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Scientists have discovered that cervical cancer can be divided into two distinct molecular subgroups – one far more aggressive than the other – offering hope of better understanding and treatment of the disease.
In the United Kingdom, there are over 3,000 new case of cervical cancer, with around 850 deaths each year. It is almost always caused by the human papillomavirus (HPV), and vaccination against this virus has successfully reduced the incidence of cervical cancer – in fact, the reduction has been by 87% among women in their 20s in England who were offered the vaccine when they were aged 12-13 years as part of the U.K. HPV vaccination program.
“Despite major steps forward in preventing cervical cancer, many women still die from the disease,” said Tim Fenton, MD, associate professor in cancer biology, School of Cancer Sciences Centre for Cancer Immunology, University of Southampton (England), and coauthor of the new study.
Two distinct subgroups
In the new study, published in Nature Communications, researchers described their breakthrough findings as a “major step forward” in understanding the disease, and said they provided a “tantalizing new clue” in determining the best treatments for individual patients.
For the observational study - part of the largest ‘omics’ study of its kind – researchers led by scientists at University College London and the University of Southampton began by applying a multiomics approach to identify combinations of molecular markers and characteristics associated with the biological processes involved in cervical cancer cells. The integrated multiomic analysis of 643 cervical squamous cell carcinomas (CSCC) – the most common histological variant of cervical cancer – represented patient populations from the United States, Europe, and sub-Saharan Africa.
To begin with they analysed and compared DNA, RNA, proteins, and metabolites in 236 CSCC cases in a publicly available U.S. database. They found that U.S. cancers fell into two distinct “omics” subgroups, which they named C1 and C2. After further investigation, the researchers identified that C1 tumors contained a much higher number of cytotoxic T cells. “The findings suggested that patients with C1 tumors would have a stronger immune response within the tumor micro-environment,” they said.
Weaker antitumor immune response
To determine if the two sub-types affect patients with cervical cancer in different ways, the team, which also included researchers from the University of Kent, the University of Cambridge, Oslo University Hospital, the University of Bergen (Norway), and the University of Innsbruck (Austria) derived molecular profiles and looked at clinical outcomes of a further 313 CSCC cases from Norway and Austria.
The researchers found that, just as in the US cohort, nearly a quarter of patients fell into the C2 subtype, and that again C1 tumors contained far more killer T cells than C2 tumors. “Importantly, the data also showed C2 was far more clinically aggressive with worse outcomes for patients,” the authors said.
Patients with C2 tumors were more than twice as likely (hazard ratio, 2.32) to die from their cervical cancer at any point during the follow-up period – up to 21 years – than those with C1 tumors. In terms of 5-year disease-specific survival, the rates were 79% survival for C1 and 66% survival for C2, the authors pointed out.
They highlighted that the difference in outcomes between patients with C1 and C2 tumors was very similar across the US and European cohorts.
Kerry Chester, PhD, professor of molecular medicine at UCL Cancer Institute, and coauthor, said: “Inclusion of patient cohorts in Norway and Austria, for which highly detailed clinical information was available to complement the molecular data, were key factors in the success of the study.”
Analyzing a further cohort of 94 Ugandan CSCC cases, the team found that C2 tumors were much more common than C1 tumors in patients who were also HIV-positive, “underlining the link to a weaker antitumor immune response” in this group.
Molecular subtyping offers better prognostic information
Cervical cancer can be caused by at least 12 different ‘high-risk’ HPV types, and there have been conflicting reports as to whether the HPV type present in a cervical cancer influences the prognosis for the patient. CSCCs can now also be categorized into two subtypes, C1 and C2, the authors explained, among which C1 tumors have a more favorable outcome.
“Although HPV16 is more likely to cause C1 tumors and HPV18 C2 tumors, HPV type is not an independent predictor of prognosis, suggesting it is the tumor type rather than the causative HPV type that is critical for the disease outcome,” they highlighted.
“Intriguingly, the C1/C2 grouping appeared to be more informative than the type of HPV present,” they added. “While certain HPV types were found more commonly in either C1 or C2 tumors, prognosis was linked to the group to which the tumor could be assigned, rather than the HPV type it contained.”
The reason that HPV16 and other alpha-9 HPV types have been associated with more favorable outcomes was possibly that these viruses are “more likely to cause C1-type tumors”, the authors suggested. Although larger numbers are needed for robust within-stage comparisons of C1 and C2 tumors, “we observe a clear trend in the survival rates between C1 and C2 by stage”, they said.
Taking molecular (C1/C2) subtyping into account may allow for more “accurate prognostication” than current staging and potentially different clinical management of patients with C1 versus C2 tumors, the authors said. This could include the identification of patients at risk of relapse who may require further adjuvant therapy after completion of up-front therapy.
New therapeutic targets
Dr. Fenton highlighted that the study findings suggested that determining whether a patient has a C1 or a C2 cervical cancer could help in planning their treatment, since it appeared to provide “additional prognostic information beyond that gained from clinical staging”. Given the differences in the antitumor immune response observed in C1 and C2 tumors, this classification might also be useful in predicting which patients are likely to benefit from emerging immunotherapy drugs, he said.
The study findings also found that CSCC can develop along “two trajectories” associated with differing clinical behavior that can be identified using defined gene expression or DNA methylation signatures, and this may guide “improved clinical management of cervical cancer patients”, they said.
“This collaborative multidisciplinary research is a major step forward in our understanding of cervical cancer,” said Dr. Chester. “Through careful molecular profiling and genetic analysis of cervical cancer tumors we have gained valuable new insight into the tumor microenvironment and factors potentially making the cancer less aggressive in some patients.”
The authors expressed hope that their study findings will stimulate functional studies of genes and their role in cervical cancer pathogenesis, potentially enabling identification of new therapeutic targets.
The study was funded by Debbie Fund (a UCL postgraduate research scholarship), Rosetrees Trust, Cancer Research UK, the Biotechnology and Biosciences Research Council, the Royal Society, and the Global Challenges Doctoral Centre at the University of Kent, MRC, PCUK, BBSRC, TUF, Orchid, and the UCLH BRC. The authors declared no competing interests.
A version of this article first appeared on Medscape UK.
Scientists have discovered that cervical cancer can be divided into two distinct molecular subgroups – one far more aggressive than the other – offering hope of better understanding and treatment of the disease.
In the United Kingdom, there are over 3,000 new case of cervical cancer, with around 850 deaths each year. It is almost always caused by the human papillomavirus (HPV), and vaccination against this virus has successfully reduced the incidence of cervical cancer – in fact, the reduction has been by 87% among women in their 20s in England who were offered the vaccine when they were aged 12-13 years as part of the U.K. HPV vaccination program.
“Despite major steps forward in preventing cervical cancer, many women still die from the disease,” said Tim Fenton, MD, associate professor in cancer biology, School of Cancer Sciences Centre for Cancer Immunology, University of Southampton (England), and coauthor of the new study.
Two distinct subgroups
In the new study, published in Nature Communications, researchers described their breakthrough findings as a “major step forward” in understanding the disease, and said they provided a “tantalizing new clue” in determining the best treatments for individual patients.
For the observational study - part of the largest ‘omics’ study of its kind – researchers led by scientists at University College London and the University of Southampton began by applying a multiomics approach to identify combinations of molecular markers and characteristics associated with the biological processes involved in cervical cancer cells. The integrated multiomic analysis of 643 cervical squamous cell carcinomas (CSCC) – the most common histological variant of cervical cancer – represented patient populations from the United States, Europe, and sub-Saharan Africa.
To begin with they analysed and compared DNA, RNA, proteins, and metabolites in 236 CSCC cases in a publicly available U.S. database. They found that U.S. cancers fell into two distinct “omics” subgroups, which they named C1 and C2. After further investigation, the researchers identified that C1 tumors contained a much higher number of cytotoxic T cells. “The findings suggested that patients with C1 tumors would have a stronger immune response within the tumor micro-environment,” they said.
Weaker antitumor immune response
To determine if the two sub-types affect patients with cervical cancer in different ways, the team, which also included researchers from the University of Kent, the University of Cambridge, Oslo University Hospital, the University of Bergen (Norway), and the University of Innsbruck (Austria) derived molecular profiles and looked at clinical outcomes of a further 313 CSCC cases from Norway and Austria.
The researchers found that, just as in the US cohort, nearly a quarter of patients fell into the C2 subtype, and that again C1 tumors contained far more killer T cells than C2 tumors. “Importantly, the data also showed C2 was far more clinically aggressive with worse outcomes for patients,” the authors said.
Patients with C2 tumors were more than twice as likely (hazard ratio, 2.32) to die from their cervical cancer at any point during the follow-up period – up to 21 years – than those with C1 tumors. In terms of 5-year disease-specific survival, the rates were 79% survival for C1 and 66% survival for C2, the authors pointed out.
They highlighted that the difference in outcomes between patients with C1 and C2 tumors was very similar across the US and European cohorts.
Kerry Chester, PhD, professor of molecular medicine at UCL Cancer Institute, and coauthor, said: “Inclusion of patient cohorts in Norway and Austria, for which highly detailed clinical information was available to complement the molecular data, were key factors in the success of the study.”
Analyzing a further cohort of 94 Ugandan CSCC cases, the team found that C2 tumors were much more common than C1 tumors in patients who were also HIV-positive, “underlining the link to a weaker antitumor immune response” in this group.
Molecular subtyping offers better prognostic information
Cervical cancer can be caused by at least 12 different ‘high-risk’ HPV types, and there have been conflicting reports as to whether the HPV type present in a cervical cancer influences the prognosis for the patient. CSCCs can now also be categorized into two subtypes, C1 and C2, the authors explained, among which C1 tumors have a more favorable outcome.
“Although HPV16 is more likely to cause C1 tumors and HPV18 C2 tumors, HPV type is not an independent predictor of prognosis, suggesting it is the tumor type rather than the causative HPV type that is critical for the disease outcome,” they highlighted.
“Intriguingly, the C1/C2 grouping appeared to be more informative than the type of HPV present,” they added. “While certain HPV types were found more commonly in either C1 or C2 tumors, prognosis was linked to the group to which the tumor could be assigned, rather than the HPV type it contained.”
The reason that HPV16 and other alpha-9 HPV types have been associated with more favorable outcomes was possibly that these viruses are “more likely to cause C1-type tumors”, the authors suggested. Although larger numbers are needed for robust within-stage comparisons of C1 and C2 tumors, “we observe a clear trend in the survival rates between C1 and C2 by stage”, they said.
Taking molecular (C1/C2) subtyping into account may allow for more “accurate prognostication” than current staging and potentially different clinical management of patients with C1 versus C2 tumors, the authors said. This could include the identification of patients at risk of relapse who may require further adjuvant therapy after completion of up-front therapy.
New therapeutic targets
Dr. Fenton highlighted that the study findings suggested that determining whether a patient has a C1 or a C2 cervical cancer could help in planning their treatment, since it appeared to provide “additional prognostic information beyond that gained from clinical staging”. Given the differences in the antitumor immune response observed in C1 and C2 tumors, this classification might also be useful in predicting which patients are likely to benefit from emerging immunotherapy drugs, he said.
The study findings also found that CSCC can develop along “two trajectories” associated with differing clinical behavior that can be identified using defined gene expression or DNA methylation signatures, and this may guide “improved clinical management of cervical cancer patients”, they said.
“This collaborative multidisciplinary research is a major step forward in our understanding of cervical cancer,” said Dr. Chester. “Through careful molecular profiling and genetic analysis of cervical cancer tumors we have gained valuable new insight into the tumor microenvironment and factors potentially making the cancer less aggressive in some patients.”
The authors expressed hope that their study findings will stimulate functional studies of genes and their role in cervical cancer pathogenesis, potentially enabling identification of new therapeutic targets.
The study was funded by Debbie Fund (a UCL postgraduate research scholarship), Rosetrees Trust, Cancer Research UK, the Biotechnology and Biosciences Research Council, the Royal Society, and the Global Challenges Doctoral Centre at the University of Kent, MRC, PCUK, BBSRC, TUF, Orchid, and the UCLH BRC. The authors declared no competing interests.
A version of this article first appeared on Medscape UK.
Scientists have discovered that cervical cancer can be divided into two distinct molecular subgroups – one far more aggressive than the other – offering hope of better understanding and treatment of the disease.
In the United Kingdom, there are over 3,000 new case of cervical cancer, with around 850 deaths each year. It is almost always caused by the human papillomavirus (HPV), and vaccination against this virus has successfully reduced the incidence of cervical cancer – in fact, the reduction has been by 87% among women in their 20s in England who were offered the vaccine when they were aged 12-13 years as part of the U.K. HPV vaccination program.
“Despite major steps forward in preventing cervical cancer, many women still die from the disease,” said Tim Fenton, MD, associate professor in cancer biology, School of Cancer Sciences Centre for Cancer Immunology, University of Southampton (England), and coauthor of the new study.
Two distinct subgroups
In the new study, published in Nature Communications, researchers described their breakthrough findings as a “major step forward” in understanding the disease, and said they provided a “tantalizing new clue” in determining the best treatments for individual patients.
For the observational study - part of the largest ‘omics’ study of its kind – researchers led by scientists at University College London and the University of Southampton began by applying a multiomics approach to identify combinations of molecular markers and characteristics associated with the biological processes involved in cervical cancer cells. The integrated multiomic analysis of 643 cervical squamous cell carcinomas (CSCC) – the most common histological variant of cervical cancer – represented patient populations from the United States, Europe, and sub-Saharan Africa.
To begin with they analysed and compared DNA, RNA, proteins, and metabolites in 236 CSCC cases in a publicly available U.S. database. They found that U.S. cancers fell into two distinct “omics” subgroups, which they named C1 and C2. After further investigation, the researchers identified that C1 tumors contained a much higher number of cytotoxic T cells. “The findings suggested that patients with C1 tumors would have a stronger immune response within the tumor micro-environment,” they said.
Weaker antitumor immune response
To determine if the two sub-types affect patients with cervical cancer in different ways, the team, which also included researchers from the University of Kent, the University of Cambridge, Oslo University Hospital, the University of Bergen (Norway), and the University of Innsbruck (Austria) derived molecular profiles and looked at clinical outcomes of a further 313 CSCC cases from Norway and Austria.
The researchers found that, just as in the US cohort, nearly a quarter of patients fell into the C2 subtype, and that again C1 tumors contained far more killer T cells than C2 tumors. “Importantly, the data also showed C2 was far more clinically aggressive with worse outcomes for patients,” the authors said.
Patients with C2 tumors were more than twice as likely (hazard ratio, 2.32) to die from their cervical cancer at any point during the follow-up period – up to 21 years – than those with C1 tumors. In terms of 5-year disease-specific survival, the rates were 79% survival for C1 and 66% survival for C2, the authors pointed out.
They highlighted that the difference in outcomes between patients with C1 and C2 tumors was very similar across the US and European cohorts.
Kerry Chester, PhD, professor of molecular medicine at UCL Cancer Institute, and coauthor, said: “Inclusion of patient cohorts in Norway and Austria, for which highly detailed clinical information was available to complement the molecular data, were key factors in the success of the study.”
Analyzing a further cohort of 94 Ugandan CSCC cases, the team found that C2 tumors were much more common than C1 tumors in patients who were also HIV-positive, “underlining the link to a weaker antitumor immune response” in this group.
Molecular subtyping offers better prognostic information
Cervical cancer can be caused by at least 12 different ‘high-risk’ HPV types, and there have been conflicting reports as to whether the HPV type present in a cervical cancer influences the prognosis for the patient. CSCCs can now also be categorized into two subtypes, C1 and C2, the authors explained, among which C1 tumors have a more favorable outcome.
“Although HPV16 is more likely to cause C1 tumors and HPV18 C2 tumors, HPV type is not an independent predictor of prognosis, suggesting it is the tumor type rather than the causative HPV type that is critical for the disease outcome,” they highlighted.
“Intriguingly, the C1/C2 grouping appeared to be more informative than the type of HPV present,” they added. “While certain HPV types were found more commonly in either C1 or C2 tumors, prognosis was linked to the group to which the tumor could be assigned, rather than the HPV type it contained.”
The reason that HPV16 and other alpha-9 HPV types have been associated with more favorable outcomes was possibly that these viruses are “more likely to cause C1-type tumors”, the authors suggested. Although larger numbers are needed for robust within-stage comparisons of C1 and C2 tumors, “we observe a clear trend in the survival rates between C1 and C2 by stage”, they said.
Taking molecular (C1/C2) subtyping into account may allow for more “accurate prognostication” than current staging and potentially different clinical management of patients with C1 versus C2 tumors, the authors said. This could include the identification of patients at risk of relapse who may require further adjuvant therapy after completion of up-front therapy.
New therapeutic targets
Dr. Fenton highlighted that the study findings suggested that determining whether a patient has a C1 or a C2 cervical cancer could help in planning their treatment, since it appeared to provide “additional prognostic information beyond that gained from clinical staging”. Given the differences in the antitumor immune response observed in C1 and C2 tumors, this classification might also be useful in predicting which patients are likely to benefit from emerging immunotherapy drugs, he said.
The study findings also found that CSCC can develop along “two trajectories” associated with differing clinical behavior that can be identified using defined gene expression or DNA methylation signatures, and this may guide “improved clinical management of cervical cancer patients”, they said.
“This collaborative multidisciplinary research is a major step forward in our understanding of cervical cancer,” said Dr. Chester. “Through careful molecular profiling and genetic analysis of cervical cancer tumors we have gained valuable new insight into the tumor microenvironment and factors potentially making the cancer less aggressive in some patients.”
The authors expressed hope that their study findings will stimulate functional studies of genes and their role in cervical cancer pathogenesis, potentially enabling identification of new therapeutic targets.
The study was funded by Debbie Fund (a UCL postgraduate research scholarship), Rosetrees Trust, Cancer Research UK, the Biotechnology and Biosciences Research Council, the Royal Society, and the Global Challenges Doctoral Centre at the University of Kent, MRC, PCUK, BBSRC, TUF, Orchid, and the UCLH BRC. The authors declared no competing interests.
A version of this article first appeared on Medscape UK.
FROM NATURE COMMUNICATIONS