Open AccessAtypical tuberous sclerosis complex presenting as familial renal cell carcinoma with leiomyomatous stroma
Author(s) -
Bah Ismaël,
Fahiminiya Somayyeh,
Bégin Louis R,
Hamel Nancy,
D'Agostino Maria D,
Tanguay Simon,
Foulkes William D
Publication year - 2018
Publication title -
the journal of pathology: clinical research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.849
H-Index - 21
ISSN - 2056-4538
DOI - 10.1002/cjp2.104
Subject(s) - tuberous sclerosis , tsc2 , pathology , missense mutation , germline , locus (genetics) , renal cell carcinoma , tsc1 , biology , phenotype , exome sequencing , cancer research , medicine , genetics , gene , pi3k/akt/mtor pathway , apoptosis
We report an atypical tuberous sclerosis complex (TSC) phenotype presenting as familial multiple renal cell carcinomas (RCCs) with (angio)leiomyomatous stroma (RCCLS) (5/7 familial RCCs) on a background of multiple angiomyolipomas, hypopigmented skin macules, and absence of neurological anomalies. In the index case and three relatives, germline genetic testing identified a heterozygous TSC2 missense pathogenic variant [c.2714 G > A, (p.Arg905Gln)], a rare TSC‐associated alteration which has previously been associated with a milder TSC phenotype. Whole‐exome sequencing of five RCCs from the index case and one RCC from his mother demonstrated either unique tumour‐specific deleterious second hits in TSC2 or significant allelic imbalance at the TSC2 gene locus (5/6 RCCs). This study confirms the key tumourigenic role of tumour‐specific TSC2 second hits in TSC‐associated RCCs and supports the notion that RCCLS may be strongly related to abnormalities of the mTOR pathway.