The genomic landscape of 2,023 colorectal cancers.

Colorectal carcinoma (CRC) is a common cause of mortality, but a comprehensive description of its genomic landscape is lacking. Here we perform whole-genome sequencing of 2,023 CRC samples from participants in the UK 100,000 Genomes Project, thereby providing a highly detailed somatic mutational landscape of this cancer. Integrated analyses identify more than 250 putative CRC driver genes, many not previously implicated in CRC or other cancers, including several recurrent changes outside the coding genome.

Analysis of 10,478 cancer genomes identifies candidate driver genes and opportunities for precision oncology.

Tumor genomic profiling is increasingly seen as a prerequisite to guide the treatment of patients with cancer. To explore the value of whole-genome sequencing (WGS) in broadening the scope of cancers potentially amenable to a precision therapy, we analysed whole-genome sequencing data on 10,478 patients spanning 35 cancer types recruited to the UK 100,000 Genomes Project. We identified 330 candidate driver genes, including 74 that are new to any cancer.

Genetic landscape of interval and screen detected breast cancer.

Interval breast cancers (IBCs) are cancers diagnosed between screening episodes. Understanding the biological differences between IBCs and screen-detected breast-cancers (SDBCs) has the potential to improve mammographic screening and patient management. We analysed and compared the genomic landscape of 288 IBCs and 473 SDBCs by whole genome sequencing of paired tumour-normal patient samples collected as part of the UK 100,000 Genomes Project.

Phenome-wide Mendelian randomisation analysis of 378,142 cases reveals risk factors for eight common cancers.

For many cancers there are only a few well-established risk factors. Here, we use summary data from genome-wide association studies (GWAS) in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify potentially causal relationships for over 3,000 traits. Our outcome datasets comprise 378,142 cases across breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, as well as 485,715 controls.

The molecular map of CLL and Richter's syndrome.

Clonal expansion of B-cells, from the early stages of monoclonal B-cell lymphocytosis through to chronic lymphocytic leukemia (CLL), and then in some cases to Richter's syndrome (RS) provides a comprehensive model of cancer evolution, notable for the marked morphological transformation and distinct clinical phenotypes. High-throughput sequencing of large cohorts of patients and single-cell studies have generated a molecular map of CLL and more recently, of RS, yielding fundamental insights into these diseases and of clonal evolution. A selection of CLL driver genes have been functionally interrogated to yield novel insights into the biology of CLL.

Whole genome sequencing refines stratification and therapy of patients with clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common form of kidney cancer, but a comprehensive description of its genomic landscape is lacking. We report the whole genome sequencing of 778 ccRCC patients enrolled in the 100,000 Genomes Project, providing the most detailed somatic mutational landscape to date. We identify new driver genes, which as well as emphasising the major role of epigenetic regulation in ccRCC highlight additional biological pathways extending opportunities for drug repurposing.

The impact of risk stratification by polygenic risk and age on breast cancer screening in women aged 40-49 years: a modelling study.

Background: Polygenic Risk Scores (PRSs) have been proposed as a mechanism for risk-stratification of screening, increasing efficiency and enabling extension of existing programmes to improve survival in our aging population. We sought to model the impact of three hypothetical programmes of annual breast cancer screening in women aged 40-49 years: screening the PRS-defined high-risk quintile, screening the oldest quintile, and screening the full population.

Methods: In this UK-based modelling study, we used the published estimate of the area under the curve (AUC) of a currently available breast cancer PRS (0·64) to calculate the proportion of cancers captured by the PRS-defined high-risk quintile.

Utility of polygenic risk scores in UK cancer screening: a modelling analysis.

Background: It is proposed that, through restriction to individuals delineated as high risk, polygenic risk scores (PRSs) might enable more efficient targeting of existing cancer screening programmes and enable extension into new age ranges and disease types. To address this proposition, we present an overview of the performance of PRS tools (ie, models and sets of single nucleotide polymorphisms) alongside harms and benefits of PRS-stratified cancer screening for eight example cancers (breast, prostate, colorectal, pancreas, ovary, kidney, lung, and testicular cancer).

Methods: For this modelling analysis, we used age-stratified cancer incidences for the UK population from the National Cancer Registration Dataset (2016-18) and published estimates of the area under the receiver operating characteristic curve for current, future, and optimised PRS for each of the eight cancer types.

Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls.

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls.

Risk factors for eight common cancers revealed from a phenome-wide Mendelian randomisation analysis of 378,142 cases and 485,715 controls.

For many cancers there are few well-established risk factors. Summary data from genome-wide association studies (GWAS) can be used in a Mendelian randomisation (MR) phenome-wide association study (PheWAS) to identify causal relationships. We performed a MR-PheWAS of breast, prostate, colorectal, lung, endometrial, oesophageal, renal, and ovarian cancers, comprising 378,142 cases and 485,715 controls.

Realistic expectations are key to realising the benefits of polygenic scores.

We must not let enthusiasm around polygenic scores allow us to forget other factors that are bigger, more modifiable, and relevant for everyone, argue

Survival in hematological malignancies in the Nordic countries through a half century with correlation to treatment.

Studies of survival in hematological malignancies (HMs) have generally shown an improvement over time, although most of these studies are limited by a short follow-up period. Using the NORDCAN database with data from Denmark, Finland, Norway and Sweden, we follow periodic increases in relative survival in seven HMs through half a century up to 2015-2019. Five-year survival improved in all seven HMs, reaching 90% for Hodgkin lymphoma (HL), myeloproliferative neoplasias and chronic lymphocytic leukemia (CLL), 60% for multiple myeloma (MM) and chronic myeloid leukemias (CMLs), 50% for the myelodysplastic syndromes and 30% for acute myeloid leukemia (AML).

Survival trends in hematological malignancies in the Nordic countries through 50 years.

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Polygenic risk scores to stratify cancer screening should predict mortality not incidence.

Population-based cancer screening programs such as mammography or colonscopy generally directed at all healthy individuals in a given age stratum. It has recently been proposed that cancer screening could be restricted to a high-risk subgroup based on polygenic risk scores (PRSs) using panels of single-nucleotide polymorphisms (SNPs). These PRSs were, however, generated to predict cancer incidence rather than cancer mortality and will not necessarily address overdiagnosis, a major problem associated with cancer screening programs.

Epidemiology, genetics and treatment of multiple myeloma and precursor diseases.

Multiple myeloma (MM) is a hematological malignancy caused by the clonal expansion of plasma cells. The incidence of MM worldwide is increasing with greater than 140 000 people being diagnosed with MM per year. Whereas 5-year survival after a diagnosis of MM has improved from 28% in 1975 to 56% in 2012, the disease remains essentially incurable.

Effect of delays in the 2-week-wait cancer referral pathway during the COVID-19 pandemic on cancer survival in the UK: a modelling study.

Background: During the COVID-19 lockdown, referrals via the 2-week-wait urgent pathway for suspected cancer in England, UK, are reported to have decreased by up to 84%. We aimed to examine the impact of different scenarios of lockdown-accumulated backlog in cancer referrals on cancer survival, and the impact on survival per referred patient due to delayed referral versus risk of death from nosocomial infection with severe acute respiratory syndrome coronavirus 2.

Methods: In this modelling study, we used age-stratified and stage-stratified 10-year cancer survival estimates for patients in England, UK, for 20 common tumour types diagnosed in 2008-17 at age 30 years and older from Public Health England.