Risks of Lynch syndrome cancers for MSH6 mutation carriers.
BACKGROUND
Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.


METHODS
We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.


RESULTS
For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).


CONCLUSIONS
We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.
Baglietto
Laura
L
Cancer Epidemiology Centre, Victorian Cancer Registry, Carlton, Victoria, Australia.
Lindor
Noralane M
NM
Dowty
James G
JG
White
Darren M
DM
Wagner
Anja
A
Gomez Garcia
Encarna B
EB
Vriends
Annette H J T
AH
Cartwright
Nicola R
NR
Barnetson
Rebecca A
RA
Farrington
Susan M
SM
Tenesa
Albert
A
Hampel
Heather
H
Buchanan
Daniel
D
Arnold
Sven
S
Young
Joanne
J
Walsh
Michael D
MD
Jass
Jeremy
J
Macrae
Finlay
F
Antill
Yoland
Y
Winship
Ingrid M
IM
Giles
Graham G
GG
Goldblatt
Jack
J
Parry
Susan
S
Suthers
Graeme
G
Leggett
Barbara
B
Butz
Malinda
M
Aronson
Melyssa
M
Poynter
Jenny N
JN
Baron
John A
JA
Le Marchand
Loic
L
Haile
Robert
R
Gallinger
Steve
S
Hopper
John L
JL
Potter
John
J
de la Chapelle
Albert
A
Vasen
Hans F
HF
Dunlop
Malcolm G
MG
Thibodeau
Stephen N
SN
Jenkins
Mark A
MA
D000328:Adult; D017677:Age Distribution; D000367:Age Factors; D000368:Aged; D000369:Aged, 80 and over; D001315:Australia / Q000453:epidemiology; D002170:Canada / Q000453:epidemiology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics; D005060:Europe / Q000453:epidemiology; D005260:Female; D017353:Gene Deletion; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D016254:Mutagenesis, Insertional; D009369:Neoplasms / Q000453:epidemiology / Q000235:genetics; D009520:New Zealand / Q000453:epidemiology; D012042:Registries; D018570:Risk Assessment; D012307:Risk Factors; D017678:Sex Distribution; D012737:Sex Factors; D014481:United States / Q000453:epidemiology
D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein