A genomic analysis of clear cell renal cell carcinoma (ccRCC), the most common form of kidney cancer, from 72 patients has uncovered 31 genes that are key to development, growth and spread of the cancer, say researchers from Mayo Clinic in Florida. Eight of these genes had not been previously linked to kidney cancer, and six other genes were never known to be involved in any form of cancer.
Their study, in the journal Oncotarget, is the most extensive analysis to date of gene expression’s role in ccRCC tumor growth and metastasis. The ccRCC subtype accounts for 80 percent of all kidney cancer cases.
This study is a thorough analysis, because overexpressed genes were functionally tested in kidney cancer cells to ensure they were important to some aspect of the cancer process, says the study’s senior investigator, molecular biologist, John A. Copland, Ph.D.
“The power of this study is that we looked at genes discovered to be over-expressed in patients’ tumors and determined their function in kidney cancer, which has not been done on a large scale before,” he says. “This is a seminal step in identifying key pathways and molecules involved in kidney cancer so that specific therapies that target these new genes can be developed to treat this cancer.”
This kidney cancer is one of the top 10 solid cancers in the U.S. Researchers expect 60,000 new cases to be diagnosed this year, with 13,000 deaths. While the prognosis for kidney cancer that has not spread is good, patients with advanced or metastatic cancer will develop drug resistance. Patients with untreated metastatic disease have a five-year overall survival rate of less than 10 percent.
The research team, which includes Mayo graduate student and lead author Christina von Roemeling, has already published several studies identifying some of the genes they discovered in the genetic analysis. In considering the importance of these discoveries to patients, they decided to publish all the genes at once in Oncotarget.
In Europe and worldwide
Kidney cancer (C44-C66) is the seventh most common cancer in Europe, with more than 115,000 new cases diagnosed in 2012 (3% of the total). In Europe (2012), the highest World age-standardised incidence rates for kidney cancer are in the Czech Republic for both men and women; the lowest rates are in Macedonia for men and Cyprus for women. UK kidney cancer incidence rates are estimated to be the 19th lowest in males in Europe, and the 17th highest in females. These data are broadly in line with Europe-specific data available elsewhere.
Kidney cancer (C44-C66) is the 13th most common cancer worldwide, with around 338,000 new cases diagnosed in 2012 (2% of the total). Kidney cancer incidence rates are highest in parts of Northern America and lowest in Middle Africa, but this partly reflects varying data quality worldwide.
Variation between countries may reflect different prevalence of risk factors, use of screening and diagnostic methods.
“We are releasing these discoveries to the scientific community so that a large effort can be mounted to find out more about these genes and how they can be effectively targeted,” Dr. Copland says. “We owe patients speedy research that focuses on new treatments to save lives.”
Targeted therapies used now to treat kidney cancer are often toxic, he adds.
“The study findings represent a very major advancement in therapeutic target identification for ccRCC and open new avenues for drug discovery and development. Novel therapeutic agents acting on these new targets should bring about a significant improvement in the prognosis of ccRCC patients,” says co-author and Mayo oncologist Han Tun, M.D.
In Australia, kidney cancer is one of the ten most common cancer diagnoses.
It is estimated that 3,000 people received a diagnosis of kidney cancer in 2012. Between 1991 and 2009 the incidence of kidney cancer has increased by approximately 30%.
The increase in diagnosed kidney cancer may be due to the ageing of the population, better diagnostic methods, or increased rate of coincidental diagnosis during scans for other reasons.
Australians have a 1 in 69 risk of developing kidney cancer before the age of 85 (1 in 51 for males and 1 in 103 for females). Males are currently twice as likely to develop kidney cancer as females.
Kidney cancer is mostly a disease seen in adults aged over 55, and is rare in children.
Worldwide, over 100,000 people die of kidney cancer each year. Kidney cancer caused 927 deaths in Australia in 2009 (575 men, 352 women), accounting for 2% of all cancer deaths, and for 0.6% of all causes deaths.
Survival from kidney cancer has increased greatly over time. The 5-year survival has risen from 47% in the period 1982–1987 to 72% in 2006–2010. The 5-year survival rate is similar for males and females overall, although females aged 50–59 (5-year survival of 83%) had a slight survival advantage over males of the same age (76%). Improved outcomes are due largely to increases in the detection and survival of early-stage renal cell carcinoma, the most common form of kidney cancer.
The researchers examined an equal number of samples (72) of normal kidney and kidney cancer tissues. They looked at over- and under-expression of RNA from the tissue, as well as protein production because genes express RNA to produce protein. They found almost 6,000 genes that fit that description. They isolated and tested 195 genes that are consistently elevated across patient samples. The researchers then narrowed the “hit” list to 31 after they tested each in living cancer cells to see if these genes contributed to either growth or spread of the tumor.
Kidney cancer is cancer that originates in the kidneys, which filter blood and remove waste. The most common type of kidney cancer in adults is renal cell carcinoma that begins in the lining of the tubes of the kidney.
In 2014, an estimated 63,920 new cases of kidney and renal pelvis cancers will be diagnosed in the U.S.
An estimated 13,860 Americans are expected to die from the disease in 2014.
In Texas, an estimated 5,450 new kidney and renal pelvis cancers are expected to be diagnosed in 2014, and 1,110 Texans are expected to die from the disease this year alone.
The average age of people when diagnosed with kidney cancer is 64. Kidney cancer is rare under age 45.
Of the many types of kidney cancer, nine out of 10 cases are diagnosed as renal cell carcinoma.
About 3 percent of all cancers diagnosed each year are kidney cancers.
“We also found genes with other functions that are key to kidney cancer survival, such as inflammation. Another found gene is linked to angiogenesis, the production of new blood vessels to support a tumor. This is a novel discovery,” says von Roemeling. “It is particularly important because ccRCC is well known for being a very angiogenic cancer.
“In addition to the potential of these genes and gene products to help us design new drugs, they could also serve as biomarkers for accurate diagnosis,” she says. “It really is a treasure trove for future research on kidney cancer.”
The exact causes of kidney cancer are unknown; however, some risk factors are linked to the disease.
Obesity: Kidney cancer risk increases for people who are extremely overweight.
Race: African Americans have a slight increased risk of kidney cancer.
Certain medicines: Use of phenacetin, a popular non-prescription pain reliever, has been linked to renal cell carcinoma. Because it has not been available for two decades, it is no longer a major concern.
High blood pressure: People with high blood pressure are at a higher risk of developing the disease. It is not known whether the condition or the medicine used to treat it is to blame for the increase in risk.
Gender: Men are twice as likely to develop the disease as women.
Family history: Those with a strong family history of renal cell carcinoma are at a higher risk to develop the cancer. Brothers and sisters of those diagnosed are at the highest risk.
Smoking: Tobacco use has a strong link to kidney cancer. Smoking raises the risk for developing kidney cancer. The risk decreases over time if tobacco use ceases.
Kidney disease: Those with kidney disease and those on dialysis have an increased risk.
Hereditary disease: People with rare inherited conditions including Birt-Hogg-Dube syndrome, hereditary leiomyoma-renal cell carcinoma, hereditary papillary renal cell carcinoma, hereditary renal oncocytoma, familial renal cancer, tuberous sclerosis, and von Hippel Lindau disease have an increased risk.
Exposure to chemicals: Some research links exposure to asbestos, benzene, cadmium, some herbicides, and organic solvents to an increased risk of developing kidney cancer.
Co-authors include Hege Ekeberg Larsen, B.S., Austin Rohl, B.S., Johnny Wei, B.S., and Laura Marlow, M.S., who are students or technicians from the Copland laboratory; Derek Radisky, Ph.D., of Mayo Clinic; Richard Drake, Ph.D., from the Medical University of South Carolina; Heng Zhu, Ph.D., from Johns Hopkins School of Medicine; and Maciek Sasinowski, M.D., Ph.D., and Heather Sasinowska, Ph.D., of Incogen, Inc.
This study was funded in part from National Institutes of Health / National Cancer Institute grants R01CA104505, R01CA136665, R01CA104505-05S1 and 5R44CA125807; a gift from the David & Lois Stulberg Endowed Fund for Kidney Cancer Research; Mr. and Mrs. Ompal Chauhan Research Fund; Kidney Cancer Research at Mayo Clinic in Florida; James C. and Sarah K. Kennedy Mayo Clinic Research Career Development Award for Clinicians; Scheidel Foundation; Fraternal Order of Eagles Florida State Auxiliary; and a grant for rare cancers from Dr. Ellis and Dona Brunton.
About Mayo Clinic
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