Assessment of genetic susceptibility to multiple primary cancers through whole-exome sequencing in two large multi-ancestry studies.
Germline genetics
Multiple primary cancers
Pleiotropy
Whole-exome sequencing
Journal
BMC medicine
ISSN: 1741-7015
Titre abrégé: BMC Med
Pays: England
ID NLM: 101190723
Informations de publication
Date de publication:
06 10 2022
06 10 2022
Historique:
received:
16
03
2022
accepted:
17
08
2022
entrez:
5
10
2022
pubmed:
6
10
2022
medline:
12
10
2022
Statut:
epublish
Résumé
Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored. To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers. We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer. Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.
Sections du résumé
BACKGROUND
Up to one of every six individuals diagnosed with one cancer will be diagnosed with a second primary cancer in their lifetime. Genetic factors contributing to the development of multiple primary cancers, beyond known cancer syndromes, have been underexplored.
METHODS
To characterize genetic susceptibility to multiple cancers, we conducted a pan-cancer, whole-exome sequencing study of individuals drawn from two large multi-ancestry populations (6429 cases, 165,853 controls). We created two groupings of individuals diagnosed with multiple primary cancers: (1) an overall combined set with at least two cancers across any of 36 organ sites and (2) cancer-specific sets defined by an index cancer at one of 16 organ sites with at least 50 cases from each study population. We then investigated whether variants identified from exome sequencing were associated with these sets of multiple cancer cases in comparison to individuals with one and, separately, no cancers.
RESULTS
We identified 22 variant-phenotype associations, 10 of which have not been previously discovered and were significantly overrepresented among individuals with multiple cancers, compared to those with a single cancer.
CONCLUSIONS
Overall, we describe variants and genes that may play a fundamental role in the development of multiple primary cancers and improve our understanding of shared mechanisms underlying carcinogenesis.
Identifiants
pubmed: 36199081
doi: 10.1186/s12916-022-02535-6
pii: 10.1186/s12916-022-02535-6
pmc: PMC9535845
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
332Subventions
Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : K99 CA246076
Pays : United States
Organisme : NCI NIH HHS
ID : T32 CA112355
Pays : United States
Organisme : NIA NIH HHS
ID : RC2 AG036607
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201358
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Investigateurs
Goncalo Abecasis
(G)
Aris Baras
(A)
Michael Cantor
(M)
Giovanni Coppola
(G)
Andrew Deubler
(A)
Aris Economides
(A)
Katia Karalis
(K)
Luca A Lotta
(LA)
John D Overton
(JD)
Jeffrey G Reid
(JG)
Katherine Siminovitch
(K)
Alan Shuldiner
(A)
Christina Beechert
(C)
Caitlin Forsythe
(C)
Erin D Fuller
(ED)
Zhenhua Gu
(Z)
Michael Lattari
(M)
Alexander Lopez
(A)
John D Overton
(JD)
Maria Sotiropoulos Padilla
(MS)
Manasi Pradhan
(M)
Kia Manoochehri
(K)
Thomas D Schleicher
(TD)
Louis Widom
(L)
Sarah E Wolf
(SE)
Ricardo H Ulloa
(RH)
Amelia Averitt
(A)
Nilanjana Banerjee
(N)
Michael Cantor
(M)
Dadong Li
(D)
Sameer Malhotra
(S)
Deepika Sharma
(D)
Jeffrey Staples
(J)
Xiaodong Bai
(X)
Suganthi Balasubramanian
(S)
Suying Bao
(S)
Boris Boutkov
(B)
Siying Chen
(S)
Gisu Eom
(G)
Lukas Habegger
(L)
Alicia Hawes
(A)
Shareef Khalid
(S)
Olga Krasheninina
(O)
Rouel Lanche
(R)
Adam J Mansfield
(AJ)
Evan K Maxwell
(EK)
George Mitra
(G)
Mona Nafde
(M)
Sean O'Keeffe
(S)
Max Orelus
(M)
Razvan Panea
(R)
Tommy Polanco
(T)
Ayesha Rasool
(A)
Jeffrey G Reid
(JG)
William Salerno
(W)
Jeffrey C Staples
(JC)
Kathie Sun
(K)
Jiwen Xin
(J)
Goncalo Abecasis
(G)
Joshua Backman
(J)
Amy Damask
(A)
Lee Dobbyn
(L)
Manuel Allen Revez Ferreira
(MAR)
Arkopravo Ghosh
(A)
Christopher Gillies
(C)
Lauren Gurski
(L)
Eric Jorgenson
(E)
Hyun Min Kang
(HM)
Michael Kessler
(M)
Jack Kosmicki
(J)
Alexander Li
(A)
Nan Lin
(N)
Daren Liu
(D)
Adam Locke
(A)
Jonathan Marchini
(J)
Anthony Marcketta
(A)
Joelle Mbatchou
(J)
Arden Moscati
(A)
Charles Paulding
(C)
Carlo Sidore
(C)
Eli Stahl
(E)
Kyoko Watanabe
(K)
Bin Ye
(B)
Blair Zhang
(B)
Andrey Ziyatdinov
(A)
Marcus B Jones
(MB)
Jason Mighty
(J)
Lyndon J Mitnaul
(LJ)
Informations de copyright
© 2022. The Author(s).
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