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www.thelancet.com/oncology Vol 15 April 2014 e156

Oophorectomy in women with BRCA1 or BRCA2 mutationsWomen with a BRCA1 or BRCA2 gene mutation reduce their risk of dying from any cause before the age of 70 years if they undergo a preventive oophorectomy, according to new research.

The prospective study, which ran from 1995 to 2011, observed 5783 women with a BRCA1 or BRCA2 mutation in 43 centres across Europe and North America. Roughly half these women had been aff ected by breast cancer when they entered the cohort; none had been aff ected by ovarian cancer. Average age on joining the study was 46 years and follow-up averaged 5·6 years, during which 186 new ovarian, fallopian, and peritoneal cancers were diagnosed. 2123 women had an oophorectomy at study baseline, 1390 had the procedure during follow-up, and 2274 did not have the procedure at all.

The hazard ratio (HR) for ovarian, fallopian tube, or peritoneal cancer associated with bilateral oophorectomy was 0·20 (95% CI 0·13–0·30; p<0·001). For women with no history of breast cancer at baseline, oophorectomy was associated with a decrease in all-cause mortality to age 70 years (HR 0·23, 95% CI 0·13–0·39; p<0·001). Importantly, preventive oophorectomies also conferred substantial benefi ts to women with a history of breast cancer (HR 0·32, 0·26–0·39; p<0·001).

“There are three benefi ts of oophorectomy”, lead author Steven Narod (University of Toronto, Toronto, ON, Canada) told The Lancet Oncology. “Preventing ovarian cancer; preventing breast cancer; and, having had breast cancer, preventing death from breast cancer.”

Southampton University’s Diana Eccles praised the study’s scale and duration of follow-up. She added that

she would have preferred more data for the eff ects of hormone replacement therapy. “From a clinical perspective, it would be quite useful to know whether that alters the risk”, she said.

In all, 108 women in the study were diagnosed with ovarian cancer. The authors estimated that women with the BRCA1 mutation who delay oophorectomy until the age of 40 years face a 4% risk of developing ovarian cancer. If they leave the procedure until the age of 50 years, the risk increases to 14%. Narod recommends scheduling preventive oophorectomies for when carriers of a BRCA1 mutation are aged 35 years. In the cohort of BRCA2 carriers, there was one diagnosis of cancer before the age of 50 years (and only ten diagnoses in total), whi ch suggests that these women are better placed to delay oophorectomy.

Talha Khan Burki

Published OnlineFebruary 28, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70093-2

For the study see J Clin Oncol 2014; published online Feb 24. http://jco.ascopubs.org/cgi/doi/10.1200/JCO.2013.53.2820

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Published OnlineMarch 7, 2014 http://dx.doi.org/10.1016/S1470-2045(14)70096-8

For the study see Science 2014; 343: 1010–14

Biomarker for fi brolamellar hepatocellular carcinomaFindings from a genetic analysis study uncovered a unique mutation that could be implicated in the pathogenesis of fi brolamellar hepato-cellular carcinoma (FL-HCC). FL-HCC is a rare disease that affl icts teens and young adults, is refractory to chemotherapy, and for which the cause remains unknown.

Joshua Honeyman and colleagues (Rockefeller University, NY, USA) analysed liver tumour tissue samples from 15 patients with FL-HCC, and compared them with normal non-infiltrated adjacent tissue. Whole-transcriptome and whole-genome sequencing showed a deletion-fusion mutation resulting in a chimeric transcript RNA in tumour samples from patients that was not present in normal tissue. Kenneth R Olivier (Mayo Clinic College of Medicine, MN, USA) commented: “The authors’

findings are remarkable for the consistency of the finding in the population tested”. Analysis of structural variation on chromosome 19 showed deletion-fusion points in the tumour DNA, with deletions that spanned about 400 kb. The recurrent chimera was the outcome of breaks in the DNA between DNAJB1 and PRKACA genes, followed by an in-frame fusion of their exons (mainly exons 1 with 2–10, respectively). This mutation was not detected in any of the paired normal tissue. In addition to the chimera, investigators also detected the wild-type copy of PRKACA in every tumour sample, suggesting a heterozygous deletion on chromosome 19.

The chimeric RNA was translated into a putative chimeric DNAJB1-PRKACA protein, which showed protein kinase A (PKA) activity. The absence of the domain that binds

the regulatory subunits of PKA resulted in higher PKA activity in cells expressing the chimeric protein versus those expressing wild-type PRKACA (p<0·001). Olivier added: “Although the sample size was small, hopefully expansion of the study set will show the same kinase defect”.

This study, in which two co-authors have FL-HCC, presents a breakthrough in the diagnosis of FL-HCC. Chimeric DNAJB1-PRKACA could be a biomarker for the early detection of FL-HCC, and a potential therapeutic target. Tim F Greten (National Cancer Institute, MD, USA) said: “The data presenting the same molecular changes in 15 of 15 examined HCC [patients] clearly call for future therapeutic studies targeting DNAJB1-PRKACA chimera. It may actually become a ‘home-run’.”

Ramla Benmaamar

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