Somatic mutations in FLCN can cause cancer

The majority of research on FLCN is within the context of BHD syndrome, which is caused by heterozygous germline mutations in the FLCN gene. However, two recent papers have reported that somatic FLCN mutations may be a factor in the development of sporadic tumours.

Sirintrapun et al. (2014) describe the case of a 74 year old man who presented with metastatic renal cancer. Molecular analysis showed that roughly a third of the primary tumour consisted of benign oncocytic cells while the remaining two thirds of the tumour was a high grade oncocytic carcinoma. The patient showed an extended 20 month progression free survival with Temsirolimus treatment.

Genetic and expression profiling revealed that both parts of the tumour had a common origin, indicating that the benign oncocytoma gave rise to the high grade tumour. A number of genomic rearrangements were present in the high grade cells only, including heterozygous loss of 17p, which contains the FLCN gene.

Thus, the authors report a rare case of somatic FLCN deletion contributing to a sporadic case of renal cell carcinoma, and the first known case of a benign oncocytoma transforming to a high grade carcinoma. However, there were additional oncogenic genomic rearrangements present in the high grade oncocytic cells, such as loss of 8p and gain of 8q, suggesting that loss of FLCN was only partly responsible for the disease progression in this patient.

In the second study, Wagle et al. (2014) describe the case of a 57 year old woman with anaplastic thyroid cancer. The patient was enrolled in a phase II clinical trial testing everolimus and had a sustained response for 18 months, at which point her tumour became resistant to treatment. Whole exome sequencing of germline, pretreatment, and resistant tumour DNA revealed that the pretreatment tumour had somatic inactivating mutations in FLCN, TSC2, and TP53, which likely lead to increased mTOR signaling in tumour cells, making the tumour particularly sensitive to treatment with mTOR inhibitiors.

The resistant tumour had developed a missense mutation (mTORF2108L) which prevents everolimus binding to mTOR. In vitro studies show that mTORF2108L is still sensitive to kinase inhibitors, such as Torin1, suggesting that kinase inhibiton may be a suitable follow up treatment for this patient. The authors suggest that sequencing tumour DNA before and during treatment may suggest the most effective treatment regimen for the patient.

These studies contain a number of interesting findings. Firstly, that somatic mutations in the FLCN gene can cause not just kidney cancer, but other tumour types when combined with additional genetic lesions. Indeed, somatic mutations in FLCN have been found in rare cases of sporadic renal cell carcinoma, colorectal cancer, and thyroid oncocytoma (Gad et al., 2007, Kahnoski et al., 2003, Khoo et al., 2003, Pradella et al., 2013). This suggests that BHD is a fundamental disease, and research insights on BHD will yield relevant results for other types of cancer.

Secondly, that FLCN mutations – and other mutations which lead to increased mTOR signaling – may indicate that the tumour will respond well to treatment with mTOR inhibitors, and indeed both patients in these studies had particularly long responses to mTOR inhibitors (20 and 18 months respectively). This is particularly exceptional in the second patient’s case, as the median survival time for anaplastic thyroid cancer is five months.

Thirdly, that a personalised medicine approach – where treatment is based on the underlying metabolic abnormalities present within that tumour – will likely improve cancer survival rates. Additionally, ongoing monitoring of how tumours evolve resistance to treatment will suggest the most effective follow up treatments, even further extending lifespan following a cancer diagnosis.

When considered as a whole, these studies demonstrate the utility of genetic sequencing of tumours to determine how tumours develop and evolve, and suggest that in the future, tumours may be classified and treated according to the mutations they carry, rather than by tumour site.

 

  • Gad S, Lefèvre SH, Khoo SK, Giraud S, Vieillefond A, Vasiliu V, Ferlicot S, Molinié V, Denoux Y, Thiounn N, Chrétien Y, Méjean A, Zerbib M, Benoît G, Hervé JM, Allègre G, Bressac-de Paillerets B, Teh BT, & Richard S (2007). Mutations in BHD and TP53 genes, but not in HNF1beta gene, in a large series of sporadic chromophobe renal cell carcinoma. British journal of cancer, 96 (2), 336-40 PMID: 17133269
  • Kahnoski K, Khoo SK, Nassif NT, Chen J, Lobo GP, Segelov E, & Teh BT (2003). Alterations of the Birt-Hogg-Dubé gene (BHD) in sporadic colorectal tumours. Journal of medical genetics, 40 (7), 511-5 PMID: 12843323
  • Khoo SK, Kahnoski K, Sugimura J, Petillo D, Chen J, Shockley K, Ludlow J, Knapp R, Giraud S, Richard S, Nordenskjöld M, & Teh BT (2003). Inactivation of BHD in sporadic renal tumors. Cancer research, 63 (15), 4583-7 PMID: 12907635
  • Pradella LM, Lang M, Kurelac I, Mariani E, Guerra F, Zuntini R, Tallini G, MacKay A, Reis-Filho JS, Seri M, Turchetti D, & Gasparre G (2013). Where Birt-Hogg-Dubé meets Cowden syndrome: mirrored genetic defects in two cases of syndromic oncocytic tumours. European journal of human genetics : EJHG, 21 (10), 1169-72 PMID: 23386036
  • Sirintrapun SJ, Geisinger KR, Cimic A, Snow A, Hagenkord J, Monzon F, Legendre BL Jr, Ghazalpour A, Bender RP, & Gatalica Z (2014). Oncocytoma-like renal tumor with transformation toward high-grade oncocytic carcinoma: a unique case with morphologic, immunohistochemical, and genomic characterization. Medicine, 93 (15) PMID: 25275525
  • Wagle N, Grabiner BC, Van Allen EM, Amin-Mansour A, Taylor-Weiner A, Rosenberg M, Gray N, Barletta JA, Guo Y, Swanson SJ, Ruan DT, Hanna GJ, Haddad RI, Getz G, Kwiatkowski DJ, Carter SL, Sabatini DM, Jänne PA, Garraway LA, & Lorch JH (2014). Response and acquired resistance to everolimus in anaplastic thyroid cancer. The New England journal of medicine, 371 (15), 1426-33 PMID: 25295501

www.bhdsyndrome.org – the primary online resource for anyone interested in BHD Syndrome.

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