Abstract 2408: Analysis of the CDKN2A gene in FAMMM Syndrome families reveals early age of onset for additional syndromic cancers
Authors: Middlebrooks Candace D. 
Published: August 2019

Abstract
Familial atypical multiple mole melanoma (FAMMM) syndrome is a familial cancer syndrome that results from mutations in several genes including the CDKN2A gene. The syndrome is currently comprised of dysplastic nevi as well as melanoma and pancreatic cancer and is also associated with lung and breast cancer. The aforementioned set of cancers is referred to as “concordant” cancers. As families with known CDKN2A mutations have been studied longitudinally, clinicians observed an abundance of other cancers or “discordant cancers.” However, it was unknown whether these cancers were related to the syndrome. We sought to determine whether these discordant cancers also occur at higher frequencies and at earlier age of onset in carriers than non-carriers.
We studied 10 FAMMM syndrome families (N = 1085 individuals) in which a causal mutation in the CDKN2A gene was identified. We performed survival analysis as well as a mixed effects cox regression with age at follow-up or cancer event as our time variable and presence or absence of a concordant or discordant cancer as our censoring variable. The survival curves showed a significant age effect with carriers having a younger age at cancer onset for concordant (as expected) as well as discordant cancers than that of non-carriers. The cox regression models were also highly significant (P = 1.24E-27 and P = 5.00E-13 for the concordant and discordant cancers, respectively). We then performed a sensitivity analysis where we removed non-melanoma skin cancers from the discordant cancer group (coding individuals with these cancers as unaffected with a discordant cancer) to ensure that these cancers were not driving the effect seen. The result was still highly significant. Furthermore, we observed a visible pattern where individuals with multiple primaries presented with melanoma first followed by various combinations of other cancer primaries later on. It is likely that melanoma is the initial cancer to occur in a series of cancer occurrences as the result of a CDKN2A mutation tumor-driving effect paired with almost unavoidable UV light exposure. The additional cancer primaries that occurred in these individuals are likely the result of additional germline or acquired somatic mutations and/or environmental exposures that have latent effects.
These analyses support the hypothesis that carriers of mutations in CDKN2A in FAMMM syndrome have increased risk for early onset of several additional cancer types that are not currently screened in these families. This suggests that early screening for these cancers would be beneficial to carriers. The implications from this study could impact clinical guidelines in cancer screening of CDKN2A mutation families as well as policies formulated in regards to insurance coverage. This in turn may reduce the morbidity of these additional cancers (due to earlier investigation and diagnosis and targeting of prevention strategies).
Citation Format: Candace D. Middlebrooks. Analysis of the CDKN2A gene in FAMMM Syndrome families reveals early age of onset for additional syndromic cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2408.