Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the Prospective Lynch Syndrome Database.
Adult
Aged
Colorectal Neoplasms, Hereditary Nonpolyposis
/ genetics
DNA Mismatch Repair
DNA-Binding Proteins
/ economics
Databases, Genetic
Female
Genetic Predisposition to Disease
Humans
Male
Middle Aged
Mismatch Repair Endonuclease PMS2
/ genetics
MutL Protein Homolog 1
/ genetics
MutS Homolog 2 Protein
/ genetics
Mutation
Penetrance
Prospective Studies
Risk Assessment
Sex Characteristics
Survival Analysis
Lynch syndrome
MLH1
MSH2
MSH6
PMS2
Journal
Genetics in medicine : official journal of the American College of Medical Genetics
ISSN: 1530-0366
Titre abrégé: Genet Med
Pays: United States
ID NLM: 9815831
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
05
02
2019
accepted:
17
06
2019
pubmed:
25
7
2019
medline:
9
6
2020
entrez:
25
7
2019
Statut:
ppublish
Résumé
Pathogenic variants affecting MLH1, MSH2, MSH6, and PMS2 cause Lynch syndrome and result in different but imprecisely known cancer risks. This study aimed to provide age and organ-specific cancer risks according to gene and gender and to determine survival after cancer. We conducted an international, multicenter prospective observational study using independent test and validation cohorts of carriers of class 4 or class 5 variants. After validation the cohorts were merged providing 6350 participants and 51,646 follow-up years. There were 1808 prospectively observed cancers. Pathogenic MLH1 and MSH2 variants caused high penetrance dominant cancer syndromes sharing similar colorectal, endometrial, and ovarian cancer risks, but older MSH2 carriers had higher risk of cancers of the upper urinary tract, upper gastrointestinal tract, brain, and particularly prostate. Pathogenic MSH6 variants caused a sex-limited trait with high endometrial cancer risk but only modestly increased colorectal cancer risk in both genders. We did not demonstrate a significantly increased cancer risk in carriers of pathogenic PMS2 variants. Ten-year crude survival was over 80% following colon, endometrial, or ovarian cancer. Management guidelines for Lynch syndrome may require revision in light of these different gene and gender-specific risks and the good prognosis for the most commonly associated cancers.
Identifiants
pubmed: 31337882
doi: 10.1038/s41436-019-0596-9
pii: S1098-3600(21)01093-5
pmc: PMC7371626
doi:
Substances chimiques
DNA-Binding Proteins
0
G-T mismatch-binding protein
0
MLH1 protein, human
0
PMS2 protein, human
EC 3.6.1.-
MSH2 protein, human
EC 3.6.1.3
Mismatch Repair Endonuclease PMS2
EC 3.6.1.3
MutL Protein Homolog 1
EC 3.6.1.3
MutS Homolog 2 Protein
EC 3.6.1.3
Types de publication
Journal Article
Multicenter Study
Observational Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
15-25Subventions
Organisme : NCI NIH HHS
ID : R01 CA104132
Pays : United States
Organisme : Department of Health
ID : NIHR-CS-012-009
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : U01 CA074799
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074783
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074806
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074800
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : UM1 CA167551
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074783
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074799
Pays : United States
Organisme : Department of Health
ID : IS-BRC-1215–20007
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : U24 CA074794
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA097735
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074794
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA074806
Pays : United States
Organisme : NCI NIH HHS
ID : U24 CA074800
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : CommentIn
Type : ErratumIn
Type : CommentIn
Type : CommentIn
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