Evaluation of DNA from the Papanicolaou Test to Detect Ovarian and Endometrial Cancers
Isaac Kinde et al
Vol. 5, Issue 167, p. 167ra4
Sci. Transl. Med. DOI: 10.1126/scitranslmed.3004952
Results from The Cancer Genome Atlas' (TCGA) analysis of several hundred endometrial cancers have classified the disease into four molecularly defined groups with differing prognoses.
According to the study, some endometrial tumors with similar histologic features actually differ in their molecular profile and might benefit from different treatments.
While the new classification does align in some ways with earlier histological categories, some patients that would have been classified in a lower-risk histological category according to current subtypes would now be grouped in the category with the worst prognosis according to the molecular results from TCGA's study published today in Nature. For patients that fall in this molecular subtype, this finding could mean that they should receive alternative treatments.
"One of the problems is that, especially for higher-grade tumors, it is difficult for pathologists to classify them. There can be disagreement among pathologists and those have important ramifications on what treatments we recommend," the study's lead author, Douglas Levine from Memorial Sloan-Kettering Cancer Center, told PGx Reporter this week. "There are cases that are just difficult and this is where molecular information can help to add another layer of clarity."
The latest study also separated a small group of subjects into a new category that looks to have extremely good prognosis. If the results hold over time, it could mean these patients, if identified based on their molecular signature, would require less or even no treatment compared to the other subtypes.
Current methods of histologic assessment classify an endometrial carcinoma as one of two types — either endometrioid tumors, with relatively better prognoses, or serous tumors, with relatively worse prognoses. Endometrioid cancers are most often treated with radiation, while serous tumors are treated with chemotherapy.
TCGA's new genomic data breaks these cancers instead into four groups: a new subgroup categorized by mutations in the gene POLE and an overall-high mutation rate; a group with high mutation rate and high microsatellite instability, but without POLE mutations; a group with high microsatellite instability but low rates of copy number alterations; and a group with high copy number alterations.
Overall, the study profiled 373 tumor samples using whole-exome sequencing, microarrays, RNA-seq, and other methods.
The POLE group, with 17 tumors, or less than 10 percent of the cohort, was associated with the best prognosis in the study, while those in the copy number-high group had the worst outcomes. The other two subgroups fell in the middle.
According to Levine, the fact that the fourth subgroup had much worse prognosis was not surprising. "The unique thing, he said, "is that we put some of the endometrioid cases with the serous cases based on the molecular features, suggesting that we can identify a subset of endometrioid cases that may have a poorer outcome."
Currently, known-serous cases frequently get treated with chemotherapy, but those classified as endometrioid, "depending what stage they are, they could get anything from nothing to radiation to chemotherapy and radiation," he said. "The suggestion from the molecular data is that maybe they should just get chemo like the serous group."
However, the molecular subgroups identified in this study must first hold up in terms of their association to cancer prognoses in follow-up investigations. "Once we do that we can then design trials that stratify based on these types."
He said researchers behind the study are planning to validate the findings in an upcoming prospective trial of chemotherapy and alternative treatments in endometrial cancer patients by measuring a variety of molecular targets to classify patients in the trial into the same four subtypes. They will evaluate whether the four subtypes hold true, that is, whether patients with the copy number-high subtype really do have worse outcomes than those in the other groups.
If so, it would suggest that some patients with these copy number-high or "serous-like" endometriod tumors might benefit from more aggressive treatment, as do those with clearly serous tumors.
The study authors suggested the results could provide a map for future clinical trials of targeted therapy. "Each tumor subtype might warrant dedicated clinical trials because of the marked genomic differences between them that are indicative of different drivers of cancer … and developing therapies for each subtype independent of the other may improve outcomes, as has been shown in breast cancer," said study co-leader Elaine Mardis of Washington University School of Medicine in a statement.
The new four-tier categorization of endometrial carcinoma is a highlight of the TCGA results, but the researchers also found other data that could potentially impact how physicians treat these tumors in the future.
Cancers in the copy number-high group — serous and serous-like endometrioid tumors — shared a number of molecular similarities with both serous ovarian tumors and basal-like, or triple-negative, breast cancers. For example, the cancers share a high frequency of TP53 mutations — between 84 and 96 percent — and a low frequency — 1 to 2 percent — of PTEN mutations.
"For ovarian serous tumors, the standard treatment is combination chemotherapy, which works very well," Levine said. "We use that same regimen for uterine serous tumors now. But in basal-like breast cancer, treatments are often different and some investigators want to test these in other groups. But it’s a question whether it will work as well in all these tumor types, because they do have all these similarities, but they also have lots of differences."
Additionally, Levine said, the study results shore up previous observations that the PI3K – AKT pathway is highly active in endometrial cancers. They also showed that the pathway is activated to a different extent in serous and in non-serous cases — significantly more so in non-serous tumors.
"Lots of drug companies [working on PI3 kinase inhibitors] are interested in studying endometrial cancer because they know this pathway has a lot of activation in this tumor type," he said. From the results, he said, "the pathway seems in fact to be so active in the non-serous cases that it might be hard to suppress it with only one of the targeted drugs available." That, he said, may be important information for these companies to use going forward.
In the group's upcoming validation study, Levine said he and his colleagues are prospectively collecting tumor samples in a three-arm trial involving just over 300 patients and testing various treatment methods and doing a "cadre of molecular tests" to reproduce these subtypes identified by the recent TCGA study. "We are screening for P53 mutations, POLE, PIK3CA, MSI — and we should be able to reproduce the four subsets within the context of this trial," he said.
"Then we can ask the question, do these endometrioid cases that have this molecular feature of being serous-like actually [do] worse— does that affect [their] response to treatment?"
If Levine and his colleagues are able to reproduce the findings, "the next trial will be to see if we give chemo to these patients who would normally get radiation or no treatment, does that actually make a difference? That would be step two of the validation process."
Nature; D. Levine, Memorial Sloane-Kettering Cancer Centre –Genome Web Daily News
The incidence of genital warts declined by more than 90% in adolescent and teenage girls in the first 4 to 5 years after introduction of the human papillomavirus (HPV) vaccine in Australia, investigators reported.
Genital warts occurred more than 70% less often among women 21 to 30, as compared with the 3 to 4 years before the vaccine became available. The reductions in wart incidence among girls and women were accompanied by 50% to 80% decreases in the incidence of genital warts among heterosexual boys and young men.
No decline in wart frequency was seen in heterosexual women or men older than 30, Basil Donovan, MD, of the University of New South Wales in Sydney, and co-authors reported online in BMJ.
"In 2011 no genital wart diagnoses were made among 235 women under 21 years of age who reported prior human papillomavirus vaccination," the authors noted. "The significant declines in the proportion of young women found to have genital warts and the absence of genital warts in vaccinated women in 2011 suggests that the human papillomavirus vaccine has high efficacy outside the trial setting. Large declines indiagnoses of genital warts in heterosexual men are probably due to herd immunity."
The study provided a glimpse of the impact of HPV vaccination in a real-world community setting as opposed to a clinical trial.
"It actually generated data consistent with what we hoped and predicted would happen," said Greg Poland, MD, of Mayo Clinic in Rochester, Minn. "It showed in a large study that [the vaccine] worked and it worked fabulously."
It is probable that the results are readily applicable to the U.S. and other countries that have introduced HPV vaccination, he added. In particular, the results should reassure girls, young women, and parents that the vaccine is safe, effective, and does not promote promiscuity, which has been a concern to some people.
In 2007 Australia implemented one of the first nationwide HPV vaccination programs for girls and young women. The nationally funded program provides free vaccination to girls 12 to 13 in schools, and a vaccination "catch-up" program from 2007 to 2009 offered vaccinations to girls 13 to 18 and women 18 to 26.
The vaccination program included a surveillance network to monitor the effect of the vaccine on the incidence of genital warts in patients seen at sexual health services clinics. The first report from the program, 2 years after its implementation, showed a 59% reduction in wart incidence among vaccine-eligible women 12 to 26 and a 39% decrease in heterosexual men of the same age.
Donovan and colleagues updated the population effects of the vaccination program for 2007 to 2011.
From 2004 to 2011, 85,770 native-born Australians made initial visits to eight sexual health services. Evaluations showed that 7,686 (9.0%) of the patients had new diagnoses of genital warts (2,394 women and 5,292 men). From 2004 to 2007 the proportion of women with genital warts increased from 8.9% to 9.6% and then decreased to 2.7% by 2011. Among men, the rate declined from 12.8% to 11.7% during the first years, followed by a decrease to 7.4% by 2011.
The largest decline in genital-wart incidence occurred among women younger than 21. From a peak of 11.5% in 2007, the incidence of genital warts decreased to 0.85% by 2011, representing a reduction of 92.6% (P<0.001). Among women 21 to 30, the incidence of genital warts declined slightly from 12.5% in 2004 to 11.3% in 2007 before falling to 3.1% by 2011, a 72.6% decrease (P<0.001). The incidence did not decline significantly among women older than 30.
Rates of genital warts among heterosexual men seen at the sexual health services facilities increased by 68% (7.2% to 12.1%) from 2004 to 2007 (P<0.01) but declined by 82.8% to a low of 2.2% in 2011 (P<0.001). The incidence not changed significantly over time among men 21 to 30 or those older than 30.
Authors of a related editorial said the study showed a "remarkable reduction" in genital warts among women younger than 21 and predicted that "near eradication of genital warts in young Australian women will probably have a major impact on the costs of sexual healthcare."
"It remains to be seen whether we will see similar dramatic reductions in HPV-16 and HPV-18 associated diseases, such as cervical cancer, vulval cancer, other anogenital cancers, and head and neck tumors as a result of national vaccination programs," wrote Simon Barton, MD, of the Chelsea and Westminster Foundation Trust in London, and Colm O'Mahony, MD, of the Countess of Chester Trust in Chester, England.
"This is likely given the reported evidence of the vaccines. It is hoped that future vaccines will protect against other HPV types, such as types 31 and 45, which are also involved in the genesis of genital cancer. Countries should carefully explore whether it is economically feasible to vaccinate young men."
Ali H, et al "Genital warts in young Australians five years into national human papillomavirus vaccination program: National surveillance data" BMJ 2013; DOI: 10.1136/bjm.f2032.
Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus
Despite major advances in our understanding of many aspects of human papillomavirus (HPV) biology, HPV entry is poorly understood. To identify cellular genes required for HPV entry, we conducted a genome-wide screen for siRNAs that inhibited infection of HeLa cells by HPV16 pseudovirus. Many retrograde transport factors were required for efficient infection, including multiple subunits of the retromer, which initiates retrograde transport from the endosome to the trans-Golgi network (TGN). The retromer has not been previously implicated in virus entry. Furthermore, HPV16 capsid proteins arrive in the TGN/Golgi in a retromer-dependent fashion during entry, and incoming HPV proteins form a stable complex with retromer subunits. We propose that HPV16 directly engages the retromer at the early or late endosome and traffics to the TGN/Golgi via the retrograde pathway during cell entry. These results provide important insights into HPV entry, identify numerous potential antiviral targets, and suggest that the role of the retromer in infection by other viruses should be assessed.
Alex Lipovsky et al Department of Immunobiology, Yale School of Medicine, New Haven, CT 06520-8011;
March 12 2013- Proceedings of the National Academy of Sciences of the United States of America
Immunising women aged 20 years or older against HPV infection is too late to offer adequate protection against genital warts, say researchers.
Researchers in Sweden followed 2,209,263 females aged 10 to 44 years and collected information on HPV vaccinations from vaccination registers. Vaccine effectiveness was calculated using incident rate ratios of genital warts, which used a time to first event of genital warts as part of the analysis.
Vaccine effectiveness was highest in girls vaccinated before the age of 14, with an effectiveness of 93%. This dropped to 80% for girls vaccinated aged 14 to 16 years, 71% for girls vaccinated at 17 to 19 years and 48% for women vaccinated aged 20 to 22 years.
What does it mean for GPs?
The authors concluded that among women vaccinated at 20 years or older ‘there was low to immeasurable effectiveness and suggestive evidence that vaccinations tended to reach women at high genital warts risk.’ They added that it suggested ‘that vaccinations in this age group were not adequate for achieving the intended health benefit.’
‘National Agenda’ seeks to marshal efforts to sharpen the clinical impact of pathology in the genomics era
Certain types of cervical abnormalities that can lead to cancer may be missed when young women go years between Pap smears, a new study suggests.
Cervical cancer mortality rates are 45 percent higher in Eastern and southeastern Kentucky than in the rest of the country, according to statistics from the Centers for Disease Control.
One in five women in Eastern and southeastern Kentucky has not had a Pap test during the past three years, and Pap tests are key to revealing cervical changes that can lead to cancer.
For those women, the three-shot HPV vaccine Gardasil, which became available several years ago and fights the virus linked with cervical cancer, should have been sending young women flocking to health care providers.So why didn't it?
University of Kentucky health behavior researchers Elisia Cohen, an associate professor of communication, and Robin C. Vanderpool, an assistant professor in the department of public health, decided to look in to why women 18-26 weren't getting the full series of shots.
Their findings were included in an article in the academic publication Journal of Communication in February. When the vaccine was introduced in 2006, it was targeted at younger teens, who often would be brought to physicians and clinics by their parents.
The researchers asked themselves: What kind of incentive would it take to get young women older than 18 to commit to getting three shots within six months, knowing it could save their lives?
They knew that simply providing the full series of three shots at no cost did not work. They recruited 246 women in 2010-11 from rural health clinics with vouchers for the full series of shots. Only 45 percent took the first shot; 14 percent of those who took the first shot returned for the second, and only 5 percent received the third.
So researchers tried again: They gave the first dose of medication free to 344 young women at health departments, medical clinics, community colleges, outdoor festivals, Wal-Mart stores, businesses and homes.Then, they asked those women if they'd like to take part in a study. This time, though, they'd make it personal: Women getting their first shot would watch a video in which area medical providers and women who had received the shots would talk about the importance of taking charge of their health. The video team used interviews and focus groups to design the DVD.
It was theorized that women who saw other young women like themselves talking positively about the vaccine's effect would be more willing to get all the shots."Really, half the battle is getting them in for dose one," Vanderpool said. "But there's also getting them in for dose two or three."One of the young women in the video talked about losing her grandmother to cervical cancer. Another addressed questions young women have about why they should get the shots when they're in a monogamous relationship, and whether young men should feel threatened by having a girlfriend who takes care of her body and health."The (video) messages were more salient," Vanderpool said. "People look like them, talk like them ... so it resonates with the young women. ... It was also about changing social norms, how people talk about this — that it's OK to get the HPV vaccine."
Plans are being made for videos to urge younger teenagers to be vaccinated — and young men as well. And while the videos are helping, legislation might, too. A bill sponsored by Rep. David Watkins, D-Henderson, requiring that young boys and girls be immunized against HPV was approved 54-40 by the House on Feb. 26. The bill, now in the Senate, would provide the ability to opt out for parents who do not want their children — girls 9-16 and boys 10-16 — immunized.
Vanderpool, assistant professor in the Department of Health Behavior in the UK College of Public Health, led the study about how the DVD helped increase the number of women who took the entire course of shots.She called it "one part research, one part community outreach.""Now that we have the vaccine and regular Pap testing, we have two ways that we can fight this cancer," she said. Cheryl Truman: (859)231-3202. Twitter: @CherylTruman.
For scientists to improve cancer treatments with targeted therapeutic drugs, they need to be able to see proteins prevalent in the cancer cells
This has been impossible, until now. Thanks to a new microscopy technique, University of Akron researcher Dr. Adam Smith, assistant professor of chemistry, has observed how clusters of epidermal growth factor receptor (EGFR) — a protein abundant in lung and colon cancers, glioblastoma and others — malfunctions in cancer cells.
“We can directly observe protein clusters, in a living cell membrane, that are invisible to traditional methods. This opens up the possibility to directly measure the effect of drugs on the target proteins,” Smith says.
Smith’s work lies at the heart of current-day cancer research, which focuses on developing targeted drugs that kill cancer cells without the collateral damage associated with traditional treatments like chemotherapy.
Specifically, Smith used a cutting-edge photon-counting technique, which enables scientists to measure the cluster size of EGFR proteins. The technique represents a significant advancement from studying the cultures with a traditional microscope, which cannot visually capture objects as small as the EGFR clusters, according to Smith, a lead author of “Conformational Coupling across the Plasma Membrane in Activation of the EGF Receptor,” published in the Jan. 31 issue of the journal Cell, which highlights the technique.
“Another difficulty with studying EGFR is that it’s located in the cell membrane, which can be thought of as a fence line that defines the cell boundary, but in reality it is more like an untamed hedge row,” says Smith, explaining how the new laser-based microscope technique overcomes that obstacle and allows scientists to study, in real time, how EGFR works in healthy cells and also how it malfunctions in cancer cells.
Smith’s subsequent work studying the interaction of drugs with the targeted EGFR “will significantly improve drug discovery, which too often relies on indirect measure of efficacy,” he says.
Partners in Smith’s research include scientists from the University of California, Berkeley, and Columbia University. The National Cancer Institute, Howard Hughes Medical Institute and the U.S. Department of Energy provided funding for this research.
On The Net:
In a newly released position paper, the SOGC, the Society of Gynecologic Oncology and the Society of Canadian Colposcopists say age 25 is too late to begin Pap testing because precancerous and cancerous lesions may have developed earlier in some women.
The same liquid samples collected during many modern-day Papanicolaou, or "Pap," tests for cervical abnormalities and human papillomavirus infection may serve as a resource for finding genetic changes linked to endometrial and ovarian cancers,
"Although improvements need to be made before applying this test in a routine clinical manner," the study authors argued, "it represents a promising step toward a broadly applicable screening methodology for the early detection of gynecologic malignancies."
Using existing genetic data on ovarian tumors and newly generated exome sequences for nearly two-dozen endometrial tumors, investigators from Johns Hopkins University and elsewhere in the US and Brazil started by sussing out which genes are most frequently mutated in the gynecological cancers.
From there, the team went on to show that mutations found in ovarian or endometrial tumors often tended to turn up in sequences from matching Pap test fluid samples, particularly in individuals with endometrial cancer.
And by bringing such findings together, the investigators narrowed in on a panel of oft-mutated genes, which dubbed "PapGene," that appears to show promise for finding endometrial or ovarian cancer-related mutations in fluid collected during Pap tests.
Though more research is needed to assess the potential genetic test and its utility in the clinic, they said, results so far hint that sequencing the PapGene panel may broaden the information that can be obtained from the sorts of patient samples already being collected routinely in the clinic.
"Our genomic sequencing approach may offer the potential to detect these cancer cells in a scalable and cost-effective way," co-senior author Luis Diaz, Jr., a researcher with the Ludwig Center for Cancer Genetics and Therapeutics at Johns Hopkins University and director of the institute's Swim Across America Laboratory, said in a statement.
Pap tests involve the collection of cervical cells to look for signs of cervical cancer or pre-cancerous lesions. For liquid-based versions of the test, which are often used today, study authors said, clinicians preserve some of the sample in a liquid form. That sample can then be used to test for the presence of DNA from HPV, a virus that sometimes leads to cervical cancer.
But Diaz and his colleagues suspected that cervical fluid might contain other informative genetic material as well. In particular, they speculated that cancers occurring in nearby endometrial or ovarian tissues might slough off mutation-containing DNA that would make its way to the cervix and get caught up in the Pap sample.
To begin testing that theory, the researchers started by trying to take stock of the most common mutations in some gynecological cancers.
Along with analyses of existing ovarian and endometrial tumor data, the team performed exome sequencing on matched tumor and normal samples from 22 individuals with endometrioid cancer, the most common endometrial cancer subtype.
After capturing protein-coding regions in the tumor and normal samples with an Agilent SureSelect Human Exome kit, the team used Illumina's GAIIx instrument to sequence each of the exomes to an average depth of around 149-fold over more than 88 percent of the bases targeted.
Within the 22 tumors tested, mutation profiles clustered in two broad groups, the researchers noted. A dozen tumors harbored more than 100 predicted somatic coding mutations (perhaps owing to alterations affecting DNA repair pathways), while the remaining 10 tumors had fewer than 100 somatic mutations apiece.
By folding in existing data on ovarian cancers and endometrial tumors from other subtypes, the investigators came up with a list of the top mutation-containing candidate genes across the gynecological cancer types.
Analyses of targeted or whole-genome sequence data on another 24 endometrial tumor samples and 22 ovarian tumor samples verified the notion that the team's gene list contained authentic cancer players: Each of the 46 tumors tested harbored a mutation within at least one of the genes.
And that prompted researchers to go a step further, testing for DNA alterations in Pap test fluid samples collected from the same 46 women whose tumors had been tested directly. There, researchers found tumor-related mutations in cervical fluid samples from all 24 women with endometrial cancer and in nine of the 22 women with ovarian cancer.
Similarly, investigators found mutations in genes from their PapGene panel through targeted sequencing on Pap test samples from two more women with ovarian cancer and another 12 women with endometrial cancer. In contrast, such alterations did not turn up in Pap test samples from 14 unaffected women.
Moreover, the sequencing-based method uncovered mutations in the PapGene panel in individuals with both early stage cancers and those whose cancers had progressed to later stages.
In an effort to ward off false-positive PapGene tests caused by amplification, sequencing, or other errors, the researchers used the so-called "Safe-SeqS" method to sequence the targeted genes in each of the cervical fluid samples.
That involves slapping 14-base DNA barcodes onto DNA fragments in samples prior to amplification and analyses so that the team can check back to see if apparent mutations in the cancer genes are present in all amplicons from the same stretch of sequence.
Going forward, the group hopes to make additional improvements to the PapGene test and to further explore its utility.
"Performing the test at different times during the menstrual cycle, inserting the cervical brush deeper into the cervical canal, and assessing more regions of the genome may boost the sensitivity," said JHU neurosurgery researcher Chetan Bettegowda, one of the first authors on the study, in a statement.
In an accompanying perspectives article in the same issue of Science Translational Medicine, researchers from the University of Texas' MD Anderson Cancer Center and the Dana-Farber Cancer Institute discussed the PapGene sequencing strategy within the context of past and current schemes for diagnosing such gynecological diseases.
They also touched on some of the issues that would need to be addressed before the test enters the clinic and noted that a similar approach may eventually offer clues about the biological processes involved in the development of such cancers.
For instance, along with the sensitivity and specificity of the genetic test, they said that it will likely be important to consider its ease and affordability. They also noted that the advent of screening strategies for ovarian and endometrial cancers based on Pap test samples may prompt changes to the frequency with which the tests are administered and/or the age of the patient groups targeted.
Evaluation of DNA from the Papanicolaou Test to Detect Ovarian and Endometrial Cancers
Isaac Kinde et al
Human papillomavirus (HPV) infection in older women is commonly due to reactivation of latent disease rather than new infection, research indicates.
The study, published in The Journal of Infectious Diseases, showed that the age-specific prevalence of HPV rose with the number of sexual partners, a finding of particular relevance to women who became sexually active during the sexual revolution of the 1960s and 1970s, say the researchers.
"Our historical experience with HPV and cervical neoplasia in postmenopausal women may not be very predictive of the experience of the baby boomer generation of women who are now entering the menopausal transition at a higher risk than their mothers," remarked study co-author Patti Gravitt (Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA) in an accompanying press statement.
Gravitt and colleagues explored age-related fluctuations in HPV infection in the USA, where the prevalence peaks among younger women around the age of sexual debut. In other geographic regions there is a second attenuated peak around the age of menopause but this bimodal distribution is not seen in the US.
"Explanations for this variability include differences in relative prevalence of new partnerships at older ages, risk of HPV reactivation at older ages, and cohort effects," writes the team.
They enrolled 843 women aged 35-60 years and tested them for HPV DNA. The women's mean age was 46.6 years, 74.3% were White, and 19.0% were Black.
The prevalence of HPV - whether all types combined or just high-risk strains - decreased with age and increased with the number of lifetime sexual partners, with a threshold observed between four and five such partners. HPV prevalence was also higher among women with a recent new sexual partner.
Interestingly, the prevalence of HPV declined with increasing age among women with fewer than five lifetime sex partners. However, among women reporting five or more lifetime partners, the prevalence of any HPV and high-risk HPV declined between ages 35-40 years, increased again during ages 40-54 years, and then decreased at ages 55-60 years.
The interaction between age and lifetime number of sex partners was modest for any HPV and statistically significant for high-risk HPV, after adjustment for recent sexual behavior, marital status, history of colposcopy, and current cytologic abnormality.
This finding is consistent with an age-associated increased risk of HPV reactivation, say the authors. The older women in this study, who experienced sexual debut at the beginning of the US sexual revolution of the 1960s and 1970s, had a lower lifetime risk for HPV infection as demonstrated by a lower self-reported lifetime number of sex partners, they note.
Gravitt and co-authors conclude: "We propose that the cohort effect of the sexual revolution in the USA is masking an increase in HPV prevalence at older ages, which may be secondary to reactivation of 'latent' infection. Further follow-up of the HPV in perimenopause cohort and national surveillance data will be required to confirm this hypothesis."
The Journal of Infectious Diseases Jan 2013
The tops and bottoms of cells do different jobs, and healthy organs and tissue contain well-organized cells that are the right way up. One of the first signs of cancer is when cells become disorganized and can end up upside down
The extracellular matrix is a protein-rich "scaffolding" that holds cells in place to form three-dimensional tissue. It is essential to the design and shape of organs.
However, unlike the inert scaffolding used on building sites, the extracellular matrix interacts with the cells that it holds in place.
For instance, in a recently published study led by the Massachusetts Institute of Technology, scientists uncovered a clue to an important question in cancer research: how do cancer cells spread? They found molecular interactions with tumor cells alter the stickiness of the matrix so the cells become unstuck and travel to other parts of the body to start new tumors.
Other studies have shown that the extracellular matrix not only sticks to the cells but also guides them into the right positions.
But what Streuli and Akhtar wanted to explore was an area that was still a mystery: how does the extracellular matrix communicate the guiding messages to the cells so they assume the correct position, the right way up?
For their study, they decided to look at epithelial cells, which make up the majority of body tissue. The particular epithelial cells they studied were the ones in the milk-producing glandular tissue of the breast. These cells also line the mammary ducts that carry milk to the nipple.
If these cells aren't organized correctly, the breast can't send milk to the nipple when a baby is suckling. And one of the first signs of cancer is that the epithelial cells become disorganized.
One of the ways the extracellular matrix connects with breast epithelial cells is via receptors called integrins. These receptors tell cells about their environment, and also send messages from within cells to their environment.
Streuli and Akhtar conducted experiments with the integrins in breast epithelial cells to see how they affected cell behavior.
In one experiment, they found cells that lacked the gene for integrins ended up the wrong way up in the extracellular matrix and also in the wrong place.
In another experiment, they discovered that removal of integrins in cultured breast cells led to the same disordered effect.
A further experiment helped the researchers understand how cells know they are the right way up.
They discovered that inside cells, the integrin receptors connect to a protein called ILK that in turn links to microtubules, a protein transport network inside cells.
They found it is the combination of integrins and microtubules within a cell that makes sure the correct proteins are sent to the top and the bottom of the cell to ensure the cell goes into position the right way up.
Streuli says in a statement that they discovered "a vital interplay between the transport machinery and the integrin receptors which makes sure that proteins are transported to the correct area of the cell."
"Without this interplay the proteins end up in the wrong place, and this can lead to cells becoming disorganized," says Streuli.
He goes on to explain that when they compared breast tissue from their experiments with that of patients in early stages of breast cancerthey appeared very similar:
"The cells were upside down and disorganized so they couldn't carry out their functions."
"We hope that our work to better understand cell polarity could ultimately lead to better diagnosis for cancer patients," he adds.
Although they only experimented with breast epithelial cells, Streuli and Akhtar believe epithelial cells from other organs would behave in the same way.
An important aspect of their work is the use of special 3D cultures to grow the cells, where they formed tiny organs that looked remarkably similar to breast tissue.
"Growing the breast cells so that they can form 3D structures rather than on hard petri dishes means they develop in a way that is much more akin to how they grow in the body," says Akhtar.
"Over 90% of cancers come from epithelial cells, which is why we chose to study them," she adds.
Streuli and Akhtar now plan to test whether changing levels of integrin leads to the disorganization of cells that is seen in the early stages of cancer.
On line published in Nature Cell Biology on 23 December. Charles Streuli and Nasreen Akhtar of the Wellcome Trust Centre for Cell-Matrix Research, an interdisciplinary unit in the Faculty of Life Sciences at the University of Manchester
There did not appear to be any difference in the sexual behaviors of adolescent girls who received the human papillomavirus (HPV) vaccine and their unvaccinated peers, researchers found.
Among girls ages 11 and 12 enrolled in a large, managed-care organization, there were no between-group differences in the rate of pregnancy, testing for or diagnosis of a sexually transmitted infection, or receipt of contraceptive counseling by a physician, according to Robert Bednarczyk, PhD, of Kaiser Permanente Center for Health Research-Southeast in Atlanta, and colleagues.
In addition, the average age at the first composite outcome was no different between vaccinated and unvaccinated girls (14.4 versus 14.6, P=0.325), which indicates "that there may not be any earlier onset of sexual activity after HPV vaccination," the researchers reported online in Pediatrics.
"It is likely that any disinhibition or risk compensation would occur closer to the time of vaccination (i.e., within 18 months) rather than much later," they wrote. "If HPV vaccination was 'a license for sex,' we would have expected to see more adverse outcomes shortly after vaccination, when the girls were more aware of their recent vaccination status."
The Advisory Committee on Immunization practices recommended in 2006 that all girls ages 11 to 12 receive the HPV vaccine, with the idea that immunity to the sexually transmitted disease will develop before sexual activity begins.
Uptake of the vaccine, however, has trailed that of other recommended adolescent vaccines, including tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis (Tdap) vaccine and the quadrivalent meningococcal conjugate vaccine (MCV4).
One concern raised about HPV vaccination is that immunized girls will increase their sexual activity because of less fear of disease. Surveys based on self-reported data have shown that girls do not plan on changing their sexual behaviors after vaccination, but no studies had examined the issue using clinical outcomes free from the bias of self-report.
Bednarczyk and colleagues did such a study using electronic data from Kaiser Permanente Georgia. Their analysis included 1,398 girls ages 11 or 12 who were enrolled in the health plan from July 2006 through December 2007 -- 35% received at least one dose of HPV vaccine in addition to other vaccines and the rest received Tdap, MCV4, or both, but not HPV vaccine.
Through 3 years of follow-up, the rate of pregnancy, testing for or diagnosis of a sexually transmitted infection, and receipt of contraceptive counseling was 5.5 per 100 person-years in the vaccinated group and 3.9 per 100 person-years in the control group, a difference that was not statistically significant after adjustment for healthcare-seeking behavior, age at vaccination, race, and socioeconomic status (incidence rate ratio 1.29, 95% CI 0.92 to 1.80).
There were no between-group differences in rates of secondary outcomes either, although the rate of receiving contraceptive counseling came close to being higher in the vaccinated group (1.39 versus 0.50 per 100 person-years; IRR 2.31, 95% CI 0.99 to 5.38).
"The administrative data used for this study did not provide an opportunity to do a detailed examination of the reasons for this counseling or of the extent of hormonal contraceptive use among girls in this cohort," the authors wrote.
They acknowledged some additional limitations, including the possibility that differences remain between the vaccinated and unvaccinated girls despite adjustment for some confounders, the use of administrative data, the possibility that some of the girls received vaccines or reproductive healthcare at outside clinics, the limited ability to generalize the findings to other age groups, and possible confounding by physician behavior.
Primary source: Pediatrics
Bednarczyk R, et al "Sexual activity-related outcomes after human papillomavirus vaccination" Pediatrics 2012; DOI: 10.1542/peds.2012-1516.