Efficiency of expanded genomic profiling (EGP) programmes in terms of final inclusion of patients in genomically matched therapies is still unknown. Fit patients with advanced and refractory ...colorectal cancer (CRC) were selected for an EGP programme. Next-generation sequencing (NGS) analysis from formalin-fixed paraffin-embedded tumour samples was performed. The purpose was to describe the prevalence of genomic alterations defined by the ESMO Scale for Clinical Actionability of Molecular Targets (ESCAT), as well as the percentage of patients finally included in genomically guided clinical trials. In total, 187 patients were recruited. Mutational profile was obtained in 177 patients (10 patients were failure due to insufficient tumour sample), copy number alterations in 41 patients and fusions in 31 patients. ESCAT-defined alterations were detected in 28.8% of the intention-to-analyse population. BRAF V600E was clustered in ESCAT I, with a prevalence of 3.7%, KRAS G12C and ERBB2 amplification were clustered in ESCAT II, whose prevalence was 4.2% and 1.6%, respectively. Most alterations were classified in ESCAT III (mutations in ERBB2, PIK3CA or FGFR genes and MET amplification) and IV (mutations in BRAF non-V600E, ERBB3, FBXW7, NOTCH, RNF43), with a single prevalence under 5%, except for PIK3CA mutation (9%). The final rate of inclusion into genomically guided clinical trials was 2.7%, including therapies targeting BRAF V600E or RNF43 mutations in two patients each, and ERBB2 mutation in one patient. In conclusion, EGP programmes in patients with advanced CRC are feasible and identify a subset of patients with potentially druggable genomic alterations. However, further efforts must be made to increase the rate of patients treated with genomically guided therapies.
Next generation sequencing panels have been developed for hereditary cancer, although there is some debate about their cost-effectiveness compared to exome sequencing. The performance of two panels ...is compared to exome sequencing. Twenty-four patients were selected: ten with identified mutations (control set) and fourteen suspicious of hereditary cancer but with no mutation (discovery set). TruSight Cancer (94 genes) and a custom panel (122 genes) were assessed alongside exome sequencing. Eighty-three genes were targeted by the two panels and exome sequencing. More than 99% of bases had a read depth of over 30x in the panels, whereas exome sequencing covered 94%. Variant calling with standard settings identified the 10 mutations in the control set, with the exception of MSH6 c.255dupC using TruSight Cancer. In the discovery set, 240 unique non-silent coding and canonic splice-site variants were identified in the panel genes, 7 of them putatively pathogenic (in ATM, BARD1, CHEK2, ERCC3, FANCL, FANCM, MSH2). The three approaches identified a similar number of variants in the shared genes. Exomes were more expensive than panels but provided additional data. In terms of cost and depth, panels are a suitable option for genetic diagnostics, although exomes also identify variants in non-targeted genes.
Actionable somatic molecular alterations are found in 15% to 20% of NSCLC in Europe. NSCLC is a tumor observed in patients with germline TP53 variants causing Li-Fraumeni syndrome (LFS), but its ...somatic molecular profile is unknown.
Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants.
Among 22 patients with NSCLC and LFS (n = 23 lung tumors), 64% were women, median age was 51 years, 84% were nonsmokers, 73% had adenocarcinoma histological subtype, and 84% were diagnosed with advanced-stage disease. These patients harbored 16 distinct germline TP53 variants; the most common was p.R158H (5/22; three in the same family). Personal and family histories of cancer were reported in 71% and 90% of patients, respectively. In most cases (87%, 13/15), lung cancer was diagnosed with a late onset. Of the 21 tumors analyzed, somatic oncogenic driver mutations were found in 19 of 21 (90%), EGFR mutations in 18 (exon 19 deletion in 12 cases, L858R in three cases, and G719A, exon 20 insertion, and missing mutation subtype, each with one case), and ROS1 fusion in one case. A PI3KCA mutation was concurrently detected at diagnosis in three EGFR exon 19-deleted tumors (3/12). The median overall survival was 37.3 months in 14 patients treated with EGFR inhibitors; seven developed resistance, five (71%) acquired EGFR-T790M mutation, and one had SCLC transformation.
Driver oncogenic alterations were observed in 90% of the LFS tumors, mainly EGFR mutations; one ROS1 fusion was also observed. The germline TP53 variants and lung cancer carcinogenesis driven by oncogenic processes need further evaluation.
Plexiform neurofibromas (PNFs) are benign peripheral nerve sheath tumors involving large nerves present in 30%–50% Neurofibromatosis type 1 (NF1) patients. Atypical neurofibromas (ANF) are distinct ...nodular lesions with atypical features on histology that arise from PNFs. The risk and timeline of malignant transformation in ANF is difficult to assess. A recent NIH workshop has stratified ANFs and separated a subgroup with multiple atypical features and higher risk of malignant transformation termed atypical neurofibromatous neoplasms with uncertain biological potential (ANNUBP). We performed an analysis of intratumor heterogeneity on eight PNFs to link histological and genomic findings. Tumors were homogeneous although histological and molecular heterogeneity was identified. All tumors were 2n, almost mutation‐free and had a clonal NF1(−/−) origin. Two ANFs from the same patient showed atypical features on histology and deletions of CDKN2A/B. One of the ANFs exhibited different areas in which the degree of histological atypia correlated with the heterozygous or homozygous loss of the CDKN2A/B loci. CDKN2A/B deletions in different areas originated independently. Results may indicate that loss of a single CDKN2A/B copy in NF1(−/−) cells is sufficient to start ANF development and that total inactivation of both copies of CDKN2A/B is necessary to form an ANNUBP.
We performed an analysis of intra‐tumor heterogeneity on eight Neurofibromatosis Type 1 associated plexiform neurofibromas and neurofibromas with atypical features (ANF) to link histological and genomic findings. All tumors were 2n, almost mutation‐free and had a clonal NF1(−/−) origin. In addition, ANFs presented losses of the CDKN2A/B locus. Single ANFs might exhibit intra‐tumor heterogeneity regarding the number of histological atypical features that correlated with the heterozygous or homozygous loss of the CDKN2A/B loci.
ERCC3, a new ovarian cancer susceptibility gene? Stradella, Agostina; del Valle, Jesús; Rofes, Paula ...
European journal of cancer (1990),
December 2020, 2020-12-00, 20201201, Letnik:
141
Journal Article
Recenzirano
Hereditary breast and ovarian cancer syndrome (HBOC) is an inherited disorder with an increased risk of breast cancer (BC) and ovarian cancers (OC). Mutations in BRCA1-BRCA2 explains less than a half ...of cases. In the last decade several genes with different penetrance have been associated with an increased risk of BC or OC. A recurrent heterozygous ERCC3 truncating mutation increases the risk for breast cancer in patients with Ashkenazi Jewish ancestry. Our study aimed to investigate the role of ERCC3 truncating variants in a cohort of patients with suspicion of HBOC.
ERCC3 screening by multigene-panel analysis in 1311 unrelated patients after our regional consensus for genetic testing in hereditary cancer was done. In addition, 453 Spanish cancer-free individuals and 51,343 GnomAD non-Finnish, non-cancer European individuals were used as control populations.
We identified 13 patients with heterozygous ERCC3 truncating variants (0.99%). Five of them also carried a mutation in a high- /moderate-penetrance HBOC gene (BRCA1, BRCA2, CHEK2, and TP53) being Multilocus Inherited Neoplasia Alleles syndrome (MINAS) patients. The frequency in 453 Spanish controls was of 0.22%; similar to that observed in 51,343 non-Finnish European GnomAD population (0.24%). We found an almost statistically significant association of truncating ERCC3 variants with BC (odds ratio OR = 2.25, confidence interval CI = 0.6–5.93, P = 0.11), and we observed for the first time a significant association with OC (OR = 4.74, CI = 1–14.34, P = 0.028), that holds even after removing MINAS cases.
To our knowledge, this is the largest HBOC series comprehensively analysed for ERCC3 mutations, and the first study identifying ERCC3 as a cancer risk for OC.
•Our results confirm the association of ERCC3 truncating mutations with breast cancer.•We also describe their association with ovarian cancer for the first time. Further studies in larger cohorts are needed to more precisely establish the associated cancer risk as well as the relation with other cancer types.
Background: Colorectal (CRC) and endometrial cancer (EC) are the most common types of cancer in Lynch syndrome (LS). Risk reducing surgeries (RRS) might impact cancer incidence and mortality. Our ...objectives were to evaluate cumulative incidences of CRC, gynecological cancer and all-cause mortality after RRS in LS individuals. Methods: Retrospective analysis of 976 LS carriers from a single-institution registry. Primary endpoints were cumulative incidence at 75 years of cancer (metachronous CRC in 425 individuals; EC and ovarian cancer (OC) in 531 individuals) and all-cause mortality cumulative incidence, comparing extended (ES) vs. segmental surgery (SS) in the CRC cohort and risk reducing gynecological surgery (RRGS) vs. surveillance in the gynecological cohort. Results: Cumulative incidence at 75 years of metachronous CRC was 12.5% vs. 44.7% (p = 0.04) and all-cause mortality cumulative incidence was 38.6% vs. 55.3% (p = 0.31), for ES and SS, respectively. Cumulative, incidence at 75 years was 11.2% vs. 46.3% for EC (p = 0.001) and 0% vs. 12.7% for OC (p N/A) and all-cause mortality cumulative incidence was 0% vs. 52.7% (p N/A), for RRGS vs. surveillance, respectively. Conclusions: RRS in LS reduces the incidence of metachronous CRC and gynecological neoplasms, also indicating a reduction in all-cause mortality cumulative incidence in females undergoing RRGS.
Only a small fraction of hereditary breast and/or ovarian cancer (HBOC) cases are caused by germline variants in the high-penetrance breast cancer 1 and 2 genes (
and
. BRCA1-associated ring domain 1 ...(
), nuclear partner of
, has been suggested as a potential HBOC risk gene, although its prevalence and penetrance are variable according to populations and type of tumor. We aimed to investigate the prevalence of
truncating variants in a cohort of patients with clinical suspicion of HBOC. A comprehensive
screening by multigene panel analysis was performed in 4015 unrelated patients according to our regional guidelines for genetic testing in hereditary cancer. In addition, 51,202 Genome Aggregation Database (gnomAD) non-Finnish, non-cancer European individuals were used as a control population. In our patient cohort, we identified 19 patients with heterozygous
truncating variants (0.47%), whereas the frequency observed in the gnomAD controls was 0.12%. We found a statistically significant association of truncating
variants with overall risk (odds ratio (OR) = 3.78; CI = 2.10-6.48;
= 1.16 × 10
). This association remained significant in the hereditary breast cancer (HBC) group (OR = 4.18; CI = 2.10-7.70;
= 5.45 × 10
). Furthermore, deleterious
variants were enriched among triple-negative BC patients (OR = 5.40; CI = 1.77-18.15;
= 0.001) compared to other BC subtypes. Our results support the role of
as a moderate penetrance BC predisposing gene and highlight a stronger association with triple-negative tumors.
RNA analyses are a potent tool to identify spliceogenic effects of DNA variants, although they are time-consuming and cannot always be performed. We present splicing assays of 20 variants that ...represent a variety of mutation types in 10 hereditary cancer genes and attempt to incorporate these results into American College of Medical Genetics and Genomics (ACMG) classification guidelines. Sixteen single-nucleotide variants, 3 exon duplications, and 1 single-exon deletion were selected and prioritized by in silico algorithms. RNA was extracted from short-term lymphocyte cultures to perform RT-PCR and Sanger sequencing, and allele-specific expression was assessed whenever possible. Aberrant transcripts were detected in 14 variants (70%). Variant interpretation was difficult, especially comparing old classification standards to generic ACMG guidelines and a proposal was devised to weigh functional analyses at RNA level. According to the ACMG guidelines, only 12 variants were reclassified as pathogenic/likely pathogenic because the other two variants did not gather enough evidence. This study highlights the importance of RNA studies to improve variant classification. However, it also indicates the challenge of incorporating these results into generic ACMG guidelines and the need to refine these criteria gene specifically. Nevertheless, 60% of variants were reclassified, thus improving genetic counseling and surveillance for carriers of these variants.
Background
Gastroenteropancreatic neuroendocrine neoplasms (GEP‐NENs) are a complex family of tumors of widely variable clinical behavior. The World Health Organization (WHO) 2010 classification ...provided a valuable tool to stratify neuroendocrine neoplasms (NENs) in three prognostic subgroups based on the proliferation index. However, substantial heterogeneity remains within these subgroups, and simplicity sometimes entails an ambiguous and imprecise prognostic stratification. The purpose of our study was to evaluate the prognostic impact of histological differentiation within the WHO 2010 grade (G) 1/G2/G3 categories, and explore additional Ki‐67 cutoff values in GEP‐NENs.
Subjects, Materials, and Methods
A total of 2,813 patients from the Spanish National Tumor Registry (RGETNE) were analyzed. Cases were classified by histological differentiation as NETs (neuroendocrine tumors well differentiated) or NECs (neuroendocrine carcinomas poorly differentiated), and by Ki‐67 index as G1 (Ki‐67 <2%), G2 (Ki‐67 3%–20%), or G3 (Ki‐67 >20%). Patients were stratified into five cohorts: NET‐G1, NET‐G2, NET‐G3, NEC‐G2, and NEC‐G3.
Results
Five‐year survival was 72%. Age, gender, tumor site, grade, differentiation, and stage were all independent prognostic factors for survival. Further subdivision of the WHO 2010 grading improved prognostic stratification, both within G2 (5‐year survival: 81% Ki‐67 3%–5%, 72% Ki‐67 6%–10%, 52% Ki‐67 11%–20%) and G3 NENs (5‐year survival: 35% Ki‐67 21%–50%, 22% Ki‐67 51%–100%). Five‐year survival was significantly greater for NET‐G2 versus NEC‐G2 (75.5% vs. 58.2%) and NET‐G3 versus NEC‐G3 (43.7% vs. 25.4%).
Conclusion
Substantial clinical heterogeneity is observed within G2 and G3 GEP‐NENs. The WHO 2010 classification can be improved by including the additive effect of histological differentiation and the proliferation index.
Implications for Practice
Gastroenteropancreatic neuroendocrine neoplasms are tumors of widely variable clinical behavior, roughly stratified by the World Health Organization (WHO) 2010 classification into three subgroups based on proliferation index. Real‐world data from 2,813 patients of the Spanish Registry RGETNE demonstrated substantial clinical heterogeneity within grade (G) 2 and G3 neuroendocrine neoplasms. Tumor morphology and further subdivision of grading substantially improves prognostic stratification of these patients and may help individualize therapy. This combined, additive effect shall be considered in future classifications of neuroendocrine tumors and incorporated for stratification purposes in clinical trials.
This article evaluates the prognostic impact of histological differentiation within the WHO 2010 grading classifications and explores additional Ki‐67 cut‐off values for gastroenteropancreatic neuroendocrine neoplasms.
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