Background
In Japan, with the introduction of multigene panel testing, there is an urgent need to build a new medical system for hereditary breast cancer patients that covers pathogenic variants ...other than
BRCA1/2
. The aim of this study was to reveal the current status of breast MRI surveillance for high-risk breast cancer susceptibility genes other than
BRCA1/2
and the characteristics of detected breast cancer.
Methods
We retrospectively examined 42 breast MRI surveillance with contrast performed on patients with hereditary tumors other than
BRCA1/2
pathogenic variants at our hospital from 2017 to 2021. MRI exams were evaluated independently by two radiologists. Final histopathological diagnosis for malignant lesions were obtained from surgical specimen.
Results
A total of 16 patients included
TP53, CDH1, PALB2, ATM
pathogenic variants and 3 variant of unknown significance. 2 patients with
TP53
pathogenic variants were detected breast cancer by annual MRI surveillance. The rate of cancer detection was 12.5% (2/16). One patient was detected synchronous bilateral breast cancer and unilateral multiple breast cancers (3 lesions in 1 patient), so there were 4 malignant lesions in total. Surgical pathology of 4 lesions were 2 ductal carcinoma in situ, 1 invasive lobular carcinoma, and 1 invasive ductal carcinoma. MRI findings of 4 malignant lesions were detected as 2 non mass enhancement, 1 focus and 1 small mass. All of 2 patients with
PALB2
pathogenic variants had previously developed breast cancer.
Conclusions
Germline
TP53
and
PALB2
were strongly associated with breast cancer, suggesting that MRI surveillance is essential for breast cancer-related hereditary predisposition.
A multitude of cellular processes involve biomolecular condensates, which has led to the suggestion that diverse pathogenic mutations may dysregulate condensates. Although proof-of-concept studies ...have identified specific mutations that cause condensate dysregulation, the full scope of the pathological genetic variation that affects condensates is not yet known. Here, we comprehensively map pathogenic mutations to condensate-promoting protein features in putative condensate-forming proteins and find over 36,000 pathogenic mutations that plausibly contribute to condensate dysregulation in over 1,200 Mendelian diseases and 550 cancers. This resource captures mutations presently known to dysregulate condensates, and experimental tests confirm that additional pathological mutations do indeed affect condensate properties in cells. These findings suggest that condensate dysregulation may be a pervasive pathogenic mechanism underlying a broad spectrum of human diseases, provide a strategy to identify proteins and mutations involved in pathologically altered condensates, and serve as a foundation for mechanistic insights into disease and therapeutic hypotheses.
Mismatch repair-deficient colon cancer is heterogeneous. Differentiating inherited constitutional variants from somatic genetic alterations and gene silencing is important for surveillance and ...genetic counseling.
This study aimed to determine the extent to which the underlying mechanism of loss of mismatch repair influences molecular and clinicopathologic features of microsatellite instability-high colon cancer.
This is a retrospective analysis.
This study was conducted at a comprehensive cancer center.
Patients with microsatellite instability-high colon cancer of stage I, II, or III were included.
Patients underwent a curative surgical resection.
The main outcome measures were hypermethylation of the MLH1 promoter, biallelic inactivation, constitutional pathogenic variants, and loss of specific mismatch repair proteins.
Of the 157 identified tumors with complete genetic analysis, 66% had hypermethylation of the MLH1 promoter, 18% had constitutional pathogenic variants, (Lynch syndrome), 11% had biallelic somatic mismatch repair gene pathogenic variants, and 6% had unexplained high microsatellite instability. The distribution of mismatch repair loss was as follows: MLH1 and PMS2 co-loss, 79% of the tumors; MSH2 and MSH6 co-loss, 10%; MSH6 alone, 3%; PMS2 alone, 2%; other combinations, 2%; no loss, 2%. Tumor mutational burden was lowest in MLH1- and PMS2-deficient tumors. MSH6-deficient tumors had the lowest levels of tumor-infiltrating lymphocytes, lowest MSI scores, and fewest frameshift deletions. Patients with MLH1 promoter hypermethylation were significantly more likely to be older and female and to have right-sided colon lesions than patients with biallelic inactivation. Mutation was the most prevalent second hit in tumors with biallelic inactivation and tumors of patients with Lynch syndrome.
This study was limited by potential selection or referral bias, missing data for some patients, and relatively small sizes of some subgroups.
Clinical characteristics of mismatch repair-deficient colon cancer vary with the etiology of microsatellite instability, and its molecular characteristics vary with the affected mismatch repair protein. See Video Abstract at http://links.lww.com/DCR/B984 .
ANTECEDENTES:El cáncer de colon deficiente en la reparación de errores de emparejamiento es heterogéneo. La diferenciación de las variantes constitucionales heredadas de las alteraciones genéticas somáticas y el silenciamiento de genes es importante para la vigilancia y el asesoramiento genético.OBJETIVO:Determinar hasta qué punto el mecanismo subyacente de pérdida de reparación de desajustes influye en las características moleculares y clinicopatológicas del cáncer de colon con alta inestabilidad de microsatélites.DISEÑO:Análisis retrospectivo.ESCENARIO:Centro integral de cáncer.PACIENTES:Pacientes con cáncer de colon con inestabilidad de microsatélites alta en estadio I, II, o III.INTERVENCIÓN:Resección quirúrgica con intención curativa.PRINCIPALES RESULTADOS Y MEDIDAS:Hipermetilación del promotor MLH1, inactivación bialélica, variante patógena constitucional y pérdida de proteínas específicas reparadoras de desajustes.RESULTADOS:De los 157 tumores identificados con un análisis genético completo, el 66 % tenía hipermetilación del promotor MLH1, el 18 % tenía una variante patogénica constitucional (síndrome de Lynch), el 11 % tenía variantes patogénicas somáticas bialélicas de algún gen MMR y el 6 % tenía una alta inestabilidad de microsatélites sin explicación. La distribución de la pérdida según la proteína de reparación del desajuste fue la siguiente: pérdida conjunta de MLH1 y PMS2, 79 % de los tumores; co-pérdida de MSH2 y MSH6, 10%; MSH6 solo, 3%; PMS2 solo, 2%; otras combinaciones, 2%; sin pérdida, 2%. La carga mutacional del tumor fue más baja en los tumores deficientes en MLH1 y PMS2. Los tumores con deficiencia de MSH6 tenían los niveles más bajos de linfocitos infiltrantes de tumores, las puntuaciones más bajas del sensor de IMS y la menor cantidad de deleciones por cambio de marco. Los pacientes con hipermetilación del promotor MLH1 tenían significativamente más probabilidades de ser mayores y mujeres y de tener lesiones en el colon derecho que los pacientes con inactivación bialélica. La mutación fue el segundo golpe más frecuente en tumores con inactivación bialélica y tumores de pacientes con síndrome de Lynch.LIMITACIONES:Sesgo potencial de selección o referencia, datos faltantes para algunos pacientes y tamaños relativamente pequeños de algunos subgrupos.CONCLUSIONES:Las características clínicas del cáncer de colon deficiente en reparación de desajustes varían con la etiología de la inestabilidad de microsatélites, y sus características moleculares varían con la proteína de reparación de desajustes afectada. Vea Resumen de video en http://links.lww.com/DCR/B984 . (Traducción-Dr. Felipe Bellolio ).
Background
Approximately 5% of colorectal cancers (CRCs) are hereditary. Lynch syndrome (LS), also known as hereditary nonpolyposis colorectal cancer (HNPCC), is the most common form of recognized ...hereditary CRC. Although Iran, as a developing country, has a high incidence of CRC, the spectrum of variants has yet to be thoroughly investigated.
Aims
This study aimed to investigate pathogenic and non‐pathogenic variants in MLH1 and MSH2 genes in Iranian patients with suspected Lynch syndrome (sLS).
Methods and results
In the present study, 25 peripheral blood samples were collected from patients with sLS and high microsatellite instability (MSI‐H). After DNA extraction, all samples underwent polymerase chain reaction and Sanger sequencing to identify the variants in the exons of MLH1 and MSH2 genes. The identified variants were interpreted using prediction tools, and were finally reported under ACMG guidelines. In our study population, 13 variants were found in the MLH1 gene and 8 in the MSH2 gene. Interestingly, 7 of the 13 MLH1 variants and 3 of the 8 MSH2 variants were novel, whereas the remaining variants were previously reported or available in databases. In addition, some patients with sLS did not have variants in the exons of the MLH1 and MSH2 genes. The variants detected in the MLH1 and MSH2 genes had specific characteristics regarding the number, area of occurrence, and their relationship with demographic and clinicopathologic features.
Conclusion
Overall, our results suggest that analysis of MLH1 and MSH2 genes alone is insufficient in the Iranian population, and more comprehensive tests are recommended for detecting LS.
•A woman with lung adenocarcinoma was found to carry a rare germline epidermal growth factor receptor (EGFR) variant, known as c.2527G > A, p.V843I.•The patient’s sister and mother also had lung ...cancer, but with only the mother carried the same EGFR p.V843I variant.•This appears to be the second reported case of familial lung cancer occurring in the context of a p.V843I germline variant.•p.V843I may be accompanied by other somatically acquired pathogenic variants in EGFR, usually in cis with the germline variant.•p.V843I is currently classified as a variant of unknown significance on ClinVar.•Reports of familial lung cancer can help with ultimate reclassification of p.V843I.•A proposed algorithm for germline variant testing in lung cancer is presented.
Somatic epidermal growth factor receptor (EGFR) pathogenic variants have been identified and are routinely tested in the molecular diagnosis of non-small cell lung cancer (NSCLC) as they represent a target for EGFR tyrosine kinase inhibitor (TKI) therapy. However, germline variants in EGFR are much less frequently reported.
Herein, we report the case of a 46-year-old woman diagnosed with lung adenocarcinoma who was found to harbor a rare germline missense variant in exon 21 of EGFR: NM_005228.5(EGFR):c.2527G>A (p.V843I). In the tumor, this variant (Cosmic ID COSV51767379) was accompanied by a secondary, known pathogenic EGFR variant in cis, also occurring in exon 21, c.2573T>G (p.L858R) (Cosmic ID 6224). Her mother was previously diagnosed with poorly differentiated lung carcinoma and her tumor was also found to harbour the p.V843I variant but no other pathogenic variants. Notably, the proband’s sister, diagnosed with a lung carcinoma with sarcomatous features at age 44, did not carry this variant or any other somatic or germline EGFR variants.
This is the second report of familial lung adenocarcinoma associated with the germline p.V843I variant, which remains classified as a variant of uncertain significance. The lack of segregation of this variant in the proband’s affected sister illustrates the complexity with evaluating lung cancer predisposition factors. Currently, there is a paucity of data regarding the therapeutic outcomes of patients with tumors expressing this rare germline variant, therefore we propose an algorithm for the identification of at-risk individuals and families as the first step for their personalized management.
•BRCA1-2 mutations (gBRCA1-2) are responsible for PDAC in 15–20% of familiar cases.•gBRCA1-2 and DDR genes mutations (gDDR) emerged as therapeutic targets for PDAC.•Rigorous studies on gBRCA1-2/DDR ...geographic distribution are lacking in PDAC.•Improving the gBRCA1-2/DDR epidemiology may lead to pharmacoethnicity-based trials.
Incidence of pancreatic ductal adenocarcinoma (PDAC) is increasing over the last years, while patients prognosis remains grim. Recently germline BRCA1 and 2 pathogenic variants (gBRCA1-2) have emerged as risk factors for PDAC development, as well as new predictors of response to specific therapeutic interventions. However, data on gBRCA1-2 incidence in PDAC are currently sparse and limited to selected categories of patients, as for positive cancer history cases, for patients affected only by early or late stages of disease and mainly from the North-American population, thus generating incomplete information about the gBRCA1/2 epidemiology.
In Western Countries gBRCA1-2 incidence ranges between 4.5% and 8% in unselected PDAC patients, raising up to 26% in cohorts with positive family cancer history. To date a limited number of studies from Asian countries are available, reporting a 10% as highest incidence of gBRCA1-2 in familiar PDAC, claiming at least in part a role of ethnicity in the gBRCA1-2 incidence and in other genes potentially implicated in the therapeutic decisions.
Drawing a better defined map for the incidence of gBRCA1-2 and other germline pathogenic variants of DNA Damage Response genes (gDDR) might help assessing the therapeutic strategies for mutated patients according to the geographic areas. These informations may enhance the chance to predict efficacy and toxicity of selected chemotherapy regimens, fostering the development and implementation of the pharmaco-ethnicity knowledge in the routine-clinical practice, and increasing the awareness of the potential incorrect generalization of trials results outside of the geographic area where they are conducted.
With the advent of gene therapies for inherited retinal degenerations (IRDs), genetic diagnostics will have an increasing role in clinical decision-making. Yet the genetic cause of disease cannot be ...identified using exon-based sequencing for a significant portion of patients. We hypothesized that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and evaluated patients with single coding pathogenic variants in RPGRIP1 to test this hypothesis.
IRD families underwent targeted panel sequencing. Unsolved cases were explored by exome and genome sequencing looking for additional pathogenic variants. Candidate pathogenic variants were then validated by Sanger sequencing, quantitative polymerase chain reaction, and in vitro splicing assays in two cell lines analyzed through amplicon sequencing.
Among 1722 families, 3 had biallelic loss-of-function pathogenic variants in RPGRIP1 while 7 had a single disruptive coding pathogenic variants. Exome and genome sequencing revealed potential noncoding pathogenic variants in these 7 families. In 6, the noncoding pathogenic variants were shown to lead to loss of function in vitro.
Noncoding pathogenic variants were identified in 6 of 7 families with single coding pathogenic variants in RPGRIP1. The results suggest that noncoding pathogenic variants contribute significantly to the genetic causality of IRDs and RPGRIP1-mediated IRDs are more common than previously thought.
Autosomal-dominant polycystic kidney disease (ADPKD) is characterized by the progressive development of kidney cysts, often resulting in end-stage renal disease (ESRD). This disorder is genetically ...heterogeneous with ∼7% of families genetically unresolved. We performed whole-exome sequencing (WES) in two multiplex ADPKD-like pedigrees, and we analyzed a further 591 genetically unresolved, phenotypically similar families by targeted next-generation sequencing of 65 candidate genes. WES identified a DNAJB11 missense variant (p.Pro54Arg) in two family members presenting with non-enlarged polycystic kidneys and a frameshifting change (c.166_167insTT) in a second family with small renal and liver cysts. DNAJB11 is a co-factor of BiP, a key chaperone in the endoplasmic reticulum controlling folding, trafficking, and degradation of secreted and membrane proteins. Five additional multigenerational families carrying DNAJB11 mutations were identified by the targeted analysis. The clinical phenotype was consistent in the 23 affected members, with non-enlarged cystic kidneys that often evolved to kidney atrophy; 7 subjects reached ESRD from 59 to 89 years. The lack of kidney enlargement, histologically evident interstitial fibrosis in non-cystic parenchyma, and recurring episodes of gout (one family) suggested partial phenotypic overlap with autosomal-dominant tubulointerstitial diseases (ADTKD). Characterization of DNAJB11-null cells and kidney samples from affected individuals revealed a pathogenesis associated with maturation and trafficking defects involving the ADPKD protein, PC1, and ADTKD proteins, such as UMOD. DNAJB11-associated disease is a phenotypic hybrid of ADPKD and ADTKD, characterized by normal-sized cystic kidneys and progressive interstitial fibrosis resulting in late-onset ESRD.
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