TY - JOUR
T1 - Analysis of the CDKN2A gene in FAMMM syndrome families reveals early age of onset for additional syndromic cancers
AU - Middlebrooks, Candace D.
AU - Stacey, Mark L.
AU - Li, Qing
AU - Snyder, Carrie
AU - Shaw, Trudy G.
AU - Richardson-Nelson, Tami
AU - Rendell, Marc
AU - Ferguson, Claire
AU - Silberstein, Peter
AU - Casey, Murray J.
AU - Bailey-Wilson, Joan E.
AU - Lynch, Henry T.
N1 - Funding Information:
This work was supported in part by the Intramural Research Program, National Human Genome Research Institute of the U.S. National Institutes of Health, which supported the research led by J.E. Bailey-Wilson. This publication was also supported by revenue from Nebraska's excise tax on cigarettes (LB595 funds) awarded to Creighton University through the Nebraska Department of Health & Human Services (DHHS), which supported the clinical studies led by H.T. Lynch. Its contents represent the views of the authors and do not necessarily represent the official views of the State of Nebraska or DHHS. Funding was also received from the Liz's Legacy fund through Kicks for a Cure, which supported the clinical studies led by H.T. Lynch.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/6/1
Y1 - 2019/6/1
N2 - Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome that results from mutations in several genes, including the CDKN2A gene. In addition to melanoma, certain other malignancies such as pancreatic cancer are known to occur more frequently in family members who carry the mutation. However, as these families have been followed over time, additional cancers have been observed in both carriers and noncarriers. We sought to determine whether these additional cancers occur at higher frequencies in carriers than noncarriers. We performed survival analyses using 10 FAMMM syndrome families (N ¼ 1,085 individuals) as well as a mixed effects Cox regression, with age at last visit to the clinic or age at cancer diagnosis as our time variable. This analysis was done separately for the known FAMMM-related cancers and "other" cancer groups. The survival curves showed a significant age effect with carriers having a younger age at cancer onset than noncarriers for FAMMM-related cancers (as expected) as well as for newly associated cancers. The Cox regression reflected what was seen in the survival curves, with all models being highly significant (P ¼ 7.15E20 and P ¼ 5.00E13 for the FAMMM-related and other cancers, respectively). These analyses support the hypothesis that CDKN2A mutation carriers in FAMMM syndrome families have increased risk for early onset of several cancer types beyond the known cancers. Therefore, these individuals should be screened for additional cancers, and mutation screening should be extended to more than first-degree relatives of an index carrier patient. Significance: This study shows that carriers of mutations in the CDKN2A gene in FAMMM syndrome are at increased risk for early onset of several cancer types beyond the known cancers.
AB - Familial atypical multiple mole melanoma (FAMMM) syndrome is a hereditary cancer syndrome that results from mutations in several genes, including the CDKN2A gene. In addition to melanoma, certain other malignancies such as pancreatic cancer are known to occur more frequently in family members who carry the mutation. However, as these families have been followed over time, additional cancers have been observed in both carriers and noncarriers. We sought to determine whether these additional cancers occur at higher frequencies in carriers than noncarriers. We performed survival analyses using 10 FAMMM syndrome families (N ¼ 1,085 individuals) as well as a mixed effects Cox regression, with age at last visit to the clinic or age at cancer diagnosis as our time variable. This analysis was done separately for the known FAMMM-related cancers and "other" cancer groups. The survival curves showed a significant age effect with carriers having a younger age at cancer onset than noncarriers for FAMMM-related cancers (as expected) as well as for newly associated cancers. The Cox regression reflected what was seen in the survival curves, with all models being highly significant (P ¼ 7.15E20 and P ¼ 5.00E13 for the FAMMM-related and other cancers, respectively). These analyses support the hypothesis that CDKN2A mutation carriers in FAMMM syndrome families have increased risk for early onset of several cancer types beyond the known cancers. Therefore, these individuals should be screened for additional cancers, and mutation screening should be extended to more than first-degree relatives of an index carrier patient. Significance: This study shows that carriers of mutations in the CDKN2A gene in FAMMM syndrome are at increased risk for early onset of several cancer types beyond the known cancers.
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U2 - 10.1158/0008-5472.CAN-18-1580
DO - 10.1158/0008-5472.CAN-18-1580
M3 - Article
C2 - 30967399
AN - SCOPUS:85066460303
VL - 79
SP - 2992
EP - 3000
JO - Cancer Research
JF - Cancer Research
SN - 0008-5472
IS - 11
ER -