Comprehensive genomic profiling of Finnish lung adenocarcinoma cohort reveals high clinical actionability and SMARCA4 altered tumors with variable histology and poor prognosis

Introduction: Lung adenocarcinoma is the most common type of lung cancer and typically carries a high number of mutations. However, the genetic background of the tumors varies according to patients' ethnic background and smoking status. Little data is available on the mutational landscape and the frequency of actionable genomic alterations in lung adenocarcinoma in the Finnish population. Materials and methods: We evaluated the gene alteration frequencies of 135 stage I-IV lung adenocarcinomas operated at Turku University Hospital between 2004 and 2017 with a large commercial comprehensive genomic profiling panel. Additionally, we correlated the alterations in selected genes with disease outcomes in 115 stage I-III patients with comprehensive follow-up data. The genomic alterations in a sub-cohort of 30 never-smokers were assessed separately. Results: Seventy percent of patients in the overall cohort and 77% in the never-smoker sub-cohort harbored an alteration or a genomic signature targetable by FDA and/or EMA approved drug for non-small cell carcinoma, respectively. In multivariable analysis for disease-specific survival, any alteration in SMARCA4 (DSS; HR 3.911, 95%CI 1.561-9.795, P = 0.004) exhibited independent prognostic significance along with stage, tumor mutation burden, and predominant histological subtypes. Conclusions: Over two thirds of our overall cohort, and especially never-smokers had an actionable genomic alteration or signature. SMARCA4 alterations, detected in 7.4% of the tumors, independently predicted a shortened overall and disease-specific survival regardless of the alteration type. Most SMARCA4 alterations in our cohort were missense mutations associated with differentiated predominant histological subtypes and immunohistochemical SMARCA4/BRG1 and TTF-1 positive status.</p

High tumor mutation burden predicts favorable outcome among patients with aggressive histological subtypes of lung adenocarcinoma : A population-based single-institution study

Objectives: Tumor mutation burden (TMB) is an emerging predictive cancer biomarker. Few studies have addressed the prognostic role of TMB in non-small cell lung carcinoma, with conflicting results. Moreover, the association of TMB with different histological subtypes of lung adenocarcinoma has hitherto not been systematically evaluated. Here we studied the prognostic value of TMB and its distribution in different histological subtypes of lung adenocarcinomas in a retrospective cohort using the most recent updated classification guidelines. Materials and methods: 176 surgically resected stage I-IV lung adenocarcinomas were histologically reclassified according to WHO 2015 guidelines. A modified classification subdividing the acinar subtype into classic acinar, complex glandular and cribriform subtypes was further applied and potentially prognostic histopathological characteristics such as tumor-infiltrating lymphocytes were evaluated. 148 patients with stage I-III tumors and complete follow-up data were included in the survival analyses. TMB was determined by a commercial next generation sequencing panel from 131 tumors, out of which 105 had survival data available. Results: Predominant micropapillary, solid and complex glandular as well as nonpredominant cribriform histological subtypes were associated with significantly shorter survival. High TMB concentrated in micropapillary, solid and acinar predominant subtypes. Interestingly, TMB >= 14 mutations/MB conferred a stage- and histology-independent survival benefit compared to TMB <14 in multivariable analysis for overall (HR 0.284, 95% CI 0.14-0.59, P=0.001) and disease-specific survival (HR 0.213, 95% CI 0.08-0.56, P=0.002). Conclusion: TMB was an independent biomarker of favorable prognosis in our cohort of lung adenocarcinoma despite being associated with predominant histological subtypes considered aggressive.Peer reviewe

Data from: Clonal diversity driven by parasitism in a freshwater snail

One explanation for the widespread abundance of sexual reproduction is the advantage that genetically diverse sexual lineages have under strong pressure from virulent coevolving parasites. Such parasites are believed to track common asexual host genotypes, resulting in negative frequency-dependent selection that counterbalances the population growth-rate advantage of asexuals in comparison with sexuals. In the face of genetically diverse asexual lineages, this advantage of sexual reproduction might be eroded, and instead sexual populations would be replaced by diverse assemblages of clonal lineages. We investigated whether parasite-mediated selection promotes clonal diversity in 22 natural populations of the freshwater snail Melanoides tuberculata. We found that infection prevalence explains the observed variation in the clonal diversity of M. tuberculata populations, while no such relationship was found between infection prevalence and male frequency. Clonal diversity and male frequency were independent of snail population density. Incorporating ecological factors such as presence/absence of fish, habitat geography and habitat type did not improve the predictive power of regression models. Approximately 11% of the clonal snail genotypes were shared among 2-4 populations, creating a web of 17 interconnected populations. Taken together, our study suggests that parasite-mediated selection coupled with host dispersal ecology promotes clonal diversity. This, in return, may erode the advantage of sexual reproduction in M. tuberculata populations

Population survey and genotypic classification of Melanoides tuberculata snails in Israel

See "Materials and Methods" in the published paper

Data from: Faster clonal turnover in high-infection habitats provides evidence for parasite-mediated selection

According to the Red Queen hypothesis for sex, parasite-mediated selection against common clones counterbalances the reproductive advantage of asexual lineages, which would otherwise outcompete sexual conspecifics. Such selection on the clonal population is expected to lead to a faster clonal turnover in habitats where selection by parasites is stronger. We tested this prediction by comparing the genetic structure of clonal and sexual populations of freshwater snail Potamopyrgus antipodarum between years 2003 and 2007 in three depth-specific habitats in Lake Alexandrina (South Island, New Zealand). These habitats differ in the risk of infection by castrating trematodes and in the relative proportion of sexual individuals. As predicted, we found that the clonal structure changed significantly in shallow and mid-water habitats, where prevalence of infection was high, but not in the deep habitat, where parasite prevalence was low. Additionally, we found that both clonal diversity and evenness of the asexual population declined in the shallow habitat. In contrast, the genetic structure (based on F–statistics) of the coexisting sexual population did not change, which suggests that the change in the clonal structure cannot be related to genetic changes in the sexual population. Finally, the frequency of sexuals had no effect on the diversity of the sympatric clonal population. Taken together, our results show a more rapid clonal turnover in high-infection habitats, which gives support for the Red Queen hypothesis for sex

Allozyme genotypes at 9 loci and ploidy information for Potamopyrgus antipodarum snails

Allozyme genotypes at 9 loci and ploidy information for Potamopyrgus antipodarum snails from Lake Alexandrina, New Zealand. Genotypes were obtained with celulose acetate electrophoresis. Ploidy level was assigned based on asymetric banding pattern in heterozygotes. Loci used for assigning ploidy level include: 6PGD, MPI, IDH2, PGM1 and PGM2 (ploidy assignment based on AAT1, AAT2, IDH1 and PEP-D was not reliable). Description of the column headings and abbreviations uded: Data in columns A, B, C, D was not used in the analyses, but can be used to track the sample back to one of the original celulose acetate gels that are stored at the department of Aquatic Ecology, Eawag, Switzerland. A-SNAIL - snail number per sample B-TUBE - eppendorf tube code C-RUN - allozyme genotyping run D-POSITION - position on gel E-YEAR - year sampled F-SITE - sampling site G-HABITAT - habitat where sample was taken (3 depth-related habitats: shallow, mid-water and deep) H-PLOIDY - ploidy level (NA - not available, 0 - homozygote, 2-diploid, 3-triploid) I- SEX_COMMON_RARE - reproductive mode, for clones common or rare (S- sexuals, C-common clones, R-rare clones). A clone was defined as ‘common’ if its frequency among triploid asexuals was above 1.5% in any of the samples (year/site/habitat combination) J-CLONE_ID - Unique clone number K-S - column names are allozyme loci names. Genotypes are coded with a single digit. Loci for which the banding pattern is unreliable for asigning ploidy level are left with 2 alleles for triploid heterozygotes