TY - JOUR
T1 - Cancer Risks for PMS2-Associated Lynch Syndrome
AU - ten Broeke, Sanne W.
AU - van der Klift, Heleen M.
AU - Tops, Carli M. J.
AU - Aretz, Stefan
AU - Bernstein, Inge
AU - Buchanan, Daniel D.
AU - de la Chapelle, Albert
AU - Capella, Gabriel
AU - Clendenning, Mark
AU - Engel, Christoph
AU - Gallinger, Steven
AU - Gomez Garcia, Encarna
AU - Figueiredo, Jane C.
AU - Haile, Robert
AU - Hampel, Heather L.
AU - Hopper, John L.
AU - Hoogerbrugge, Nicoline
AU - Doeberitz, Magnus von Knebel
AU - Le Marchand, Loic
AU - Letteboer, Tom G. W.
AU - Jenkins, Mark A.
AU - Lindblom, Annika
AU - Lindor, Noralane M.
AU - Mensenkamp, Arjen R.
AU - Moller, Pal
AU - Newcomb, Polly A.
AU - van Os, Theo A. M.
AU - Pearlman, Rachel
AU - Pineda, Marta
AU - Rahner, Nils
AU - Redeker, Egbert J. W.
AU - Olderode-Berends, Maran J. W.
AU - Rosty, Christophe
AU - Schackert, Hans K.
AU - Scott, Rodney
AU - Senter, Leigha
AU - Spruijt, Liesbeth
AU - Steinke-Lange, Verena
AU - Suerink, Manon
AU - Thibodeau, Stephen
AU - Vos, Yvonne J.
AU - Wagner, Anja
AU - Winship, Ingrid
AU - Hes, Frederik J.
AU - Vasen, Hans F. A.
AU - Wijnen, Juul T.
AU - Nielsen, Maartje
AU - Win, Aung Ko
PY - 2018/10/10
Y1 - 2018/10/10
N2 - PurposeLynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.MethodsA modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.ResultsIn total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.ConclusionHeterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
AB - PurposeLynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.MethodsA modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.ResultsIn total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% [95% CI, 7.9% to 22%] for males and 12% [95% CI, 6.7% to 21%] for females) and endometrial cancer (13% [95% CI, 7.0%-24%]), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.ConclusionHeterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
KW - NONPOLYPOSIS COLORECTAL-CANCER
KW - HEREDITARY BREAST
KW - ENDOMETRIAL CANCER
KW - FAMILY-HISTORY
KW - MUTATIONS
KW - MLH1
KW - PREVALENCE
KW - VARIANTS
KW - CARRIERS
KW - GENES
U2 - 10.1200/JCO.2018.78.4777
DO - 10.1200/JCO.2018.78.4777
M3 - Article
C2 - 30161022
SN - 0732-183X
VL - 36
SP - 2961
EP - 2968
JO - Journal of Clinical Oncology
JF - Journal of Clinical Oncology
IS - 29
ER -