Features of colorectal adenomas among young patients with Lynch syndrome according to path_MMR: Results from the PRED-IdF registry.

BACKGROUND: Lynch syndrome (LS) is the most frequent inherited colorectal cancer syndrome. AIM: To assess the burden of adenoma in LS patients under 50 years-old followed in the PRED-IdF network. METHODS: From January 2010 to January 2019, all patients under 50 years of age with a confirmed LS germline mutation were included. The main objective was the description of adenomas characteristics according to path_MMR. RESULTS: We analyzed data from 708 patients (mean age 34.8 ± 8.6), of which 41.8 % were male. Among these patients, 37.6% had path_MLH1, 45.4% path_MSH2, 13.9% path_MSH6, 2.9% path_PMS2, and 1.2% path_EpCAM. The analysis included 1721 (70.9%) follow-up colonoscopies. A total of 682 adenomas were detected, including 140 (20.5%) advanced adenomas. The adenoma detection rates during the first and follow-up colonoscopies were 19.2% and 20.5%, respectively. Most adenomas were <10 mm (57.9%), located in the proximal colon (334, 48.9%), and presented as non-polypoid lesions (493, 72.3%). The median growth time for adenomas was 23 months (range 9-114) irrespective of the path_MMR mutation (p = 0.62). CONCLUSION: LS patients under 50 years of age have a high burden of adenomas, particularly small non-polypoid adenomas located in the proximal colon. These results highlight the need for intensive screening, with a particular focus on the proximal colon.

MSH3: a confirmed predisposing gene for adenomatous polyposis.

BACKGROUND: The MSH3 gene is part of the DNA mismatch repair system, but has never been shown to be involved in Lynch syndrome. A first report of four patients from two families, bearing biallelic MSH3 germline variants, with a phenotype of attenuated colorectal adenomatous polyposis raised the question of its involvement in hereditary cancer predisposition. The patients' tumours exhibited elevated microsatellite alterations at selected tetranucleotide repeats (EMAST), a hallmark of MSH3 deficiency. METHODS: We report five new unrelated patients with MSH3-associated polyposis. We describe their personal and familial history and study the EMAST phenotype in various normal and tumour samples, which are relevant findings based on the rarity of this polyposis subtype so far. RESULTS: All patients had attenuated colorectal adenomatous polyposis, with duodenal polyposis in two cases. Both women had breast carcinomas. EMAST phenotype was present at various levels in different samples of the five patients, confirming the MSH3 deficiency, with a gradient of instability in polyps depending on their degree of dysplasia. The negative EMAST phenotype ruled out the diagnosis of germline MSH3 deficiency for two patients: one homozygous for a benign variant and one with a monoallelic large deletion. CONCLUSION: This report lends further credence to biallelic MSH3 germline pathogenic variants being involved in colorectal and duodenal adenomatous polyposis. Large-scale studies may help clarify the tumour spectrum and associated risks. Ascertainment of EMAST may help with the interpretation of variants of unknown significance. We recommend adding MSH3 to dedicated diagnostic gene panels.

Mismatch Repair Deficiency and Lynch Syndrome Among Adult Patients With Glioma.

PURPOSE: The Lynch syndrome (LS)-glioma association is poorly documented. As for mismatch repair deficiency (MMRd) in glioma, a hallmark of LS-associated tumors, there are only limited data available. We determined MMRd and LS prevalence in a large series of unselected gliomas, and explored the associated characteristics. Both have major implications in terms of treatment, screening, and prevention. METHODS: Somatic next-generation sequencing was performed on 1,225 treatment-naive adult gliomas referred between 2017 and June 2022. For gliomas with ≥1 MMR pathogenic variant (PV), MMR immunohistochemistry (IHC) was done. Gliomas with ≥1 PV and protein expression loss were considered MMRd. Eligible patients had germline testing. To further explore MMRd specifically in glioblastomas, isocitrate dehydrogenase (IDH)-wild type (wt), we performed IHC, and complementary sequencing when indicated, in a series of tumors diagnosed over the 2007-2021 period. RESULTS: Nine gliomas were MMRd (9/1,225; 0.73%). Age at glioma diagnosis was <50 years for all but one case. Eight were glioblastomas, IDH-wt, and one was an astrocytoma, IDH-mutant. ATRX (n = 5) and TP53 (n = 8) PV were common. There was no TERT promoter PV or EGFR amplification. LS prevalence was 5/1,225 (0.41%). One 77-year-old patient was a known LS case. Four cases had a novel LS diagnosis, with germline PV in MSH2 (n = 3) and MLH1 (n = 1). One additional patient had PMS2-associated constitutional mismatch repair deficiency. Germline testing was negative in three MSH6-deficient tumors. In the second series of glioblastomas, IDH-wt, MMRd prevalence was 12.5% in the <40-year age group, 2.6% in the 40-49 year age group, and 1.6% the ≥50 year age group. CONCLUSION: Screening for MMRd and LS should be systematic in glioblastomas, IDH-wt, diagnosed under age 50 years.

Lynch syndrome: influence of additional susceptibility variants on cancer risk.

Some patients with Lynch syndrome (LS) have extreme phenotypes, i.e. cancer before the recommended screening age, or cancer for which there are no screening guidelines. We made the hypothesis that additional germline variants in cancer susceptibility genes (CSG) could explain some of these phenotypes. We compared the prevalence of additional CSG variants in LS patients with a cancer diagnosis before age 30 (early-onset, EO group) and after 40 (usual-onset, UO group). While there was no overall difference, we did find an excess of pathogenic variants and variants of unknown significance in EO cases when only gastrointestinal CSG were considered (OR 2.25; 95% CI: 1.01-5.06, p value = 0.04). Four EO cases stood out: two with POLE/POLD1 variants in the key exonuclease domain, one with a BMPR1A duplication and one with an EPCAM deletion. Additional germline variants should be considered in future screening recommendations, as they might influence cancer risk.

Impact of Sarcopenia on Survival in Patients Treated with FOLFIRINOX in a First-Line Setting for Metastatic Pancreatic Carcinoma.

Sarcopenia, defined as decreased muscle mass and strength, can be evaluated by a computed tomography (CT) examination and might be associated with reduced survival in patients with carcinoma. The prognosis of patients with metastatic pancreatic carcinoma is poor. The FOLFIRINOX (a combination of 5-fluorouracil, irinotecan, and oxaliplatin) chemotherapy regimen is a validated first-line treatment option. We investigated the impact of sarcopenia on overall survival (OS) and progression-free survival (PFS) in patients with metastatic pancreatic carcinoma. Clinical data and CT examinations of patients treated with FOLFIRINOX were retrospectively reviewed. Sarcopenia was estimated using baseline CT examinations. Seventy-five patients were included. Forty-three (57.3%) were classified as sarcopenic. The median OS of non-sarcopenic and sarcopenic patients were 15.6 and 14.1 months, respectively (p = 0.36). The median PFS was 10.3 in non-sarcopenic patients and 9.3 in sarcopenic patients (p = 0.83). No differences in toxicity of FOLFIRINOX were observed. There was a trend towards a higher probability of short-term death (within 4 months of diagnosis) in sarcopenic patients. In this study, the detection of sarcopenia failed to predict a longer OS or PFS in selected patients deemed eligible by a physician for triplet chemotherapy and receiving the FOLFIRINOX regimen in a first-line setting, confirming the major importance of a comprehensive patient assessment by physicians in selecting the best treatment option.

Mechanisms of esophageal stricture after extensive endoscopic resection: a transcriptomic analysis.

Background and study aims Esophageal stricture is the most frequent adverse event after endoscopic resection for early esophageal neoplasia. Currently available treatments for the prevention of esophageal stricture are poorly effective and associated with major adverse events. Our aim was to identify transcripts specifically overexpressed or repressed in patients who have developed a post-endoscopic esophageal stricture, as potential targets for stricture prevention. Patients and methods We conducted a prospective single-center study in a tertiary endoscopy center. Patients scheduled for an endoscopic resection and considered at risk of esophageal stricture were offered inclusion in the study. The healthy mucosa and resection bed were biopsied on Days 0, 14, and 90. A transcriptomic analysis by microarray was performed, and the differences in transcriptomic profile compared between patients with and without esophageal strictures. Results Eight patients, four with esophageal stricture and four without, were analyzed. The mean ± SD circumferential extension of the mucosal defect was 85 ±â€Š11 %. The transcriptomic analysis in the resection bed at day 14 found an activation of the interleukin (IL)-1 group (Z score = 2.159, P  = 0.0137), while interferon-gamma (INFγ) and NUPR1 were inhibited (Z score = -2.375, P  = 0.0022 and Z score = -2.333, P  = 0.00131) in the stricture group. None of the activated or inhibited transcripts were still significantly so in any of the groups on Day 90. Conclusions Our data suggest that IL-1 inhibition or INFγ supplementation could constitute promising targets for post-endoscopic esophageal stricture prevention.

Outcomes of endoscopic mucosal resection for large superficial non-ampullary duodenal adenomas.

Endoscopic mucosal resection (EMR) is the recommended treatment for superficial non-ampullary duodenal epithelial tumors larger than 6 mm. This endoscopic technique carries a high risk of adverse events. Our aim was to identify the risk factors for adverse events following EMR for non-ampullary duodenal adenomatous lesions. We retrospectively analyzed a prospectively collected database of consecutive endoscopic resections for duodenal lesions at a tertiary referral center for therapeutic endoscopy. We analyzed patients with non-ampullary duodenal adenomatous lesions ≥ 10 mm resected by EMR, and searched for factors associated with adverse events after EMR. 167 duodenal adenomatous lesions, with a median size of 25 (25-40) mm, were resected by EMR between January 2015 and December 2020. Adverse events occurred in 37/167 (22.2%) after endoscopic resection, with 29/167 (17.4%) delayed bleeding, 4/167 (2.4%) immediate perforation and 4/167 (2.4%) delayed perforation. In logistic regression, the size of the lesion was the only associated risk factor of adverse events (OR = 2.81, 95% CI [1.27; 6.47], p = 0.012). Adverse events increased mean hospitalization time (7.7 ± 9 vs. 1.9 ± 1 days, p < 0.01). None of the currently recommended preventive methods, particularly clips, affected the adverse event rate. EMR of centimetric and supracentimetric duodenal adenomatous lesions carries a high risk of adverse events, increasing with the size of the lesion and with no benefit from any preventive method. These results suggest that these procedures should be performed in expert centers, and underline the need for novel endoscopic tools to limit the rate of adverse events.

Predictive factors for the success of endoscopic dilation of esophageal caustic stricture: the experience of a French tertiary reference center.

BACKGROUND: Predictors of the efficacy of endoscopic dilation for caustic esophageal stricture have been poorly studied. METHODS: All patients undergoing an endoscopic dilation for an esophageal caustic stricture between 1990 and 2015 in a French national reference center were included. Success of dilation was defined by self-food autonomy without the need for reconstructive esophageal surgery. RESULTS: During the study period, 894 patients were admitted after caustic ingestion. Among them, 101 patients developed esophageal stricture and 92 patients were eligible for analysis (missing data in 8 cases, 1 patient died before endoscopic dilation). In this cohort (median age 42 years, women 53%, strong alkali 74%, suicide attempt 77%, hydrostatic balloon use 93%), the overall success rate of dilation was 57% with a median number of 3 dilation sessions (274 sessions, range 1-17). Factors predicting the success of the procedure were: non-inflammatory stricture or non-inflammatory intercalated mucosa between stricture (88% vs 47%, p = 0.001), a single stricture versus 2 or more strictures (69% vs 47% vs 33%, respectively, p = 0.04), a stricture of less than 5 cm (70% vs 27%, p < 0.001) and the existence of mild/ moderately tight or very tight stricture (70% vs 21% of success, p < 0.001). Perforation rate was 6.5% (18/274) requiring emergency surgery in 2 cases. CONCLUSION: Several characteristics of caustic esophageal strictures are significantly associated with the success rate of endoscopic dilation. Our data may be useful for customizing treatment strategies in patients with a caustic stricture.

Therapeutic Management of Advanced Hepatocellular Carcinoma: An Updated Review.

Hepatocellular carcinoma (HCC) usually occurs in the setting of liver cirrhosis and more rarely in a healthy liver. Its incidence has increased in the past years, especially in western countries with the rising prevalence of non-alcoholic fatty liver disease. The prognosis of advanced HCC is low. In the first-line setting of advanced HCC, sorafenib, a tyrosine kinase inhibitor, was the only validated treatment for many years. In 2020, the combination of atezolizumab, an immune checkpoint inhibitor, and bevacizumab showed superiority to sorafenib alone in survival, making it the first-line recommended treatment. Regorafenib and lenvatinib, other multikinase inhibitors, were also validated in the second and first-line settings, respectively. Transarterial chemoembolization can be an alternative treatment for patients with intermediate-stage HCC and preserved liver function, including unresectable multinodular HCC without extrahepatic spread. The current challenge in advanced HCC lies in the selection of a patient for the optimal treatment, taking into account the underlying liver disease and liver function. Indeed, all trial patients present with a Child-Pugh score of A, and the optimal approach for other patients is still unclear. Furthermore, the combination of atezolizumab and bevacizumab should be considered in the absence of medical contraindication. Many trials testing immune checkpoint inhibitors in association with anti-angiogenic agents are ongoing, and primary results are promising. The landscape in advanced HCC management is undergoing profound change, and many challenges remain for optimal patient management in the years to come. This review aimed to provide an overview of current systemic treatment options for patients with advanced unresectable HCC who are not candidates for liver-directed therapy.

Endoscopic management of non-ampullary duodenal adenomas.

Duodenal polyps are found in 0.1 % to 0.8 % of all upper endoscopies. Duodenal adenomas account for 10 % to 20 % of these lesions. They can be sporadic or occur in the setting of a hereditary predisposition syndrome, mainly familial adenomatous polyposis. Endoscopy is the cornerstone of management of duodenal adenomas, allowing for diagnosis and treatment, primarily by endoscopic mucosal resection. The endoscopic treatment of duodenal adenomas has a high morbidity, reaching 15 % in a prospective study, consisting of bleeding and perforations, and should therefore be performed in expert centers. The local recurrence rate ranges from 9 % to 37 %, and is maximal for piecemeal resections of lesions > 20 mm. Surgical resection of the duodenum is flawed with major morbidity and considered a rescue procedure in cases of endoscopic treatment failures or severe endoscopic complications such as duodenal perforations. In this paper, we review the existing evidence on endoscopic diagnosis and treatment of non-ampullary duodenal adenomas.

Further delineation of the NTHL1 associated syndrome: A report from the French Oncogenetic Consortium.

Biallelic pathogenic variants in the NTHL1 (Nth like DNA glycosylase 1) gene cause a recently identified autosomal recessive hereditary cancer syndrome predisposing to adenomatous polyposis and colorectal cancer. Half of biallelic carriers also display multiple colonic or extra-colonic primary tumors, mainly breast, endometrium, urothelium, and brain tumors. Published data designate NTHL1 as an important contributor to hereditary cancers but also underline the scarcity of available informations. Thanks to the French oncogenetic consortium (Groupe Génétique et Cancer), we collected NTHL1 variants from 7765 patients attending for hereditary colorectal cancer or polyposis (n = 3936) or other hereditary cancers (n = 3829). Here, we describe 10 patients with pathogenic biallelic NTHL1 germline variants, that is, the second largest NTHL1 series. All carriers were from the "colorectal cancer or polyposis" series. All nine biallelic carriers who underwent colonoscopy presented adenomatous polyps. For digestive cancers, average age at diagnosis was 56.2 and we reported colorectal, duodenal, caecal, and pancreatic cancers. Extra-digestive malignancies included sarcoma, basal cell carcinoma, breast cancer, urothelial carcinoma, and melanoma. Although tumor risks remain to be precisely defined, these novel data support NTHL1 inclusion in diagnostic panel testing. Colonic surveillance should be conducted based on MUTYH recommendations while extra-colonic surveillance has to be defined.

Organ Preservation after Endoscopic Resection of Early Esophageal Cancer with a High Risk of Lymph Node Involvement.

Background: Esophagectomy is recommended after endoscopic resection of an early esophageal cancer when pejorative histoprognostic criteria indicate a high risk of lymph node involvement. Our aim was to analyze the clinical outcomes of a non-surgical, organ preserving management in this clinical setting. Patients and Methods: This retrospective study was performed in two tertiary centers from 2015 to 2020. Patients were included if they had histologically complete resection of an early esophageal cancer, with poor differentiation, lymphovascular invasion or deep submucosal invasion. Endoscopic resection was followed by chemoradiotherapy or follow-up in case of surgical contraindications or patient refusal. Outcome measures were disease-free survival (DFS), overall survival (OS), cancer specific survival (CSS) and toxicity of chemoradiotherapy. Results: Forty-one patients (36 with squamous cell carcinoma and 5 with adenocarcinomas) were included. The estimated high risk of lymph node involvement was based on poor differentiation (10/41; 24%), lympho-vascular invasion (11/41; 27%), muscularis mucosa invasion or deep sub-mucosal invasion (38/41; 93%). Thirteen patients (13/41; 32%) were closely monitored, and 28 (28/41; 68%) were treated by chemoradiotherapy or radiotherapy alone. In the close follow-up group, DFS, OS and CSS were 92%, 92% and 100%, respectively vs. 75%, 79% and 96%, respectively in the chemoradiotherapy group at the end of the follow-up. Serious adverse events related to chemoradiotherapy occurred in 10% of the patients. There were no treatment-related deaths. Conclusions: Our study shows that close follow-up may be an alternative to systematic esophagectomy after endoscopic resection of early esophageal cancer with a predicted high risk of lymph node involvement.

MUTYH-associated polyposis: Review and update of the French recommendations established in 2012 under the auspices of the National Cancer institute (INCa).

MUTYH-associated polyposis (MAP) was first described in 2002. It is an autosomal recessive condition associated with germline pathogenic variants of both MUTYH alleles. In 2011, a group of French experts reviewed the available data on this syndrome and established recommendations concerning the indications and strategies for molecular analysis of the MUTYH gene in index cases and their relatives, as well as the clinical management of affected individuals under the auspices of the French Institut National du Cancer (INCa). Some of these recommendations have become obsolete as a result of recent progress, especially those concerning the molecular strategy for MUTYH testing, as this gene has recently been included in a consensus panel of 14 colorectal cancer predisposition genes, justifying revision of the previous report. We report here the revised version of this work, which successively considers the phenotype and tumor risks associated with this genotype, differential diagnoses, criteria and strategy for molecular genetic testing and recommendations for the management of affected individuals. We also discuss the phenotype and tumor risks associated with monoallelic pathogenic variants of MUTYH.

National recommendations of the French Genetics and Cancer Group - Unicancer on the modalities of multi-genes panel analyses in hereditary predispositions to tumors of the digestive tract.

In case of suspected hereditary predisposition to digestive cancers, next-generation sequencing can analyze simultaneously several genes associated with an increased risk of developing these tumors. Thus, "Gastro Intestinal" (GI) gene panels are commonly used in French molecular genetic laboratories. Lack of international recommendations led to disparities in the composition of these panels and in the management of patients. To harmonize practices, the Genetics and Cancer Group (GGC)-Unicancer set up a working group who carried out a review of the literature for 31 genes of interest in this context and established a list of genes for which the estimated risks associated with pathogenic variant seemed sufficiently reliable and high for clinical use. Pancreatic cancer susceptibility genes have been excluded. This expertise defined a panel of 14 genes of confirmed clinical interest and relevant for genetic counseling: APC, BMPR1A, CDH1, EPCAM, MLH1, MSH2, MSH6, MUTYH, PMS2, POLD1, POLE, PTEN, SMAD4 and STK11. The reasons for the exclusion of the others 23 genes have been discussed. The paucity of estimates of the associated tumor risks led to the exclusion of genes, in particular CTNNA1, MSH3 and NTHL1, despite their implication in the molecular pathways involved in the pathophysiology of GI cancers. A regular update of the literature is planned to up-grade this panel of genes in case of new data on candidate genes. Genetic and epidemiological studies and international collaborations are needed to better estimate the risks associated with the pathogenic variants of these genes either selected or not in the current panel.

A colonic mass revealing a disseminated crystal storing histiocytosis secondary to indolent multiple myeloma: a case report with literature review.

BACKGROUND: Crystal storing histiocytosis is a rare disorder associated with monoclonal gammopathy. In this disease, monoclonal heavy and light chains accumulate in the lysosome of macrophages, leading to histiocytic reaction in different organs. It is secondary to the presence of a small B-cell clone, responsible for monoclonal immunoglobulin production. Histological diagnosis is a challenge and differential diagnoses include fibroblastic and histiocytic neoplasm. Clinical manifestations depend on the involved organs, rarely including peritoneum or digestive tract. CASE PRESENTATION: We present a case of a 75-year-old with a medical history of colonic carcinoma. She presented with abdominal pain and inflammatory syndrome revealing a colonic mass. Hemicolectomy was performed. Initial diagnosis was fibroblastic tumour. The patient worsened, and diagnosis of a diffuse crystal storing histiocytosis was finally done. Haematological exploration found an indolent IgG-kappa multiple myeloma. The initial treatment with conventional chemotherapy did not permit an improvement of the patient condition. Immunotherapy with anti-CD38 monoclonal antibody (daratumumab) was proposed with a clinical and biological response. CONCLUSION: This case report emphasizes the histopathological challenge of histiocytic tumours which may involve digestive track. It focuses on the concept of monoclonal gammopathy of clinical significance, which can have a large spectrum of manifestations.

Medical Treatment of Advanced Pancreatic Neuroendocrine Neoplasms.

Pancreatic neuroendocrine neoplasms (panNENs) are relatively rare but their incidence has increased almost sevenfold over the last four decades. Neuroendocrine neoplasms are classified according to their histologic differentiation and their grade. Their grade is based on their Ki-67 proliferation index and mitotic index. Their prognosis is highly variable according to these elements and treatments also vary according to their classification. Surgery is the only curative treatment for localized and advanced panNENs and offers a better prognosis than non-surgical treatments. In the case of an advanced panNEN without the possibility of resection and/or ablation, medical treatment remains the cornerstone for improving survival and preserving quality-of-life. PanNENs are considered as chemosensitive tumors, unlike midgut neuroendocrine tumors. Thus, panNENs can be treated with chemotherapy, but targeted therapies and somatostatin analogs are also treatment options. The scarcity and heterogeneity of NENs make their management difficult. The present review aims to clarify the medical treatments currently available for advanced panNENs, based on their characteristics, and to propose a treatment algorithm.

[MUTYH-associated polyposis: Review and update of the French recommendations established in 2012 under the auspices of the National Cancer Institute (INCa)]. / La polypose associée à MUTYH : synthèse et actualisation des recommandations françaises établies en 2012 sous l'égide de l'Institut national du cancer (INCa).

MUTYH-associated polyposis (MUTYH-associated polyposis, MAP) is an autosomal recessive inheritance disorder related to bi-allelic constitutional pathogenic variants of the MUTYH gene which was first described in 2002. In 2011, a group of French experts composed of clinicians and biologists, performed a summary of the available data on this condition and drew up recommendations concerning the indications and the modalities of molecular analysis of the MUTYH gene in index cases and their relatives, as well as the management of affected individuals. In view of recent developments, some recommendations have become obsolete, in particular with regard to the molecular analysis strategy since MUTYH gene has been recently included in a consensus panel of 14 genes predisposing to colorectal cancer. This led us to revise all the points of the previous expertise. We report here the revised version of this work which successively considers the phenotype and the tumor risks associated with this genotype, the differential diagnoses, the indication criteria and the strategy of the molecular analysis and the recommendations for the management of affected individuals. We also discuss the phenotype and the tumor risks associated with mono-allelic pathogenic variants of MUTYH gene.

Genetic, structural, and functional characterization of POLE polymerase proofreading variants allows cancer risk prediction.

PURPOSE: Polymerase proofreading-associated polyposis is a dominantly inherited colorectal cancer syndrome caused by exonuclease domain missense variants in the DNA polymerases POLE and POLD1. Manifestations may also include malignancies at extracolonic sites. Cancer risks in this syndrome are not yet accurately quantified. METHODS: We sequenced POLE and POLD1 exonuclease domains in 354 individuals with early/familial colorectal cancer (CRC) or adenomatous polyposis. We assessed the pathogenicity of POLE variants with yeast fluctuation assays and structural modeling. We estimated the penetrance function for each cancer site in variant carriers with a previously published nonparametric method based on survival analysis approach, able to manage unknown genotypes. RESULTS: Pathogenic POLE exonuclease domain variants P286L, M294R, P324L, N363K, D368N, L424V, K425R, and P436S were found in ten families. The estimated cumulative risk of CRC at 30, 50, and 70 years was 11.1% (95% confidence interval [CI]: 4.2-17.5), 48.5% (33.2-60.3), and 74% (51.6-86.1). Cumulative risk of glioblastoma was 18.7% (3.2-25.8) at 70 years. Variants interfering with DNA binding (P286L and N363K) had a significantly higher mutagenic effect than variants disrupting ion metal coordination at the exonuclease site. CONCLUSION: The risk estimates derived from this study provide a rational basis on which to provide genetic counseling to POLE variant carriers.

High Prevalence of Somatic Oncogenic Driver Alterations in Patients With NSCLC and Li-Fraumeni Syndrome.

INTRODUCTION: 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. METHODS: Retrospective study of clinical and molecular profiles of patients with NSCLC and germline TP53 variants. RESULTS: 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. CONCLUSIONS: 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.