Numbers of mutations to different types of colorectal cancer

BACKGROUND: The numbers of oncogenic mutations required for transformation are uncertain but may be inferred from how cancer frequencies increase with aging. Cancers requiring more mutations will tend to appear later in life. This type of approach may be confounded by biologic heterogeneity because different cancer subtypes may require different numbers of mutations. For example, a sporadic cancer should require at least one more somatic mutation relative to its hereditary counterpart. METHODS: To better estimate numbers of mutations before transformation, 1,022 colorectal cancers were classified with respect to microsatellite instability (MSI) and germline DNA mismatch repair mutations characteristic of hereditary nonpolyposis colorectal cancer (HNPCC). MSI- cancers were also classified with respect to clinical stage. Ages at cancer and a Bayesian algorithm were used to estimate the numbers of oncogenic mutations required for transformation for each cancer subtype. RESULTS: Ages at MSI+ cancers were consistent with five or six oncogenic mutations for hereditary (HNPCC) cancers, and seven or eight mutations for its sporadic counterpart. Ages at cancer were consistent with seven mutations for sporadic MSI- cancers, and were similar (six to eight mutations) regardless of clinical cancer stage. CONCLUSION: Different biologic subtypes of colorectal cancer appear to require different numbers of oncogenic mutations before transformation. Sporadic MSI+ cancers may require more than a single additional somatic alteration compared to hereditary MSI+ cancers because the epigenetic inactivation of MLH1 commonly observed in sporadic MSI+ cancers may be a multistep process. Interestingly, estimated numbers of MSI- cancer mutations were similar (six to eight mutations) regardless of clinical cancer stage, suggesting a propensity to spread or metastasize does not require additional mutations after transformation. Estimates of oncogenic mutation numbers may help explain some of the biology underlying different cancer subtypes

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T > G in intron 6, c.1408+729A > G in intron 11, and c.1408+731C > T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.Instituto Multidisciplinario de Biología Celula

Pseudoexons provide a mechanism for allele-specific expression of APC in familial adenomatous polyposis

Allele-specific expression (ASE) of the Adenomatous Polyposis Coli (APC) gene occurs in up to one-third of families with adenomatous polyposis (FAP) that have screened mutation-negative by conventional techniques. To advance our understanding of the genomic basis of this phenomenon, 54 APC mutation-negative families (21 with classical FAP and 33 with attenuated FAP, AFAP) were investigated. We focused on four families with validated ASE and scrutinized these families by sequencing of the blood transcriptomes (RNA-seq) and genomes (WGS). Three families, two with classical FAP and one with AFAP, revealed deep intronic mutations associated with pseudoexons. In all three families, intronic mutations (c.646-1806T > G in intron 6, c.1408+729A > G in intron 11, and c.1408+731C > T in intron 11) created new splice donor sites resulting in the insertion of intronic sequences (of 127 bp, 83 bp, and 83 bp, respectively) in the APC transcript. The respective intronic mutations were absent in the remaining polyposis families and the general population. Premature stop of translation as the predicted consequence as well as co-segregation with polyposis supported the pathogenicity of the pseudoexons. We conclude that next generation sequencing on RNA and genomic DNA is an effective strategy to reveal and validate pseudoexons that are regularly missed by traditional screening methods and is worth considering in apparent mutation-negative polyposis families.Instituto Multidisciplinario de Biología Celula

SALSA - a sectional aerosol module for large scale applications

"The sectional aerosol module SALSA is introduced. The model has been designed to be implemented in large scale climate models, which require both accuracy and computational efficiency. We have used multiple methods to reduce the computational burden of different aerosol processes to optimize the model performance without losing physical features relevant to problematics of climate importance. The optimizations include limiting the chemical compounds and physical processes available in different size sections of aerosol particles; division of the size distribution into size sections using size sections of variable width depending on the sensitivity of microphysical processing to the particles sizes; the total amount of size sections to describe the size distribution is kept to the minimum; furthermore, only the relevant microphysical processes affecting each size section are calculated. The ability of the module to describe different microphysical processes was evaluated against explicit microphysical models and several microphysical models used in air quality models. The results from the current module show good consistency when compared to more explicit models. Also, the module was used to simulate a new particle formation event typical in highly polluted conditions with comparable results to more explicit model setup.""The sectional aerosol module SALSA is introduced. The model has been designed to be implemented in large scale climate models, which require both accuracy and computational efficiency. We have used multiple methods to reduce the computational burden of different aerosol processes to optimize the model performance without losing physical features relevant to problematics of climate importance. The optimizations include limiting the chemical compounds and physical processes available in different size sections of aerosol particles; division of the size distribution into size sections using size sections of variable width depending on the sensitivity of microphysical processing to the particles sizes; the total amount of size sections to describe the size distribution is kept to the minimum; furthermore, only the relevant microphysical processes affecting each size section are calculated. The ability of the module to describe different microphysical processes was evaluated against explicit microphysical models and several microphysical models used in air quality models. The results from the current module show good consistency when compared to more explicit models. Also, the module was used to simulate a new particle formation event typical in highly polluted conditions with comparable results to more explicit model setup.""The sectional aerosol module SALSA is introduced. The model has been designed to be implemented in large scale climate models, which require both accuracy and computational efficiency. We have used multiple methods to reduce the computational burden of different aerosol processes to optimize the model performance without losing physical features relevant to problematics of climate importance. The optimizations include limiting the chemical compounds and physical processes available in different size sections of aerosol particles; division of the size distribution into size sections using size sections of variable width depending on the sensitivity of microphysical processing to the particles sizes; the total amount of size sections to describe the size distribution is kept to the minimum; furthermore, only the relevant microphysical processes affecting each size section are calculated. The ability of the module to describe different microphysical processes was evaluated against explicit microphysical models and several microphysical models used in air quality models. The results from the current module show good consistency when compared to more explicit models. Also, the module was used to simulate a new particle formation event typical in highly polluted conditions with comparable results to more explicit model setup."Peer reviewe

EPHB2 germline variants in patients with colorectal cancer or hyperplastic polyposis

BACKGROUND: Ephrin receptor B2 (EPHB2) has recently been proposed as a novel tumor suppressor gene in colorectal cancer (CRC). Inactivation of the gene has been shown to correlate with progression of colorectal tumorigenesis, and somatic mutations have been reported in both colorectal and prostate tumors. METHODS: Here we have analyzed the EPHB2 gene for germline alterations in 101 individuals either with 1) CRC and a personal or family history of prostate cancer (PC), or 2) intestinal hyperplastic polyposis (HPP), a condition associated with malignant degeneration such as serrated adenoma and CRC. RESULTS: Four previously unknown missense alterations were observed, which may be associated with the disease phenotype. Two of the changes, I361V and R568W, were identified in Finnish CRC patients, but not in over 300 Finnish familial CRC or PC patients or more than 200 population-matched healthy controls. The third change, D861N, was observed in a UK HPP patient, but not in additional 40 UK HPP patients or in 200 UK healthy controls. The fourth change R80H, originally identified in a Finnish CRC patient, was also found in 1/106 familial CRC patients and in 9/281 healthy controls and is likely to be a neutral polymorphism. CONCLUSION: We detected novel germline EPHB2 alterations in patients with colorectal tumors. The results suggest a limited role for these EPHB2 variants in colon tumor predisposition. Further studies including functional analyses are needed to confirm this

Effect of remdesivir post hospitalization for COVID-19 infection from the randomized SOLIDARITY Finland trial

We report the first long-term follow-up of a randomized trial (NCT04978259) addressing the effects of remdesivir on recovery (primary outcome) and other patient-important outcomes one year after hospitalization resulting from COVID-19. Of the 208 patients recruited from 11 Finnish hospitals, 198 survived, of whom 181 (92%) completed follow-up. At one year, self-reported recovery occurred in 85% in remdesivir and 86% in standard of care (SoC) (RR 0.94, 95% CI 0.47-1.90). We infer no convincing difference between remdesivir and SoC in quality of life or symptom outcomes (p > 0.05). Of the 21 potential long-COVID symptoms, patients reported moderate/major bother from fatigue (26%), joint pain (22%), and problems with memory (19%) and attention/concentration (18%). In conclusion, after a one-year follow-up of hospitalized patients, one in six reported they had not recovered well from COVID-19. Our results provide no convincing evidence of remdesivir benefit, but wide confidence intervals included possible benefit and harm.Peer reviewe

Is Symptomatic Long QT Syndrome Associated with Depression in Women and Men?

We examined whether long QT syndrome (LQTS) mutation carrier status or symptomatic LQTS are associated with depression, and whether there are sex differences in these potential relationships. The sample comprised 782 participants (252 men). Of the 369 genetically defined LQTS mutation carriers, 169 were symptomatic and 200 were asymptomatic. The control group consisted of 413 unaffected relatives. Depression was assessed using the Beck Depression Inventory-II (BDI-II). No association was found for LQTS mutation carrier status with depression. The multinomial logistic regression showed that LQTS mutation carrier men with arrhythmic events scored higher on depression compared with the control group, even when adjusting for age, beta-blockers, antidepressants, and social support (OR = 1.09, 95 % CI [1.02, 1.15], p = .007). The binary logistic regression comparing symptomatic and asymptomatic LQTS mutation carriers showed that symptomatic LQTS was associated with depression in men (OR = 1.10, 95 % CI [1.03, 1.19], p = .009). The results were unchanged when additionally adjusted for education. These findings suggest that symptomatic LQTS is associated with depression in men but not in women. Overall, however, depression is more frequent in women than men. Thus, regular screening for depression in LQTS mutation carriers and their unaffected family members can be important.Peer reviewe

Identification of MAMDC1 as a candidate susceptibility gene for systemic lupus erythematosus (SLE)

Peer reviewe