Multilocus Inherited Neoplasia Alleles Syndrome: A Case Series and Review

TY - JOUR

T1 - Multilocus Inherited Neoplasia Alleles Syndrome

T2 - A Case Series and Review

AU - Whitworth, James

AU - Skytte, Anne-Bine

AU - Sunde, Lone

AU - Lim, Derek H

AU - Arends, Mark J

AU - Happerfield, Lisa

AU - Frayling, Ian M

AU - van Minkelen, Rick

AU - Woodward, Emma R

AU - Tischkowitz, Marc D

AU - Maher, Eamonn R

PY - 2016/3

Y1 - 2016/3

N2 - Mendelian causes of inherited cancer susceptibility are mostly rare and characterized by variable expression and incomplete penetrance. Phenotypic variability may result from a range of causes including locus heterogeneity, allelic heterogeneity, genetic and environmental modifier effects, or chance. Another potential cause is the presence of 2 or more inherited cancer predisposition alleles in the same individual. Although the frequency of such occurrences might be predicted to be low, such cases have probably been underascertained because standard clinical practice has been to test candidate inherited cancer genes sequentially until a pathogenic mutation is detected. However, recent advances in next-generation sequencing technologies now provide the opportunity to perform simultaneous parallel testing of large numbers of inherited cancer genes. Herein we provide examples of patients who harbor pathogenic mutations in multiple inherited cancer genes and review previously published examples to illustrate the complex genotype-phenotype relationships in these cases. We suggest that clinicians should proactively consider the likelihood of this phenomenon (referred to herein as multilocus inherited neoplasia alleles syndrome [MINAS]) in patients with unusual inherited cancer syndrome phenotypes. To facilitate the clinical management of novel cases of MINAS, we have established a database to collect information on what is likely to be an increasingly recognized cohort of such individuals.

AB - Mendelian causes of inherited cancer susceptibility are mostly rare and characterized by variable expression and incomplete penetrance. Phenotypic variability may result from a range of causes including locus heterogeneity, allelic heterogeneity, genetic and environmental modifier effects, or chance. Another potential cause is the presence of 2 or more inherited cancer predisposition alleles in the same individual. Although the frequency of such occurrences might be predicted to be low, such cases have probably been underascertained because standard clinical practice has been to test candidate inherited cancer genes sequentially until a pathogenic mutation is detected. However, recent advances in next-generation sequencing technologies now provide the opportunity to perform simultaneous parallel testing of large numbers of inherited cancer genes. Herein we provide examples of patients who harbor pathogenic mutations in multiple inherited cancer genes and review previously published examples to illustrate the complex genotype-phenotype relationships in these cases. We suggest that clinicians should proactively consider the likelihood of this phenomenon (referred to herein as multilocus inherited neoplasia alleles syndrome [MINAS]) in patients with unusual inherited cancer syndrome phenotypes. To facilitate the clinical management of novel cases of MINAS, we have established a database to collect information on what is likely to be an increasingly recognized cohort of such individuals.

UR - http://www.scopus.com/inward/record.url?scp=84979642422&partnerID=8YFLogxK

U2 - 10.1001/jamaoncol.2015.4771

DO - 10.1001/jamaoncol.2015.4771

M3 - Review

C2 - 26659639

SN - 2374-2437

VL - 2

SP - 373

EP - 379

JO - JAMA Oncology

JF - JAMA Oncology

IS - 3

ER -