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CM-Score : A validated scoring system to predict CDKN2A germline mutations in melanoma families from Northern Europe

Potjer, Thomas P.; Helgadottir, Hildur; Leenheer, Mirjam; Van Der Stoep, Nienke; Gruis, Nelleke A.; Höiom, Veronica; Olsson, Håkan LU ; Van Doorn, Remco; Vasen, Hans F.A. and Van Asperen, Christi J., et al. (2018) In Journal of Medical Genetics 55(10). p.661-668
Abstract

Background: Several factors have been reported that influence the probability of a germline CDKN2A mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. Methods: Five clinical features and their association with CDKN2A mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with CDKN2A mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring... (More)

Background: Several factors have been reported that influence the probability of a germline CDKN2A mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. Methods: Five clinical features and their association with CDKN2A mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with CDKN2A mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (CDKN2A Mutation(CM)-Score) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with CDKN2A mutation). Results: All five features were significantly associated (p<0.05) with a CDKN2A mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to >90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98). Conclusion: We developed a practical scoring system to predict CDKN2A mutation status among melanoma-prone families. We suggest that CDKN2A analysis should be recommended to families with a CM-Score of ≥16 points.

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published
subject
keywords
cancer: dermatological, cancer: head and neck, clinical genetics, genetic epidemiology, genetic screening/counselling
in
Journal of Medical Genetics
volume
55
issue
10
pages
661 - 668
publisher
BMJ Publishing Group
external identifiers
  • scopus:85049171102
ISSN
0022-2593
DOI
10.1136/jmedgenet-2017-105205
language
English
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yes
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34f8c307-d33c-45a1-8ab6-422e189d06fe
date added to LUP
2018-07-17 10:07:18
date last changed
2019-03-19 03:57:25
@article{34f8c307-d33c-45a1-8ab6-422e189d06fe,
  abstract     = {<p>Background: Several factors have been reported that influence the probability of a germline CDKN2A mutation in a melanoma family. Our goal was to create a scoring system to estimate this probability, based on a set of clinical features present in the patient and his or her family. Methods: Five clinical features and their association with CDKN2A mutations were investigated in a training cohort of 1227 Dutch melanoma families (13.7% with CDKN2A mutation) using multivariate logistic regression. Predefined features included number of family members with melanoma and with multiple primary melanomas, median age at diagnosis and presence of pancreatic cancer or upper airway cancer in a family member. Based on these five features, a scoring system (CDKN2A Mutation(CM)-Score) was developed and subsequently validated in a combined Swedish and Dutch familial melanoma cohort (n=421 families; 9.0% with CDKN2A mutation). Results: All five features were significantly associated (p&lt;0.05) with a CDKN2A mutation. At a CM-Score of 16 out of 49 possible points, the threshold of 10% mutation probability is approximated (9.9%; 95% CI 9.8 to 10.1). This probability further increased to &gt;90% for families with ≥36 points. A CM-Score under 16 points was associated with a low mutation probability (≤4%). CM-Score performed well in both the training cohort (area under the curve (AUC) 0.89; 95% CI 0.86 to 0.92) and the external validation cohort (AUC 0.94; 95% CI 0.90 to 0.98). Conclusion: We developed a practical scoring system to predict CDKN2A mutation status among melanoma-prone families. We suggest that CDKN2A analysis should be recommended to families with a CM-Score of ≥16 points.</p>},
  author       = {Potjer, Thomas P. and Helgadottir, Hildur and Leenheer, Mirjam and Van Der Stoep, Nienke and Gruis, Nelleke A. and Höiom, Veronica and Olsson, Håkan and Van Doorn, Remco and Vasen, Hans F.A. and Van Asperen, Christi J. and Dekkers, Olaf M. and Hes, Frederik J.},
  issn         = {0022-2593},
  keyword      = {cancer: dermatological,cancer: head and neck,clinical genetics,genetic epidemiology,genetic screening/counselling},
  language     = {eng},
  month        = {04},
  number       = {10},
  pages        = {661--668},
  publisher    = {BMJ Publishing Group},
  series       = {Journal of Medical Genetics},
  title        = {CM-Score : A validated scoring system to predict CDKN2A germline mutations in melanoma families from Northern Europe},
  url          = {http://dx.doi.org/10.1136/jmedgenet-2017-105205},
  volume       = {55},
  year         = {2018},
}