bims-lifras 2022-09-11 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022‒09‒11
eight papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study.
Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome.
A High Percentage of NSCLC With Germline CHEK2 Mutation Harbors Actionable Driver Alterations: Survey of a Cancer Genomic Database and Review of Literature.
Association between germline pathogenic variants in cancer-predisposing genes and lymphoma risk.
Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.
Lynch Syndrome: From Carcinogenesis to Prevention Interventions.
Congenital midline spinal hamartoma in an infant with DICER1 syndrome: A case report.
Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.

Ann Hum Genet. 2022 Sep 08.

Germline variants screening of MLH1, MSH2, MSH6 and PMS2 genes in 64 Algerian Lynch syndrome families: The first nationwide study.

Asma-Lamia Boumehdi, Farid Cherbal, Feriel Khider, Mohammed Oukkal, Hassen Mahfouf, Ferhat Zebboudj, Mustapha Maaoui.

  Colorectal cancer is the second leading cause of cancer-related deaths in women and men in Algeria. Lynch syndrome (LS) is an autosomal dominant disease caused by heterozygous germline pathogenic variants in mismatch repair genes (MMR) and frequently predisposes to colorectal cancer. However, data about MMR germline pathogenic variants in Algerian patients are limited. This first nationwide study aims to describe clinicopathologic features and germline variants in MMR genes in Algerian families with suspected LS. Sixty-four (64) families with suspected LS were studied. Index cases with LS who fulfilled Amsterdam criteria were screened by PCR-direct sequencing for germline variants in MMR genes: MLH1 (exons 1, 9, 10, 13, 16), MSH2 (exons 5, 6, 7, 12), MSH6 (exons 4 and 8) and PMS2 (exons 6 and 10). We selected these specific risk exons genes since they have a higher probability of harboring pathogenic variants. In addition, two unrelated LS patients were screened by next-generation sequencing using a cancer panel of 30 hereditary cancer genes. Six germline pathogenic variants and one germline likely pathogenic variant were identified in 19 (29.68%) families (4 MLH1, 2 MSH2 and 1 MSH6). Of index cases and relatives who underwent genetic testing (n = 76), 30 (39.47%) had MMR pathogenic gene variants, one (0.13%) had MMR gene likely pathogenic variant and three had MMR variant of uncertain significance, respectively. Two novel germline pathogenic variants in MLH1 (2) and one germline likely pathogenic variant in MSH6 (1) never published in individuals with LS have been detected in the present study. The recurrent MLH1 germline pathogenic variant c.1546C>T has been found in nine LS families, six of them related with two large kindreds, from four North central provinces of Algeria. In addition, the common MSH2 germline pathogenic variant c.942+3A>T has been detected in five unrelated patients with a strong LS family history. The accumulative knowledge about clinicopathological and genetic characteristics of LS in Algerian patients will impact clinical management in the areas of both prevention and treatment.

Keywords:  Algerian patients; Lynch syndrome; MMR genes; NGS; cancer panel; colorectal cancer; genealogical data; genetic testing; genotype-phenotype correlation; germline variants

DOI:  https://doi.org/10.1111/ahg.12482
Cancers (Basel). 2022 Aug 31. pii: 4233. [Epub ahead of print]14(17):

Whole-Exome Sequencing Identifies Pathogenic Germline Variants in Patients with Lynch-Like Syndrome.

Wellington Dos Santos, Edilene Santos de Andrade, Felipe Antonio de Oliveira Garcia, Natália Campacci, Cristina da Silva Sábato, Matias Eliseo Melendez, Rui Manuel Reis, Henrique de Campos Reis Galvão, Edenir Inez Palmero.

  Lynch syndrome (LS) is the most common hereditary colorectal cancer (CRC) syndrome, characterized by germline pathogenic variants in mismatch repair (MMR)-related genes that lead to microsatellite instability. Patients who meet the clinical criteria for LS and MMR deficiency and without any identified germline pathogenic variants are frequently considered to have Lynch-like syndrome (LLS). These patients have a higher risk of CRC and extracolonic tumors, and little is known about their underlying genetic causes. We investigated the germline spectrum of LLS patients through whole-exome sequencing (WES). A total of 20 unrelated patients with MMR deficiency who met the clinical criteria for LS and had no germline variant were subjected to germline WES. Variant classification was performed according to the American College of Medical Genetics and Genomics (ACMG) criteria. Pathogenic/likely pathogenic variants were identified in 35% of patients in known cancer genes such as MUTYH and ATM. Besides this, rare and potentially pathogenic variants were identified in the DNA repair gene POLN and other cancer-related genes such as PPARG, CTC1, DCC and ALPK1. Our study demonstrates the germline mutational status of LLS patients, a population at high risk of colorectal cancer.

Keywords:  Lynch-like syndrome; cancer predisposition; hereditary colorectal cancer

DOI:  https://doi.org/10.3390/cancers14174233
JTO Clin Res Rep. 2022 Sep;3(9): 100387

A High Percentage of NSCLC With Germline CHEK2 Mutation Harbors Actionable Driver Alterations: Survey of a Cancer Genomic Database and Review of Literature.

Shannon S Zhang, Jessica K Lee, Hanna Tukachinsky, Alexa B Schrock, Misako Nagasaka, Sai-Hong Ignatius Ou.

  Introduction: Germline CHEK2 mutations are rare and have not been associated with increased risk of NSCLC.Methods: We identified two sequential primary NSCLCs harboring distinct actionable driver alterations (EGFR E746 _S752 delinsV and CD74-ROS1) in a patient with NSCLC with a novel germline CHEK2 mutation S5fs∗54 (c.14_20delCGGATGT). We queried a genomic database of NSCLC samples profiled by plasma next-generation sequencing (Foundation Medicine Inc.) and performed a literature search of germline CHEK2 mutations in NSCLC.
Results: Of 6101 patients with unique NSCLC profiled by plasma next-generation sequencing, 53 cases (0.87%) of germline CHEK2 mutation were identified (male-to-female ratio, 49%:51%; median age = 75 y). The median allele frequency of CHEK2 was 49% (interquartile range: 49%-51%). Ten unique CHEK2 germline mutations were identified. Literature review identified 15 additional cases of germline CHEK2 mutations in NSCLC. Overall, a total of 70 CHEK2 germline mutations (21 unique CHEK2 alterations) were identified. Among these 70 CHEK2 germline mutations, 54.3% were amino acid substitutions (point mutation), 40.0% were frameshift mutations, and 5.7% were splice site mutations. Of these 70 total cases assessed, 29 (41.4%) potentially actionable driver alterations were identified with KRAS G12C mutation (27.6%) being the most common and KRAS G12A/C/D/R/S/V mutations together constituting 51.7% of these driver mutations.
Conclusions: Germline CHEK2 mutations are rare in NSCLC. A large proportion of these cases harbor actionable driver alterations. The relationship between germline CHEK2 mutations and actionable driver alterations in NSCLC may be worth further investigation.

Keywords:  Actionable driver mutation; EGFR; Germline CHEK2 mutation; KRAS; NSCLC; Plasma genotyping; Tumor genotyping

DOI:  https://doi.org/10.1016/j.jtocrr.2022.100387
Cancer Sci. 2022 Sep 05.

Association between germline pathogenic variants in cancer-predisposing genes and lymphoma risk.

Yoshiaki Usui, Yusuke Iwasaki, Keitaro Matsuo, Mikiko Endo, Yoichiro Kamatani, Makoto Hirata, Kokichi Sugano, Teruhiko Yoshida, Koichi Matsuda, Yoshinori Murakami, Yoshinobu Maeda, Hidewaki Nakagawa, Yukihide Momozawa.

  The application of advanced molecular technology has significantly expanded lymphoma classification, allowing risk stratification and treatment optimization. Limited evidence suggests the presence of a genetic predisposition in lymphoma, indicating the potential for better individualized clinical management based on a novel lymphoma classification. Herein, we examined the impact of germline pathogenic variants in 27 cancer-predisposing genes with lymphoma risk and explored the clinical characteristics of pathogenic variant carriers. This study included 2,066 lymphoma patients and 38,153 cancer-free controls from the Japanese population. Following quality control of sequencing data, samples from 1,982 lymphoma patients and 37,592 controls were further analyzed. We identified 309 pathogenic variants among 4,850 variants in the 27 cancer-predisposing genes. Pathogenic variants in the following four cancer-predisposing genes were associated with a high risk of lymphoma: ATM (odds ratio [OR], 2.63; 95% confidence interval [CI], 1.25-5.51; p = 1.06 × 10-2 ), BRCA1 (OR, 5.88; 95% CI, 2.65-13.02; p = 1.27 × 10-5 ), BRCA2 (OR, 2.94; 95% CI, 1.60-5.42; p = 5.25 × 10-4 ), and TP53 (OR, 5.22; 95% CI, 1.43-19.02; p = 1.23 × 10-2 ). The proportion of carriers of these genes was 1.6% of lymphoma patients. Furthermore, pathogenic variants in these genes were especially associated with a higher risk of mantle cell lymphoma (OR, 21.57; 95% CI, 7.59-61.26; p = 8.07 × 10-9 ). These results provide novel insights concerning monogenic form into lymphoma classification. Some lymphoma patients may benefit from surveillance and targeted treatment, such as other neoplasms.

Keywords:  cancer-predisposing gene; case-control study; germline pathogenic variant; lymphoma; mantle cell lymphoma

DOI:  https://doi.org/10.1111/cas.15522
J Surg Oncol. 2022 Sep 05.

Short and long-term outcomes of prophylactic total gastrectomy in 54 consecutive individuals with germline pathogenic mutations in the CDH1 gene.

Mason D Stillman, Nicole Kusche, Sabrina Toledano, Kimberly J Hilfrank, Changhwan Yoon, Joel T Gabre, Sheila D Rustgi, Chin Hur, Fay Kastrinos, Sandra W Ryeom, Sam S Yoon.

  BACKGROUND: Germline mutation of CDH1 is rare and leads to hereditary diffuse gastric cancer (DGC).METHODS: Patients (pts) with CDH1 mutation who underwent multidisciplinary counseling followed by open prophylactic total gastrectomy (PTG) by a single surgeon were reviewed.
RESULTS: Fifty-four pts with a median age of 41 years (16-70 years) underwent PTG between 2006 and 2021. Median operative time was 161 min, and median hospital stay was 7 days (range 6-12). There were 5 complications (9.2%) within 30 days, and two complications (pulmonary embolism and pancreatitis) required readmission. There were no anastomotic leaks. The pathologic analysis of the first 10 pts included the entire gastric mucosa, revealing a median of 15 foci of DGC (range 5-136). The subsequent 44 pts with more limited analysis had a median of 2 foci (range 0-5), and two pts (3.7%) had no foci identified. Median maximum weight loss was 19%. In long-term follow-up (median 4.6 years) of 20 pts, median global QOL was 2.0 (very good), the majority had persistent difficulty with certain foods or liquids, and all stated they would again elect PTG over surveillance endoscopy.
CONCLUSIONS: PTG can be performed safely at high-volume referral centers with very good QOL but nutritional sequelae persist.

Keywords:  germline CDH1 mutation; hereditary diffuse gastric cancer; prophylactic gastrectomy

DOI:  https://doi.org/10.1002/jso.27084
Cancers (Basel). 2022 Aug 24. pii: 4102. [Epub ahead of print]14(17):

Lynch Syndrome: From Carcinogenesis to Prevention Interventions.

Donatella Gambini, Stefano Ferrero, Elisabetta Kuhn.

  Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.

Keywords:  Lynch syndrome; carcinogenesis; colorectal cancer; endometrial cancer; ovarian cancer; prevention

DOI:  https://doi.org/10.3390/cancers14174102
Front Oncol. 2022 ;12 963768

Congenital midline spinal hamartoma in an infant with DICER1 syndrome: A case report.

Rawan Hammad, Winnie Lo, Haiying Chen, Manohar Shroff, David Malkin, Anita Villani, Avram Denburg.

  Congenital spinal hamartomas are rare benign tumors. They are mostly seen in infants and are typically asymptomatic at presentation. Spinal hamartomas have not been associated with any known cancer predisposition syndrome. DICER1 syndrome is a well-characterized cancer predisposition syndrome caused by a germline mutation in the DICER1 gene, which shows variable expressivity. To our knowledge, spinal hamartoma has never been described in individuals with DICER1 syndrome. Here, we describe a rare association of congenital spinal hamartoma and DICER1 syndrome in a 5-week-old infant, with molecular findings suggestive of the implication of DICER1 in the pathogenesis of this tumor.

Keywords:  DICER1; cancer predisposition; case report; congenital midline spinal hamartoma; infant

DOI:  https://doi.org/10.3389/fonc.2022.963768
J Clin Immunol. 2022 Sep 06.

Novel Germline TET2 Mutations in Two Unrelated Patients with Autoimmune Lymphoproliferative Syndrome-Like Phenotype and Hematologic Malignancy.

Marta López-Nevado, Javier Ortiz-Martín, Cristina Serrano, María A Pérez-Saez, José L López-Lorenzo, Francisco J Gil-Etayo, Edgar Rodríguez-Frías, Oscar Cabrera-Marante, Pablo Morales-Pérez, María S Rodríguez-Pinilla, Rebeca Manso, Rocío N Salgado-Sánchez, Ana Cerdá-Montagud, Juan F Quesada-Espinosa, María J Gómez-Rodríguez, Estela Paz-Artal, Cecilia Muñoz-Calleja, Reyes Arranz-Sáez, Luis M Allende.

  Somatic mutations in the ten-eleven translocation methylcytosine dioxygenase 2 gene (TET2) have been associated to hematologic malignancies. More recently, biallelic, and monoallelic germline mutations conferring susceptibility to lymphoid and myeloid cancer have been described. We report two unrelated autoimmune lymphoproliferative syndrome-like patients who presented with T-cell lymphoma associated with novel germline biallelic or monoallelic mutations in the TET2 gene. Both patients presented a history of chronic lymphoproliferation with lymphadenopathies and splenomegaly, cytopenias, and immune dysregulation. We identified the first compound heterozygous patient for TET2 mutations (P1) and the first ALPS-like patient with a monoallelic TET2 mutation (P2). P1 had the most severe form of autosomal recessive disease due to TET2 loss of function resulting in absent TET2 expression and profound increase in DNA methylation. Additionally, the immunophenotype showed some alterations in innate and adaptive immune system as inverted myeloid/plasmacytoid dendritic cells ratio, elevated terminally differentiated effector memory CD8 + T-cells re-expressing CD45RA, regulatory T-cells, and Th2 circulating follicular T-cells. Double-negative T-cells, vitamin B12, and IL-10 were elevated according to the ALPS-like suspicion. Interestingly, the healthy P1's brother carried a TET2 mutation and presented some markers of immune dysregulation. P2 showed elevated vitamin B12, hypergammaglobulinemia, and decreased HDL levels. Therefore, novel molecular defects in TET2 confirm and expand both clinical and immunological phenotype, contributing to a better knowledge of the bridge between cancer and immunity.

Keywords:  ALPS; ALPS-like; Germline mutation; Immune dysregulation; Lymphoma lymphoproliferation; Malignancy; Somatic mutation; TET2

DOI:  https://doi.org/10.1007/s10875-022-01361-y