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Published on: September 20, 2016
CDKN2A mutation in a non-FAMMM kindred with cancers at multiple sites results in a functionally abnormal protein
1Department of Medicine, McGill University, Montreal General Hospital Research Institute, Québec, Canada.
Abstract:
The CDKN2A gene encodes p16 (CDKN2A), a cell-cycle inhibitor protein which prevents inappropriate cell cycling and, hence, proliferation. Germ-line mutations in CDKN2A predispose to the familial atypical multiple-mole melanoma (FAMMM) syndrome but also have been seen in rare families in which only 1 or 2 individuals are affected by cutaneous malignant melanoma (CMM). We therefore sequenced exons 1alpha and 2 of CDKN2A using lymphocyte DNA isolated from index cases from 67 families with cancers at multiple sites, where the patterns of cancer did not resemble those attributable to known genes such as hMLH1, hMLH2, BRCA1, BRCA2, TP53 or other cancer susceptibility genes. We found one mutation, a mis-sense mutation resulting in a methionine to isoleucine change at codon 53 (M531) of exon 2. The individual tested had developed 2 CMMs but had no dysplastic nevi and lacked a family history of dysplastic nevi or CMM. Other family members had been diagnosed with oral cancer (2 persons), bladder cancer (1 person) and possibly gall-bladder cancer. While this mutation has been reported in Australian and North American melanoma kindreds, we did not observe it in 618 chromosomes from Scottish and Canadian controls. Functional studies revealed that the CDKN2A variant carrying the M531 change was unable to bind effectively to CDK4, showing that this mutation is of pathological significance. Our results have confirmed that CDKN2A mutations are not limited to FAMMM kindreds but also demonstrate that multi-site cancer families without melanoma are very unlikely to contain CDKN2A mutations.
Insights
The CDKN2A gene, a cell-cycle inhibitor, is linked to melanoma risk. A specific mutation (M531) was found in a multi-cancer family, confirming its pathological significance beyond familial atypical multiple-mole melanoma syndrome.
Area of Science:
- Genetics
- Oncology
- Molecular Biology
Background:
- The CDKN2A gene encodes the p16 protein, a crucial cell-cycle inhibitor.
- Germline mutations in CDKN2A are associated with familial atypical multiple-mole melanoma (FAMMM) syndrome and cutaneous malignant melanoma (CMM).
- Previous studies have primarily linked CDKN2A mutations to melanoma-predisposed families.
Purpose of the Study:
- To investigate CDKN2A mutations in families with multiple cancer types, not fitting known cancer susceptibility gene patterns.
- To determine if CDKN2A mutations are present in families with diverse cancers, including those without a strong melanoma history.
- To assess the functional impact of a novel CDKN2A mutation found in a multi-cancer family.
Main Methods:
- Sequencing of CDKN2A exons 1alpha and 2 in DNA from 67 families with various cancers.
- Analysis of mutation M531 in affected individuals and family members.
- Functional studies to evaluate the binding capacity of the mutated CDKN2A protein to CDK4.
- Screening of control populations (618 chromosomes) for the M531 mutation.
Main Results:
- One missense mutation (M531) in CDKN2A exon 2 was identified in an individual with two CMMs and family members with oral, bladder, and gall-bladder cancers.
- The M531 mutation was not found in Scottish and Canadian control populations.
- Functional assays demonstrated that the M531 variant of CDKN2A exhibited impaired binding to CDK4, indicating pathological significance.
- The study found CDKN2A mutations are unlikely in multi-site cancer families without a clear melanoma link.
Conclusions:
- CDKN2A mutations are not exclusive to FAMMM kindreds and can occur in individuals with CMM without typical risk factors.
- The identified M531 mutation in CDKN2A is functionally significant and associated with diverse cancer types.
- Multi-site cancer families lacking melanoma are unlikely to harbor CDKN2A mutations.
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