Parent of origin effects on age at colorectal cancer diagnosis.
Genomic imprinting refers to a parent-of-origin specific effect on gene expression. At least 1% of genes in the human genome are modulated in this manner. We sought evidence for genomic imprinting in colorectal cancer by studying the ages at diagnosis in the offspring of 2,061 parent-child pairs in which both parent and child were affected by nonsyndromic colorectal cancer. Families were ascertained through the colon Cancer Family Registry [http://epi.grants.cancer.gov/CFR/] from both population-based and clinic-based sources. We found that the affected offspring of affected fathers were on average younger than offspring of affected mothers (55.8 vs. 53.7 years; p = 0.0003), but when divided into sons and daughters, this difference was driven entirely by younger age at diagnosis in daughters of affected fathers compared to sons (52.3 years vs. 55.1 years; p = 0.0004). A younger age at diagnosis in affected daughters of affected fathers was also observable in various subsets including families that met Amsterdam II Criteria, families that did not meet Amsterdam Criteria, and in families with documented normal DNA mismatch repair in tumors. Imprinting effects are not expected to be affected by the sex of the offspring. Possible explanations for these unexpected findings include: (i) an imprinted gene on the pseudoautosomal regions of the X chromosome; (ii) an imprinted autosomal gene that affects a sex-specific pathway; or (iii) an X-linked gene unmasked because of colonic tissue-specific preferential inactivation of the maternal X chromosome.
Lindor
Noralane M
NM
Department of Medical Genetics, Mayo Clinic, Rochester, MN, USA. nlindor@mayo.edu
Rabe
Kari G
KG
Petersen
Gloria M
GM
Chen
Helen
H
Bapat
Bharati
B
Hopper
John
J
Young
Joanne
J
Jenkins
Mark
M
Potter
John
J
Newcomb
Polly
P
Templeton
Allyson
A
Lemarchand
Loic
L
Grove
John
J
Burgio
Michael R
MR
Haile
Robert
R
Green
Jane
J
Woods
Michael O
MO
Seminara
Daniela
D
Limburg
Paul J
PJ
Thibodeau
Stephen N
SN
D000328:Adult; D000367:Age Factors; D017668:Age of Onset; D000368:Aged; D000369:Aged, 80 and over; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics*; D005220:Fathers; D005260:Female; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D018392:Genomic Imprinting / Q000235:genetics*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009035:Mothers; D055815:Young Adult