Breast cancer research needs to evaluate whether a person's ethnicity influences their response to treatment and its outcome, according to researchers at Imperial College London and published in The Lancet online.
Emerging evidence suggests that particular drugs may benefit people from one ethnic group more than others, because of differences in their genetic makeup. Most key trials looking at treatments for breast cancer have been carried out in predominantly caucasian populations in Europe, North America and Australasia.
Other populations might not respond to a drug in the same way as the Caucasian populations in these trials. The researchers suggested that clinical trials should record participants' ethnicity and analyse whether there are differences in how patients from particular ethnic groups respond to a particular therapy.
One example is a drug called Herceptin (trastuzumab), which is commonly used to treat people with breast cancer that is HER-2 positive. Most studies of trastuzumab have not reported the ethnicity of participants. A recent study showed that people with a particular genotype responded better than others to treatment with this drug. The genotype in question is more common in some ethnic groups than in others, so it could be argued that an individual's ethnicity could be a key factor in determining which treatments are most likely to benefit them.
Another research group at the University of Miami, Fl has been looking at whether breast tissue samples from different ethnicities include groups of differentially expressed genes. Gene expression in breast tissue from African-American women differs
from that in Caucasian and Hispanic women, just as gene expression in Hispanic women differs from both African-American and Caucasian women.
In their latest study, Baumbach et al. are focusing on women with “triple-negative” breast cancer. These women are negative for the genes for estrogen receptor (ER), progesterone receptor (PR) and HER2/neu, an epidermal growth factor receptor. This combination is associated with a particularly poor prognosis.
Thee results showed surprising differences in normal tissues; some of the differences were specific to African-Americans and were not found in Hispanics or Caucasians. They tended to have a basal-like phenotype and to have an aggressive form of breast cancer before the age of 50. The research also showed that in considering BRCA1 and BRCA2, while they had a lower incidence of deleterious germline mutations but a higher number of missense mutations. They are now doing real time PCR analyses to see if the biggest differences can be validated and proteomic research will follow in the future, making this a large and very important long term study that may influence treatment paradigms in the future.
4 comments:
I'm mixed race, my husband is mixed race from different origins, as a result our daughter is mixed race all over the place, as is our son.
I guess choosing suitable treatment, even when armed with research on ethic groups gets really complex at that point doesn't it?
Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.
Eur J Cancer Prev. 2007 Dec;16(6):549-54.
Links
Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.
Weiss-Salz I, Harlap S, Friedlander Y, Kaduri L, Levy-Lahad E, Yanetz R, Deutsch L, Hochner H, Paltiel O.
Department of Health Services Research, Ministry of Health, Jerusalem, Isreal. gilsalz@012.net.il
To study the risk factors associated with breast cancer in women younger than 40 years, a cohort study (The Jerusalem Perinatal Study) of 42 822 female offspring born in hospitals in West Jerusalem during 1964-1976 was carried out. Hazard ratios of potential parental and perinatal risk factors for early breast cancer were measured. The overall incidence of breast cancer was 5.2/100 000 person-years. The highest incidence was found among Jewish women of West Asian ancestry (8.6/100 000 person-years), specifically those whose maternal grandfathers were born in Iraq, Iran or Afghanistan (9.5/100 000 person-years). Using Cox models we found independent risk factors for early breast cancer to be paternal age (relative risk/year=1.06, 95% confidence interval=1.02-1.10, P=0.005), and ancestry from Iraq/Iran/Afghanistan (relative risk=3.1, 95% confidence interval=1.50-6.52, P=0.002). The study confirms a previously observed effect of advanced paternal age on the occurrence of early breast cancer and identifies a novel population group at increased risk for the disease. The excess risk of early breast cancer associated with ancestry from Iraq, Iran and Afghanistan suggests involvement of genetic determinants, environmental exposures and/or lifestyle factors and mandates further investigation.
Labels: Ethnic ancestry and increased paternal age are risk factors for breast cancer before the age of 40 years.
posted by concerned heart at 9:34 AM 0 Comments Links to this post
Sunday, June 3, 2007
Independent mutational events and common ancestry genetic mutations discovered in diffuse gastric cancer and
Published: 10 hours ago, 16:24 EST, June 03, 2007
Genetic mutations identified for type of gastric cancer
Researchers have identified novel genetic mutations that are linked to hereditary diffuse gastric cancer, with these mutations being due to both independent mutational events and common ancestry, according to a study in the June 6 issue of JAMA. This study is being released early to coincide with its presentation at the annual meeting of the American Society of Clinical Oncology.
According to background information in the article, gastric cancer is the second most common cause of cancer death worldwide. There are two major variants of this cancer: an intestinal type and a diffuse type. "A decline in the overall incidence of gastric cancer can be attributed primarily to a decrease of the intestinal variant of gastric cancer with the diffuse type remaining stable or possibly even increasing." Hereditary diffuse gastric cancer (HDGC) is caused by mutations in the gene CDH1, and is characterized by an increased risk for diffuse gastric cancer and lobular breast cancer. "The identification of CDH1 mutations offers the opportunity of cancer risk-reduction strategies for unaffected at-risk individuals," the authors write.
Pardeep Kaurah, M.Sc., of the BC Cancer Agency, Vancouver, and colleagues conducted a study to assess the frequency of mutations in the CDH1 gene and whether these mutations occurred due to independent mutational events or common ancestry. The study included 38 families diagnosed clinically with HDGC, who were analyzed for CDH1 mutations. Twenty-six families had at least two gastric cancer cases with one case of diffuse gastric cancer in a person younger than 50 years; 12 families had either a single case of diffuse gastric cancer diagnosed in a person younger than 35 years or multiple cases of diffuse gastric cancer diagnosed in persons older than 50 years.
Thirteen mutations (6 novel) were identified in 15 of the 38 families (40 percent detection rate). Two families from this study plus two additional families carrying the novel 2398delC mutation shared a common haplotype (a group of alleles of different genes on a single chromosome that are closely enough linked to be inherited usually as a unit), suggesting a founder effect (a population group with an unusual frequency of a gene due to there having been only a small number of original members, one or more of whom had that gene). All four families originate from the southeast coast of Newfoundland.
Due to concentrations of lobular breast cancer cases, two branches of this family had been diagnosed as having hereditary breast cancer and were tested for BRCA mutations. Within these four families, the cumulative risk by age 75 years in mutation carriers for clinically detected gastric cancer was 40 percent for males and 63 percent for females and the risk for breast cancer in female mutation carriers was 52 percent.
"Our results confirm that between 30 percent and 40 percent of families with a positive family history of gastric cancer and more than 50 percent of families with 2 diffuse gastric cancer cases diagnosed prior to age 50 years will carry germline mutations in the CDH1 gene," the researchers write.
"This extended family with the 2398delC founder mutation is a useful resource for determining risk-modifying factors in the development of diffuse gastric cancer or lobular breast cancer, such as diet or genetic polymorphisms, and for studying secondary genetic events that lead to cancer formation. The identification of this mutation could permit population-based screening of diffuse gastric cancer within specific regions of Newfoundland. Testing for the founder mutation will be particularly valuable for potential HDGC families from Newfoundland in which there is no known living relative with either diffuse gastric cancer or lobular breast cancer from whom a high-quality peripheral blood DNA sample can be obtained for full CDH1 genetic screening because testing a single mutation can be readily performed on suboptimal DNA from archival tissue samples."
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Clinical Implications of Founder and Recurrent CDH1 Mutations in Hereditary Diffuse Gastric Cancer
Kirsten N. Kangelaris, MD; Stephen B. Gruber, MD, PhD, MPH
JAMA. 2007;297:2410-2411. Published online June 3, 2007 (doi:10.1001/jama.297.21.2410).
Hereditary diffuse gastric cancer (HDGC) is an autosomal-dominant cancer susceptibility syndrome characterized by early onset diffuse gastric cancer and lobular breast cancer.1 The clinical presentation of this particular form of familial gastric cancer was described more than 40 years ago2 and the phenotype can be dramatic. One descendant of the original Maori kindred from New Zealand died of gastric cancer at the age of 14 years; more than 25 of his relatives have succumbed to cancer.3 In a Michigan family with HDGC, 1 family member died from gastric cancer at the age of 17 years, and numerous other family members died of metastatic disease before reaching age 50 years.4 Fortunately, genetic testing has already transformed the care of families with HDGC, and the tragic outcomes in these 2 representative families can now largely be avoided. Prophylactic gastrectomy has the potential to eliminate the risk of gastric cancer in gene carriers,5-7 while surveillance and other strategies for breast cancer prevention offer protection to women at risk.8
In this issue of JAMA, Kaurah and colleagues9 report a large family-based study that offers insight into the distribution and clinical meaning of the mutations in the E-cadherin (CDH1) gene that cause HDGC. In one sense, this study simply extends prior work showing that mutations causing HDGC span the entire coding region of the gene10 and confirms that the lifetime risk of cancer among gene carriers is very high.11 In the present study by Kaurah et al, the authors estimate that the cumulative risk of gastric cancer in 2 of their largest families is approximately 40% in men and approximately 60% for women, with a corresponding 52% risk of breast cancer. These findings represent slightly lower risks of gastric cancer and higher risks of breast cancer than reported in a previously published meta-analysis,11 but the risk estimates from both studies overlap and it is clear that the absolute risks are high. Perhaps the most valuable contributions of the present study are the data illustrating how difficult it can be to determine whether a change in a gene sequence is a pathogenic mutation or a benign polymorphism, and the data emphasizing how the same mutation in the same gene can arise by either common ancestry or chance.
The full story starts in New Zealand, spans the globe, and ends in Newfoundland, with families and investigators from 6 countries in 3 continents contributing to the present study. Guilford and colleagues3 first discovered that germline mutation of CDH1 causes HDGC in their 1998 study of 3 separate families in New Zealand.3 Other groups quickly confirmed that germline mutations in CDH1 were responsible for HDGC in families of diverse ethnic origins.3, 12-13 In the study by Kaurah et al,9 a multinational group of investigators summarize the clinical and genetic findings in 38 families with HDGC ascertained between 2004 and 2006, nearly doubling the published world experience. Some of the findings are entirely consistent with the earlier literature. In this new series, the sensitivity of detecting CDH1 mutations in families meeting criteria for HDGC is 39%, with 15 mutations detected in 38 families (clinical criteria as defined by the International Gastric Cancer Linkage Consortium14). The sensitivity increased to 54% (14 mutations in 26 families) when more stringent diagnostic criteria were applied that considered only those families defined by at least 2 gastric cancer cases with 1 or more diffuse-type gastric cancer cases diagnosed before age 50 years. Thus, the sensitivity has not changed substantially from the corresponding sensitivity of 31% and 48% published by this group in 2004.10
The distribution and broad spectrum of CDH1 mutations also are similar to a previous report.10 Genetic testing for CDH1 is arduous because of the relatively large size of the gene, broad distribution along the entire coding sequence of CDH1, and heterogeneous mutation spectrum, which includes point mutations, deletions, and insertions.15 Until the present study, almost all of the more than 50 germline CDH1 mutations reported have been novel. Among those mutations identified more than once, none appeared to represent recognizable founder mutations.16-18 In the study by Kaurah et al9 recurrent mutations accounted for 54% of all mutations found. This proportion is higher than the 10% recurrent mutations previously suggested in the literature but that is to be expected as evidence from genetic testing accumulates. So how difficult is it to detect mutations, and why do recurrent mutations arise?
Mutation detection is not easy, and even when mutations are discovered, they are not always easy to interpret. One strength of the study by Kaurah et al9 is careful attention to the functional significance of sequence variation. It is fairly typical to use computational approaches to predict whether a sequence variant is likely to cause disease or simply represents meaningless variation. Ideally, experimental evidence would confirm that the sequence variant actually alters the function of the protein, and that is exactly what Kaurah et al have demonstrated. Cell invasion assays and splicing assays characterize the mutations quite convincingly. However, the sensitivity of genetic testing, even when conducted as carefully as in this study, is still only 50% in the best of circumstances. Therefore, the conclusions are that either undiscovered genes are contributing to HDGC or cryptic mutations of CDH1 are very difficult to identify. This serves as a useful reminder of the cautionary tale of relying exclusively on sequencing to detect mutations, as has been learned in BRCA1 or BRCA2. Some mutations, like gene dosage mutations caused by loss of 1 allele, are simply not detectable by sequencing alone.19
The second novel contribution of this study by Kaurah et al9 is the elegant characterization and analysis of recurrent mutations. Are these the result of independent CDH1 mutational events or common ancestry? The answer turns out to be both. To answer this question the investigators used haplotype analysis to determine whether the same exact mutation arose multiple different times in human history. Haplotype analysis shows more than just the mutation: it shows the similarity of the neighboring chromosomal region that harbors the mutation. In some respects, haplotype analysis provides a view of the mutation in its chromosomal context, somewhat like a high-resolution satellite view of a house on Earth. Zoom out a little, and it becomes apparent whether the view reveals the exact same house (eg, mutation) or an identical house in the same neighborhood on a parallel street.
For example, 3 families reported in this study have the same CDH1 A634V mutation, which means that valine is substituted for alanine at the 634rd amino acid in the protein. Haplotype analysis shows that 2 Portuguese families with this mutation must be distantly related because they both share the exact same mutation on the exact same piece of DNA. The third family is English, and they carry the exact same mutation. However, the surrounding DNA is different, indicating that their mutation arose independently of the Portuguese mutation. Similarly, 2 other families (including 1 of Norwegian/Swedish descent) have an identical splicing mutation and also share a common haplotype, while a third family from Brazil has the same mutation in a completely different context. In Newfoundland, haplotype analysis shows that a recurrent mutation is actually a founder mutation, or an ancestral mutation that accounts for a relatively large distribution of a disease in a specific population. Whether this founder mutation accounts for the higher incidence of gastric cancer that is observed in Newfoundland compared with the rest of Canada20 remains quite speculative but it does emphasize the fact that researchers are increasingly recognizing that, in terms of some genetic mutations, it is a small world after all.
The value of studies like the one by Kaurah et al9 is that these investigations help clinicians understand and manage HDGC with more precision, help families understand the risks accompanying a mutation in CDH1, and help population geneticists better understand the distribution of recurrent mutations in CDH1. It is clear that not all families with the same mutation are related to one another, but all of these families are already beginning to recognize that the threshold of preventive molecular medicine has arrived and that the future of HDGC will not resemble the past.
AUTHOR INFORMATION
Corresponding Author: Stephen B. Gruber, MD, PhD, MPH, Departments of Internal Medicine, Epidemiology, and Human Genetics, University of Michigan, Ann Arbor, MI 48105 (sgruber@umich.edu).
Labels: 2398delC founder mutation, CDH1 gene, diffuse gastric cancer or lobular breast cancer
posted by concerned heart at 11:52 PM 0 Comments Links to this post
@TrulyAce
Yes it does indeed. The important thing I suspect is that research just gives you a tool to work out what mutations to look for and which ones actually are important, irrespective of ethnicity per se.
It is well known, for example, that African-American women tend to get a more aggressive form of breast cancer and get it younger, so if some therapies are more effective against those known mutations, that's a good thing - it becomes more of a real chance to impact the cause of the disease, rather than a wild shot in the dark.
In the past, women who had the HER-2 mutation had a poorer prognosis but now this has changed because of Herceptin, which targets the HER-2 receptor. That's progress indeed.
@concerned heart
Thanks for sharing those links, very interesting stuff indeed.
I think as we learn more about the science and biology of differences, there may be hope for better, improved treatments down the road if we know what to target.
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