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Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

Abstract Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention.
PMID
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Authors

Mayor MeshTerms

Germ-Line Mutation

Keywords
Journal Title jama
Publication Year Start




 
PMID- 28873162
OWN - NLM
STAT- MEDLINE
DA  - 20170905
DCOM- 20170912
LR  - 20170912
IS  - 1538-3598 (Electronic)
IS  - 0098-7484 (Linking)
VI  - 318
IP  - 9
DP  - 2017 Sep 05
TI  - Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of
      Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.
PG  - 825-835
LID - 10.1001/jama.2017.11137 [doi]
AB  - Importance: Guidelines for cancer genetic testing based on family history may
      miss clinically actionable genetic changes with established implications for
      cancer screening or prevention. Objective: To determine the proportion and
      potential clinical implications of inherited variants detected using simultaneous
      sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared
      with genetic test results based on current guidelines. Design, Setting, and
      Participants: From January 2014 until May 2016 at Memorial Sloan Kettering Cancer
      Center, 10336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of
      these patients with advanced cancer were referred by their oncologists for
      germline analysis of 76 cancer predisposition genes. Patients with clinically
      actionable inherited mutations whose genetic test results would not have been
      predicted by published decision rules were identified. Follow-up for potential
      clinical implications of mutation detection was through May 2017. Exposure: Tumor
      and germline sequencing compared with the predicted yield of targeted germline
      sequencing based on clinical guidelines. Main Outcomes and Measures: Proportion
      of clinically actionable germline mutations detected by universal tumor-normal
      sequencing that would not have been detected by guideline-directed testing.
      Results: Of 1040 patients, the median age was 58 years (interquartile range,
      50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of
      genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as
      the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%)
      had clinically actionable mutations conferring cancer susceptibility, including
      149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95%
      CI, 8.1%-11.7%) would not have had these mutations detected using clinical
      guidelines, including 65 with moderate- to high-penetrance mutations. Frequency
      of inherited mutations was related to case mix, stage, and founder mutations.
      Germline findings led to discussion or initiation of change to targeted therapy
      in 38 patients tested (3.7%) and predictive testing in the families of 13
      individuals (1.3%), including 6 for whom genetic evaluation would not have been
      initiated by guideline-based testing. Conclusions and Relevance: In this referral
      population with selected advanced cancers, universal sequencing of a broad panel 
      of cancer-related genes in paired germline and tumor DNA samples was associated
      with increased detection of individuals with potentially clinically significant
      heritable mutations over the predicted yield of targeted germline testing based
      on current clinical guidelines. Knowledge of these additional mutations can help 
      guide therapeutic and preventive interventions, but whether all of these
      interventions would improve outcomes for patients with cancer or their family
      members requires further study. Trial Registration: clinicaltrials.gov
      Identifier: NCT01775072.
FAU - Mandelker, Diana
AU  - Mandelker D
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Zhang, Liying
AU  - Zhang L
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Kemel, Yelena
AU  - Kemel Y
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
FAU - Stadler, Zsofia K
AU  - Stadler ZK
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Joseph, Vijai
AU  - Joseph V
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Zehir, Ahmet
AU  - Zehir A
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Pradhan, Nisha
AU  - Pradhan N
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Arnold, Angela
AU  - Arnold A
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Walsh, Michael F
AU  - Walsh MF
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Li, Yirong
AU  - Li Y
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Balakrishnan, Anoop R
AU  - Balakrishnan AR
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Syed, Aijazuddin
AU  - Syed A
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Prasad, Meera
AU  - Prasad M
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Nafa, Khedoudja
AU  - Nafa K
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Carlo, Maria I
AU  - Carlo MI
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Cadoo, Karen A
AU  - Cadoo KA
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Sheehan, Meg
AU  - Sheehan M
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Fleischut, Megan H
AU  - Fleischut MH
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Salo-Mullen, Erin
AU  - Salo-Mullen E
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Trottier, Magan
AU  - Trottier M
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Lipkin, Steven M
AU  - Lipkin SM
AD  - Weill Cornell Medical College, New York, New York.
FAU - Lincoln, Anne
AU  - Lincoln A
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Mukherjee, Semanti
AU  - Mukherjee S
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
FAU - Ravichandran, Vignesh
AU  - Ravichandran V
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Cambria, Roy
AU  - Cambria R
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Galle, Jesse
AU  - Galle J
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Abida, Wassim
AU  - Abida W
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Arcila, Marcia E
AU  - Arcila ME
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Benayed, Ryma
AU  - Benayed R
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
FAU - Shah, Ronak
AU  - Shah R
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
FAU - Yu, Kenneth
AU  - Yu K
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Bajorin, Dean F
AU  - Bajorin DF
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Coleman, Jonathan A
AU  - Coleman JA
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Leach, Steven D
AU  - Leach SD
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Lowery, Maeve A
AU  - Lowery MA
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Garcia-Aguilar, Julio
AU  - Garcia-Aguilar J
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Kantoff, Philip W
AU  - Kantoff PW
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Sawyers, Charles L
AU  - Sawyers CL
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Dickler, Maura N
AU  - Dickler MN
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Saltz, Leonard
AU  - Saltz L
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Motzer, Robert J
AU  - Motzer RJ
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - O'Reilly, Eileen M
AU  - O'Reilly EM
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Scher, Howard I
AU  - Scher HI
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Baselga, Jose
AU  - Baselga J
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Klimstra, David S
AU  - Klimstra DS
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Solit, David B
AU  - Solit DB
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Hyman, David M
AU  - Hyman DM
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Berger, Michael F
AU  - Berger MF
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Ladanyi, Marc
AU  - Ladanyi M
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
FAU - Robson, Mark E
AU  - Robson ME
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
FAU - Offit, Kenneth
AU  - Offit K
AD  - Memorial Sloan Kettering Cancer Center, New York, New York.
AD  - Sloan Kettering Institute, New York, New York.
AD  - Weill Cornell Medical College, New York, New York.
LA  - eng
GR  - P30 CA008748/CA/NCI NIH HHS/United States
PT  - Journal Article
PL  - United States
TA  - JAMA
JT  - JAMA
JID - 7501160
RN  - 0 (Biomarkers, Tumor)
RN  - 0 (DNA, Neoplasm)
SB  - AIM
SB  - IM
MH  - Aged
MH  - Biomarkers, Tumor/genetics
MH  - DNA Mutational Analysis/methods
MH  - DNA, Neoplasm/*analysis
MH  - Female
MH  - Genetic Predisposition to Disease
MH  - Genetic Testing
MH  - *Germ-Line Mutation
MH  - Humans
MH  - Male
MH  - Middle Aged
MH  - Neoplasms/*genetics
MH  - Phenotype
MH  - Prospective Studies
EDAT- 2017/09/06 06:00
MHDA- 2017/09/13 06:00
CRDT- 2017/09/06 06:00
AID - 2652651 [pii]
AID - 10.1001/jama.2017.11137 [doi]
PST - ppublish
SO  - JAMA. 2017 Sep 5;318(9):825-835. doi: 10.1001/jama.2017.11137.