%). Tissue immunostainings revealed no progesterone receptor expression and low intraepithelial inflammation. The 5-year survival rate (60%) was significantly lower than that of BRCA2 mutation carriers (76%, p = .03) but not of BRCA1 mutation carriers (51%, p = .37).
CONCLUSIONS: Our data suggests some co-dominant effect of both mutations but the outcome of these patients more closely resembled that of BRCA1 mutation carriers with poor prognosis factors.

Keywords:  BRCA; COEUR cohort; Heterozygosity; High-grade serous ovarian carcinoma; Hormone receptor; Survival

DOI:  https://doi.org/10.1016/j.ygyno.2019.11.019
Fam Cancer. 2019 Nov 19.

MLH1 promoter hypermethylation: are you absolutely sure about the absence of MLH1 germline mutation? About a new case.

Caroline Kientz, Fabienne Prieur, Alix Clemenson, Marie-Odile Joly, Marie-Laure Stachowicz, Jessie Auclair, Valéry Attignon, Renaud Schiappa, Qing Wang.

  Lynch syndrome accounts for 3-5% of colorectal cancers and is due to a germline mutation in one of the mismatch repair genes MLH1, MSH2, MSH6, and PMS2. Somatic hypermethylation of the MLH1 promoter is commonly associated to sporadic cases. Strategies have been developed to identify patients with Lynch Syndrome based on clinical findings, tumoral phenotype, family history and immunohistochemistry analysis. However, there still are some pitfalls in this strategy, possibly responsible for an underdiagnosis of Lynch syndrome. Here we report the case of a 37 years-old man presenting with two concomitant tumors located in the rectosigmoid and in the ileocecal angle. Both tumors were microsatellites instability-high (MSI-H) and showed a loss of MLH1 and PMS2 protein expression, but only one had MLH1 promoter hypermethylation. Constitutional analysis of mismatch repair genes could not be performed from a blood sample, because of the early death of the patient. However, tumoral tissue analyses revealed in both tumors a pathogenic variant in the MLH1 gene. Further analysis of the surrounding tumor-free tissue also showed the presence of this alteration of the MHL1 gene. Finally, the same pathogenic variant was present constitutionally in one of the siblings of the patient, confirming its hereditary nature. This new case of concomitant presence of MLH1 promoter hypermethylation and MLH1 germline mutation demonstrates that the presence of MLH1 promoter hypermethylation should not rule out the diagnosis of Lynch Syndrome.

Keywords:  BRAF; Lynch syndrome; MLH1; MLH1 promoter hypermethylation; MSI

DOI:  https://doi.org/10.1007/s10689-019-00151-7
PeerJ. 2019 ;7 e7972

Identification of novel BRCA1 large genomic rearrangements by a computational algorithm of amplicon-based Next-Generation Sequencing data.

Arianna Nicolussi, Francesca Belardinilli, Valentina Silvestri, Yasaman Mahdavian, Virginia Valentini, Sonia D'Inzeo, Marialaura Petroni, Massimo Zani, Sergio Ferraro, Stefano Di Giulio, Francesca Fabretti, Beatrice Fratini, Angela Gradilone, Laura Ottini, Giuseppe Giannini, Anna Coppa, Carlo Capalbo.

   Background: Genetic testing for BRCA1/2 germline mutations in hereditary breast/ovarian cancer patients requires screening for single nucleotide variants, small insertions/deletions and large genomic rearrangements (LGRs). These studies have long been run by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The recent introduction of next-generation sequencing (NGS) platforms dramatically improved the speed and the efficiency of DNA testing for nucleotide variants, while the possibility to correctly detect LGRs by this mean is still debated. The purpose of this study was to establish whether and to which extent the development of an analytical algorithm could help us translating NGS sequencing via an Ion Torrent PGM platform into a tool suitable to identify LGRs in hereditary breast-ovarian cancer patients.
Methods: We first used NGS data of a group of three patients (training set), previously screened in our laboratory by conventional methods, to develop an algorithm for the calculation of the dosage quotient (DQ) to be compared with the Ion Reporter (IR) analysis. Then, we tested the optimized pipeline with a consecutive cohort of 85 uncharacterized probands (validation set) also subjected to MLPA analysis. Characterization of the breakpoints of three novel BRCA1 LGRs was obtained via long-range PCR and direct sequencing of the DNA products.
Results: In our cohort, the newly defined DQ-based algorithm detected 3/3 BRCA1 LGRs, demonstrating 100% sensitivity and 100% negative predictive value (NPV) (95% CI [87.6-99.9]) compared to 2/3 cases detected by IR (66.7% sensitivity and 98.2% NPV (95% CI [85.6-99.9])). Interestingly, DQ and IR shared 12 positive results, but exons deletion calls matched only in five cases, two of which confirmed by MLPA. The breakpoints of the 3 novel BRCA1 deletions, involving exons 16-17, 21-22 and 20, have been characterized.
Conclusions: Our study defined a DQ-based algorithm to identify BRCA1 LGRs using NGS data. Whether confirmed on larger data sets, this tool could guide the selection of samples to be subjected to MLPA analysis, leading to significant savings in time and money.

Keywords:  Analytical validation; BRCA1 LGRs; DQ analysis; Deep coverage; MLPA; NGS

DOI:  https://doi.org/10.7717/peerj.7972
Breast Cancer Res Treat. 2019 Nov 21.

Exome sequencing study of Russian breast cancer patients suggests a predisposing role for USP39.

Ekaterina S Kuligina, Anna P Sokolenko, Ilya V Bizin, Alexandr A Romanko, Kirill A Zagorodnev, Maria O Anisimova, Daria D Krylova, Elena I Anisimova, Maria A Mantseva, Ashok K Varma, Syed K Hasan, Valeria I Ni, Andrey V Koloskov, Evgeny N Suspitsin, Aigul R Venina, Svetlana N Aleksakhina, Tatiana N Sokolova, Ana Marija Milanović, Peter Schürmann, Darya S Prokofyeva, Marina A Bermisheva, Elza K Khusnutdinova, Natalia Bogdanova, Thilo Dörk, Evgeny N Imyanitov.

   PURPOSE: Germline variants in known breast cancer (BC) predisposing genes explain less than half of hereditary BC cases. This study aimed to identify missing genetic determinants of BC.
METHODS: Whole exome sequencing (WES) of lymphocyte DNA was performed for 49 Russian patients with clinical signs of genetic BC predisposition, who lacked Slavic founder mutations in BRCA1, BRCA2, CHEK2, and NBS1 genes.
RESULTS: Bioinformatic analysis of WES data was allowed to compile a list of 229 candidate mutations. 79 of these mutations were subjected to a three-stage case-control analysis. The initial two stages, which involved up to 797 high-risk BC patients, 1504 consecutive BC cases, and 1081 healthy women, indicated a potentially BC-predisposing role for 6 candidates, i.e., USP39 c.*208G > C, PZP p.Arg680Ter, LEPREL1 p.Pro636Ser, SLIT3 p.Arg154Cys, CREB3 p.Lys157Glu, and ING1 p.Pro319Leu. USP39 c.*208G > C was strongly associated with triple-negative breast tumors (p = 0.0001). In the third replication stage, we genotyped the truncating variant of PZP (rs145240281) and the potential splice variant of USP39 (rs112653307) in three independent cohorts of Russian, Byelorussian, and German ancestry, comprising a total of 3216 cases and 2525 controls. The data obtained for USP39 rs112653307 supported the association identified in the initial stages (the combined OR 1.72, p = 0.035).
CONCLUSIONS: This study suggests the role of a rare splicing variant in BC susceptibility. USP39 encodes an ubiquitin-specific peptidase that regulates cancer-relevant tumor suppressors including CHEK2. Further epidemiological and functional studies involving these gene variants are warranted.

Keywords:  Case–control study; Germline mutations; Hereditary breast cancer; Non-BRCA1/2; Whole exome sequencing

DOI:  https://doi.org/10.1007/s10549-019-05492-6
Annu Rev Med. 2019 Nov 22.

Current Approaches to Germline Cancer Genetic Testing.

Elena M Stoffel, John M Carethers.

The prevalence of genetic predisposition to cancer is greater than initially appreciated, yet most affected individuals remain undiagnosed. Deleterious germline variants in cancer predisposition genes are implicated in 1 in 10 cases of advanced cancer. Next-generation sequencing technologies have made germline and tumor DNA sequencing more accessible and less expensive. Expanded access to clinical genetic testing will improve identification of individuals with genetic predisposition to cancer and provide opportunities to effectively reduce morbidity through precision cancer therapies and surveillance. Cross-disciplinary clinical education in genomic medicine is needed to translate advances in genomic medicine into improved health outcomes. Expected final online publication date for the Annual Review of Medicine, Volume 71 is January 27, 2020. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

DOI: https://doi.org/10.1146/annurev-med-052318-101009