1. Goodwin, Peter M.

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AMSTERDAM, Netherlands-RECQL gene mutations have been found in a group of Chinese patients with familial breast cancer who did not have mutations in any of the four established high-penetrance breast cancer susceptibility genes: BRCA1, BRCA2, TP53 and PTEN, according to findings reported here at the European Breast Cancer conference (Abstract 153).

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"We found that RECQL was present in 0.54 percent of the Southern Chinese women in our group, and we also know that a similar group of Northern Chinese women, from Beijing, had a RECQL incidence of 2 percent," said lead author of the study, Ava Kwong, PhD, FRCS., Assistant Dean and Clinical Associate Professor at the University of Hong Kong and Director of the Hong Kong Hereditary and High Risk Breast and Ovarian Cancer Program.


Targeting Mutations

Blood samples were tested from 1,114 patients with breast cancer in the Hong Kong Hereditary Breast Cancer Family Registry (who did not have mutated BRCA, TP53 or PTEN) and 88 healthy controls. The study found six patients with germline RECQL mutations. The mean age at diagnosis was 49.3 year, and Kwong reported that multiple cancer types-including hepatocellular carcinoma, colorectal cancer, lung cancer, and prostate cancer-were reported in each family.


While the RECQL mutation was known to be associated with poor prognosis in liver, pancreatic, and head and neck cancers across all populations, in the study families it was found to be associated with cardiovascular disorders.


Kwong told OT the study was prompted because they had been looking at family cancers in general and particularly at young women. "We started doing typical genes like the BRCA 1 and 2 and what we're doing now is a four-gene panel including these two plus PTEN and P53," she said. And she added that, while RECQL germline mutation had recently been identified to be associated with increased risk of breast cancer, the genetic contribution in the Chinese population had not been determined. And since the incidence of RECQL mutation differs between different ethnicities, it was important to validate it in different ethnicities.

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She insisted the mutation's prevalence of around one half percent of patients was significant. "That doesn't sound like a lot: but that is very similar to the rate of PTEN mutation that we see in Hong Kong-which is also a very high-penetrance gene." And she added they had already postulated it was a pathogenic mutation and therefore needed investigation. Kwong added tha the RECQL mutation is not unique to the Chinese population and had been described in other ethnic populations in association with breast cancer, for example, in Poland and Quebec. "[Also] our previous work on other mutations associated with breast cancer-BRCA 1 and 2, for example-led us to believe the loci vary between different ethnicities.


Additionally, amongst the six individuals with RECQL there were two mutation loci-repeated positions-which Kwong described as a "recurrent mutation founder effect," typically occurring in the DNA of one or more individuals who were founders of a distinct population. She said the team had previously noted such a founder effect in Hong Kong with BRCA mutations, and small geographical regions like Hong Kong were more likely to generate repeated mutations, and so were good places to seek new cancer-associated mutations.


She explained that when a newly formed colony is small, its founders can strongly affect the population's genetic makeup well into the future-such as in the three well-known founder BRCA mutations among Ashkenazi Jews. "The scale of the Chinese diaspora means that the RECQL mutation is most likely to be fairly prevalent in countries outside Asia," Kwong, said. And she noted that in 2010 there were nearly 3.5 million people of Chinese origin living in the U.S., and many more elsewhere around the planet.


"We don't yet have enough information to know what are the risks, but if the frequency is comparable to PTEN we can hopefully eventually do more population studies to find out whether the risk is high enough for us to intervene as clinicians-for example with preventive surgery or perhaps one day [with] drug treatments," she said.


Kwong added this level of incidence means the RECQL mutation may be important enough to be included in genetic screening for people of Chinese origin with a family history of breast cancer wherever they live in the world. "Using the present guidelines to screen for mutations we may miss these patients who carry a high penetrance gene," she said.


"Based on our BRCA mutation studies for example, frequencies may be comparable amongst different ethnicities but the loci of mutations may be different. Also the penetrance may be different," Kwong explained. "The risk estimation we have right now is based on Western data, and clinical management could be different depending on ethnicity compared to western guidelines."


Genetic Screening

Karen Gelmon MD, Professor of Medicine at the University of British Columbia, Medical Oncologist at the BC Cancer Agency, Vancouver, told OT that identifying a new genetic mutation in a Chinese population was important. "We're going to see more of these genetic risks being identified, which may have implications not just for how we treat breast cancer in terms of some of the new drugs but also potentially in terms of identifying high risk women more successfully," she said.


Gelmon added a key question was to ask whether to extend testing for these mutations beyond just tumors to wide-scale population screening of women-which she regarded as feasible with the increasing understanding of inherited genetics and identifying high risk patients. "There's going to be more talk about more global, comprehensive, screening of both the patients and the tumors," she told OT.


"Adding a test for this mutation could help refine possible preventive strategies," said Chair of the European Breast Cancer Conference Fatima Cardoso, MD, Director of the Breast Unit of the Champalimaud Clinical Centre in Lisbon, Portugal.


And she added that if the finding was confirmed by further research it could lead to the RECQL mutation being included into genetic screening for breast cancer in families at high risk. "From clinical practice we are all aware of patients and families where the genetic risk appears to be very high but where no known mutation is found in the four genes that are usually tested for, she said. "Knowing where the loci are situated in people of ethnic Chinese origin makes it easier and quicker to check for the mutation, and will enable those who are found to carry it to consider and discuss possible preventive strategies," Cardoso said.


Peter M. Goodwin is a contributing editor.