Naomi Livni

Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue

Genome-wide DNA sequencing was used to decrypt the phylogeny of multiple samples from distinct areas of cancer and morphologically normal tissue taken from the prostates of three men. Mutations were present at high levels in morphologically normal tissue distant from the cancer, reflecting clonal expansions, and the underlying mutational processes at work in morphologically normal tissue were also at work in cancer. Our observations demonstrate the existence of ongoing abnormal mutational processes, consistent with field effects, underlying carcinogenesis. This mechanism gives rise to extensive branching evolution and cancer clone mixing, as exemplified by the coexistence of multiple cancer lineages harboring distinct ERG fusions within a single cancer nodule. Subsets of mutations were shared either by morphologically normal and malignant tissues or between different ERG lineages, indicating earlier or separate clonal cell expansions. Our observations inform on the origin of multifocal disease and have implications for prostate cancer therapy in individual cases.

Metastatic Mucinous Tubular and Spindle Cell Carcinoma of the Kidney Responding to Sunitinib

TO THE EDITOR: Mucinous tubular and spindle cell carcinoma (MTSCC) of the kidney is a rare subtype of renal cell carcinoma (RCC). Fewer than 80 cases have been reported in the literature. Patients are usually female, and the mean age of patients in one series was 53 years. The majority of MTSCCs are indolent, and reports of recurrence and distant metastases are rare. Furthermore, almost all cases of nodal or metastatic disease are associated with a high nuclear grade or sarcomatoid element in the primary tumor. There are no published reports of systemic treatment in patients with metastatic disease. We describe here a patient with widespread metastatic MTSCC of the kidney treated successfully with sunitinib. A 61-year-old white female presented with several months of proximal limb myalgia and polyarthralgia. Polymyalgia rheumatica was diagnosed, and prednisone 10 mg daily was commenced. As a result of persistent elevation of inflammatory markers and a lifelong smoking history, chest radiography was undertaken, and a right-sided pulmonary nodule was demonstrated. A computed tomography (CT) scan of chest, abdomen, and pelvis showed a 3-cm right renal mass, a 3-cm left adrenal mass, bulky retroperitoneal adenopathy, a right pulmonary nodule, left hilar adenopathy, and widespread sclerotic bone metastases. Histology from a biopsy of the lower pole renal mass was consistent with an RCC with spindle cell morphology. Zoledronic acid infusions were initiated. Because of the unusually aggressive presentation, a further biopsy of the renal mass was undertaken at our institution. The biopsy was consistent with an MTSCC of the kidney. Biopsy of the retroperitoneal nodal mass was carried out to exclude a higher grade component or a second pathologic process and confirmed the diagnosis of MTSCC. Immunohistochemical staining for c-KIT was absent, as were mutations in exons 9, 11, 13, and 17 of c-KIT and exons 12, 14, and 18 of PDGFRA. The patient became progressively symptomatic with myalgia, arthralgia, and malaise, and sunitinib was commenced at 50 mg daily on the 4 weeks on/2 weeks off schedule, 7 weeks after the first zoledronic acid infusion. The patient tolerated treatment well, experiencing grade 1 mucositis and diarrhea only. Symptomatic improvement was reported within a few days of starting treatment; a restaging CT at 12 weeks demonstrated a reduction in size of the retroperitoneal nodal mass and left adrenal lesion and stability of other lesions, consistent with a partial response to therapy. At 24 weeks, the patient continues to derive clinical benefit from therapy, and a restaging CT shows stable disease. This is the first report, to our knowledge, of MSTCC of the kidney treated with sunitinib, and it is noteworthy that both symptomatic and radiologic responses occurred. A limitation of this report is that despite the fact that biopsies of both renal and retroperitoneal lesions were performed, it remains possible that the patient has a second diagnosis such as non–small-cell lung carcinoma. However, it should be noted that tumor shrinkage occurred in response to sunitinib in the biopsy-proven MSTCC retroperitoneal lymph node lesion. Sunitinib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors, plateletderived growth factor receptors, and c-KIT, and is a standard of care for the first-line treatment of advanced clear cell renal carcinoma. A pivotal phase III trial demonstrated a progression-free survival benefit of sunitinib versus interferon alfa but included patients with clear cell histology only. An expanded access trial of sunitinib allowed all histologic subtypes of RCC, but only 13% of patients had non– clear cell histology, and it is not known whether this population included any patients with MSTCC. The molecular pathology of MSTCC is unknown, and as a consequence, it is impossible to speculate with confidence which of the multiple targets of sunitinib may be implicated in a response to therapy. In light of this report, physicians who treat RCC may wish to consider sunitinib therapy for patients with MSTCC.

The PROFILE Feasibility Study: Targeted Screening of Men With a Family History of Prostate Cancer

A better assessment of prostate cancer (PrCa) risk is needed to improve screening. The PROFILE pilot study explored the feasibility of single nucleotide polymorphism profiling in men with a family history (FH) of PrCa to investigate the probability of detecting PrCa at prostate biopsy (PB). The results of the present pilot study have demonstrated that PB is a feasible and safe method of PrCa screening in men with a FH.

Appraising the relevance of DNA copy number loss and gain in prostate cancer using whole genome DNA sequence data.

A variety of models have been proposed to explain regions of recurrent somatic copy number alteration (SCNA) in human cancer. Our study employs Whole Genome DNA Sequence (WGS) data from tumor samples (n = 103) to comprehensively assess the role of the Knudson two hit genetic model in SCNA generation in prostate cancer. 64 recurrent regions of loss and gain were detected, of which 28 were novel, including regions of loss with more than 15% frequency at Chr4p15.2-p15.1 (15.53%), Chr6q27 (16.50%) and Chr18q12.3 (17.48%). Comprehensive mutation screens of genes, lincRNA encoding sequences, control regions and conserved domains within SCNAs demonstrated that a two-hit genetic model was supported in only a minor proportion of recurrent SCNA losses examined (15/40). We found that recurrent breakpoints and regions of inversion often occur within Knudson model SCNAs, leading to the identification of ZNF292 as a target gene for the deletion at 6q14.3-q15 and NKX3.1 as a two-hit target at 8p21.3-p21.2. The importance of alterations of lincRNA sequences was illustrated by the identification of a novel mutational hotspot at the KCCAT42, FENDRR, CAT1886 and STCAT2 loci at the 16q23.1-q24.3 loss. Our data confirm that the burden of SCNAs is predictive of biochemical recurrence, define nine individual regions that are associated with relapse, and highlight the possible importance of ion channel and G-protein coupled-receptor (GPCR) pathways in cancer development. We concluded that a two-hit genetic model accounts for about one third of SCNA indicating that mechanisms, such haploinsufficiency and epigenetic inactivation, account for the remaining SCNA losses.

Height, selected genetic markers and prostate cancer risk: results from the PRACTICAL consortium.

Background:Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer.Methods:We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions.Results:The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01–1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group.Conclusions:There was no evidence of gene-environment interaction between height and the selected candidate SNPs.Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.Background: Evidence on height and prostate cancer risk is mixed, however, recent studies with large data sets support a possible role for its association with the risk of aggressive prostate cancer. Methods: We analysed data from the PRACTICAL consortium consisting of 6207 prostate cancer cases and 6016 controls and a subset of high grade cases (2480 cases). We explored height, polymorphisms in genes related to growth processes as main effects and their possible interactions. Results: The results suggest that height is associated with high-grade prostate cancer risk. Men with height >180 cm are at a 22% increased risk as compared to men with height <173 cm (OR 1.22, 95% CI 1.01–1.48). Genetic variants in the growth pathway gene showed an association with prostate cancer risk. The aggregate scores of the selected variants identified a significantly increased risk of overall prostate cancer and high-grade prostate cancer by 13% and 15%, respectively, in the highest score group as compared to lowest score group. Conclusions: There was no evidence of gene-environment interaction between height and the selected candidate SNPs. Our findings suggest a role of height in high-grade prostate cancer. The effect of genetic variants in the genes related to growth is seen in all cases and high-grade prostate cancer. There is no interaction between these two exposures.

Erratum: Analysis of the genetic phylogeny of multifocal prostate cancer identifies multiple independent clonal expansions in neoplastic and morphologically normal prostate tissue (Nature Genetics (2015) 47 (367-372))

In the version of this article initially published, the following two sentences were omitted from the Acknowledgments: “Sequencing was carried out at the Millard and Muriel Jacobs Genome Facility at the California Institute of Technology. This work was supported by US National Institutes of Health grants to P.W.S. (GM084389) and to R.V.A. (AI056189), by Cornell University salary and start-up funds to E.M.S. and by the Howard Hughes Medical Institute to P.W.S.” The error has been corrected in the HTML and PDF versions of the article.