bims-lifras 2023-03-05 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2023–03–05
nine papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Clinical and genomic features of non-small cell lung cancer occurring in families.
Prevalence of Pathogenic Germline Mutations in 13 Hereditary Cancer-Related Genes in Breast Cancer Patients in Narathiwat Province, Thailand.
Atypical ATMs: Broadening the phenotypic spectrum of ATM-associated hereditary cancer.
Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception.
Germline Variants in Childhood Cutaneous Melanoma.
Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico.
Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications.
Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer.
Improving Rates of Germline BRCA Mutation Testing for Patients With Ovarian Cancer in Vancouver Island, British Columbia, Canada.

Thorac Cancer. 2023 Mar 03.

Clinical and genomic features of non-small cell lung cancer occurring in families.

Shingo Miyabe, Shin Ito, Ikuro Sato, Jiro Abe, Keiichi Tamai, Mai Mochizuki, Haruna Fujimori, Kazunori Yamaguchi, Norihisa Shindo, Hiroshi Shima, Tomoko Yamazaki, Makoto Abue, Yoshinori Okada, Jun Yasuda.

   BACKGROUND: Exposure to environmental carcinogens, such as through smoking, is a major factor in the carcinogenesis of non-small cell lung cancer (NSCLC). However, genetic factors may also contribute.
METHODS: To identify candidate tumor suppressor genes for NSCLC, we included 23 patients (10 related pairs and 3 individuals) with NSCLC who had other NSCLC-affected first-degree relatives in a local hospital. Exome analyses for both germline and somatic (NSCLC specimens) DNA were performed for 17 cases. Germline exome data of these 17 cases revealed that most of the short variants were identical to the variants in 14KJPN (a Japanese reference genome panel of more than 14 000 individuals) and only a nonsynonymous variant in the DHODH gene, p.A347T, was shared between a pair of NSCLC patients in the same family. This variant is a known pathogenic variant of the gene for Miller syndrome.
RESULTS: Somatic genetic alterations in the exome data of our samples showed frequent mutations in the EGFR and TP53 genes. Principal component analysis of the patterns of 96 types of single nucleotide variants (SNVs) suggested the existence of unique mechanisms inducing somatic SNVs in each family. Delineation of mutational signatures of the somatic SNVs with deconstructSigs for the pair of germline pathogenic DHODH variant-positive cases showed that the mutational signatures of these cases included SBS3 (homologous recombination repair defect), SBS6, 15 (DNA mismatch repair), and SBS7 (ultraviolet exposure), suggesting that disordered pyrimidine production causes increased errors in DNA repair systems in these cases.
CONCLUSION: Our results suggest the importance of the detailed collection of data on environmental exposure along with genetic information on NSCLC patients to identify the unique combinations that cause lung tumorigenesis in a particular family.

Keywords:  DHODH; exome; mutational signature; non-small cell lung cancer; tumor suppressor gene

DOI:  https://doi.org/10.1111/1759-7714.14825
Asian Pac J Cancer Prev. 2023 Feb 01. pii: 90486. [Epub ahead of print]24(2): 525-530

Prevalence of Pathogenic Germline Mutations in 13 Hereditary Cancer-Related Genes in Breast Cancer Patients in Narathiwat Province, Thailand.

Panupong Sukpan, Kanyanatt Kanokwiroon, Hutcha Sriplung, Wison Laochareonsuk, Pongsakorn Choochuen, Nasuha Auseng, Kasemsun Wanawanakorn, Surasak Sangkhathat.

   BACKGROUND: BRCA1 and BRCA2 genes are known to increase breast cancer's lifetime risk. Early identification of women with this inherited risk can potentially reduce the risk of breast and/or ovarian cancer and, together with early screening, decrease the mortality rate.
OBJECTIVE: This study explored the frequency and distribution of genetic variants in consecutive cases of breast cancer in Narathiwat province, one of the three provinces in the southernmost Thai border.
MATERIAL & METHOD: A series of 64 consecutive breast cancer patients who underwent treatment in two general hospitals in the province during the period from the year 2021 to 2022. Genotyping studies were performed using a whole exome sequencing platform. Moderate to high penetrance variants recommended by the National Comprehensive Cancer Network (NCCN) guidelines 2022 (ATM, BARD1, BRCA1, BRCA2, CDH1, CHEK2, NF1, PALB2, PTEN, RAD51C, RAD51D, STK11, TP53) were annotated and filtered for pathogenic, likely pathogenic, or high-impact variants.
RESULTS: Pathogenic germline variants were found in 8/64 cases (12.5%), namely BRCA1 in 3 (4.7%), BRCA2 in 4 (6.3%), ATM in 1 (1.6%), and PALB2 in 1 (1.6%). One patient had two concomitant germline mutations in BRCA2 and ATM.
CONCLUSION: This is the first study on the frequency of germline mutations in BRCA1/2 and other breast cancer-predisposing genes in the southernmost provinces of Thailand. At least one pathogenic germline mutation was identified in 12.5% of the study patients, which suggests that genetic testing in this population has a high potential to provide benefits.

Keywords:  Germline variants; breast cancer; hereditary cancer

DOI:  https://doi.org/10.31557/APJCP.2023.24.2.525
Front Oncol. 2023 ;13 1068110

Atypical ATMs: Broadening the phenotypic spectrum of ATM-associated hereditary cancer.

Nicholas A Borja, Rachel Silva-Smith, Marilyn Huang, Dipen J Parekh, Daniel Sussman, Mustafa Tekin.

  Heterozygous, loss-of-function germline variants in ATM have been associated with an increased lifetime risk of breast, pancreas, prostate, stomach, ovarian, colorectal, and melanoma cancers. We conducted a retrospective review of thirty-one unrelated patients found to be heterozygous for a germline pathogenic variant in ATM and identified a significant proportion of patients in this cohort with cancers not currently associated with the ATM hereditary cancer syndrome, including carcinomas of the gallbladder, uterus, duodenum, kidney, and lung as well as a vascular sarcoma. A comprehensive review of the literature found 25 relevant studies where 171 individuals with a germline deleterious ATM variant have been diagnosed with the same or similar cancers. The combined data from these studies were then used to estimate the prevalence of germline ATM pathogenic variants in these cancers, which ranged between 0.45% and 2.2%. Analysis of tumor sequencing performed in large cohorts demonstrated that the frequency of deleterious somatic ATM alterations in these atypical cancers equaled or exceeded the alteration frequency in breast cancer and occurred at a significantly higher rate than in other DNA-damage response tumor suppressors, namely BRCA1 and CHEK2. Furthermore, multi-gene analysis of somatic alterations in these atypical cancers demonstrated significant co-occurrence of pathogenic alterations in ATM with BRCA1 and CHEK2, while there was significant mutual exclusivity between pathogenic alterations in ATM and TP53. This indicates that germline ATM pathogenic variants may play a role in cancer initiation and progression in these atypical ATM malignancies, potentially influencing these cancers to be driven toward DNA-damage repair deficiency and away from loss of TP53. As such, these findings provide evidence for broadening of the ATM-cancer susceptibility syndrome phenotype to improve the recognition of affected patients and provide more efficacious, germline-directed therapies.

Keywords:  ATM; ataxia-telangiectasia mutated (ATM); cancer susceptibility association; germline; hereditary cancer; pathogenic variant (PV)

DOI:  https://doi.org/10.3389/fonc.2023.1068110
Breast Cancer Res Treat. 2023 Mar 01.

Pathogenic variants among females with breast cancer and a non-breast cancer reveal opportunities for cancer interception.

Brittany L Bychkovsky, Min-Tzu Lo, Amal Yussuf, Carrie Horton, Parichehr Hemyari, Holly LaDuca, Judy E Garber, Rochelle Scheib, Huma Q Rana.

   PURPOSE: Herein, we report the frequency and distribution of germline pathogenic variants (PVs) among females with breast cancer (BC) and at least one other non-BC who underwent multi-gene panel testing (MGPT). Among females with PVs diagnosed first with BC or ovarian cancer (OC), we sought to enumerate the frequency of subsequent PV-associated cancers.
METHODS: Females with BC and cancer of ≥ 1 other site (multiple primary cancers, MPC) who underwent MGPT through Ambry Genetics from March 2012 to December 2016 were included if they had testing of at least 21 genes of interest (ATM, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, MLH1, MSH2, MSH6, MUTYH, NBN, NF1, PALB2, PMS2, PTEN, RAD51C, RAD51D, STK11, and TP53). Phenotypic data were abstracted from test requisition forms and clinical notes.
RESULTS: Of 6,617 evaluable patients, most were White (70.8%) and median age at first cancer, second cancer, and MGPT was 49 (interquartile range [IQR]: 18), 59 (IQR: 16), and 63 (IQR: 16) years, respectively. PVs were found among 14.1% (932/6617) of the overall cohort and in 16.4% (440/2687) of females who were diagnosed first with BC. Among those, 55.2% (243/440) had an actionable PV associated with a subsequent cancer diagnosis including 150 OCs. Of the 2443 females with breast and ovarian cancer, few (n = 97, 9.5%) were diagnosed first with OC, limiting our analysis.
CONCLUSIONS: Females with MPC, including BC, have a high frequency of germline PVs (14.1%). These data delineate the opportunities for intercepting subsequent cancers associated with genetic risk among females diagnosed first with BC.

Keywords:  Breast cancer; Cancer interception; Genetics; Germline; Multiple primary cancers; Pathogenic variants; Survivorship

DOI:  https://doi.org/10.1007/s10549-023-06870-x
J Invest Dermatol. 2023 Feb 28. pii: S0022-202X(23)00155-0. [Epub ahead of print]

Germline Variants in Childhood Cutaneous Melanoma.

Peter A Johansson, Jane M Palmer, Hayley R Hamilton, David C Whiteman, Antonia L Pritchard, Nicholas K Hayward.



Keywords:  childhood; cutaneous melanoma; genetic risk; germline variants; paediatric

DOI:  https://doi.org/10.1016/j.jid.2023.02.014
Front Genet. 2023 ;14 1094260

Evaluation of genetic alterations in hereditary cancer susceptibility genes in the Ashkenazi Jewish women community of Mexico.

Clara Estela Díaz-Velásquez, Rina Gitler, Adriana Antoniano, Ronny Kershenovich Sefchovich, Aldo Hugo De La Cruz-Montoya, Héctor Martínez-Gregorio, Ernesto Arturo Rojas-Jiménez, Ricardo Cortez Cardoso Penha, Luis Ignacio Terrazas, Talia Wegman-Ostrosky, Ephrat Levi-Lahad, Jovanny Zabaleta, Sandra Perdomo, Felipe Vaca-Paniagua.

  Background: Individuals of Ashkenazi Jewish ancestry have been identified as having higher prevalence of specific pathogenic variants associated with susceptibility to specific rare and chronic diseases. In Mexico, the prevalence and composition of rare cancer predisposing germline variants in Ashkenazi Jewish individuals has not been evaluated. Aim and methods: We aimed to evaluate the prevalence of pathogenic variants by massive parallel sequencing in a panel of 143 cancer-predisposing genes in 341 women from the Ashkenazi Jewish community of Mexico, who were contacted and invited to participate in the study through the ALMA Foundation for Cancer Reconstruction. Pre- and posttest genetic counseling was given and a questionnaire on personal, gyneco-obstetric, demographic and lifestyle variables was conducted. From peripheral blood DNA, the complete coding region, and splicing sites of a panel of 143 cancer susceptibility genes, including 21 clinically relevant genes, were sequenced. The Mexican founder mutation BRCA1 ex9-12del [NC_000017.10(NM_007294):c. (825+1-826-1)_(4,589+1-4,590-1)del] was also evaluated. Results: Among study participants (mean age ±standard deviation: 47 ± 14) 15% reported a personal history of cancer (50/341). Fourteen percent of participants (48/341) were carriers of pathogenic and likely pathogenic variants distributed among seven high-risk genes (APC, CHEK2, MSH2, BMPR1A, MEN1, MLH1, and MSH6), whereas 18.2% (62/341) had variants of uncertain clinical significance in genes associated with breast and ovarian cancer susceptibility (list of genes with VUS). Pathogenic and likely pathogenic variants in 16 susceptibility genes with ambiguous or non-well-established risk association for cancer were detected in 17.6% (60/341) of participants. Sixty four percent of participants reported current alcohol consumption compared with the 39 percent prevalence of alcohol consumption in Mexican women. None of the participants carried the recurrent Ashkenazi and Mexican founder mutations in BRCA1 or BRCA2, but 2% (7/341) had pathogenic Ashkenazi Jewish founder variants in BLM. Conclusion: Our findings show a diverse pathogenic variant composition among the recruited individuals of Ashkenazi Jewish ancestry in Mexico consistent with being a high-risk population for genetic diseases, which warrants further investigation to adequately assess the burden of hereditary breast cancer in this group and implement appropriate preventative programs.

Keywords:  APC; Ashkenazi Jews; founder variant; genetic screening; massive parallel sequencing; panel of genes

DOI:  https://doi.org/10.3389/fgene.2023.1094260
J Exp Clin Cancer Res. 2023 Mar 04. 42(1): 57

Current advances in understanding the molecular profile of hereditary diffuse gastric cancer and its clinical implications.

Hui Jun Lim, Lizhe Zhuang, Rebecca C Fitzgerald.

  Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant cancer syndrome attributed to germline CDH1 mutations that carries a high risk for early onset DGC. HDGC raises a significant health issue due to its high penetrance and mortality unless diagnosed early. The definitive treatment is to undergo prophylactic total gastrectomy which is associated with significant morbidity., highlighting the urgent need for alternative treatment methods. However, there is limited literature examining potential therapeutic strategies building on emerging insights into the molecular basis of progressive lesions in the context of HDGC. The aim of this review is to summarise the current understanding of HDGC in the context of CDH1 pathogenic variants followed by a review of the proposed mechanisms for progression. In addition, we discuss the development of novel therapeutic approaches and highlight pertinent areas for further research. A literature search was therefore performed for relevant studies examining CDH1 germline variants, second-hit mechanisms of CDH1, pathogenesis of HDGC and potential therapeutic strategies in databases, including PubMed, ScienceDirect and Scopus. Germline mutations are mostly truncating CDH1 variants affecting extracellular domains of E-cadherin, generally due to frameshift, single nucleotide variants or splice site mutations. A second somatic hit of CDH1 most commonly occurs via promoter methylation as shown in 3 studies, but studies are limited with a small sample size. The multi-focal development of indolent lesions in HDGC provide a unique opportunity to understand genetic events that drive the transition to the invasive phenotype. To date, a few signalling pathways have been shown to facilitate the progression of HDGC, including Notch and Wnt. In in-vitro studies, the ability to inhibit Notch signalling was lost in cells transfected with mutant forms of E-cadherin, and increased Notch-1 activity correlated with apoptosis resistance. Furthermore, in patient samples, overexpression of Wnt-2 was associated with cytoplasmic and nuclear β-catenin accumulation and increased metastatic potential. As loss-of-function mutations are challenging to target therapeutically, these findings pave the way towards a synthetic lethal approach in CDH1-deficient cells with some promising results in-vitro. In future, if we could better understand the molecular vulnerabilities in HDGC, there may be opportunities to offer alternative treatment pathways to avoid gastrectomy.

Keywords:  CDH1 pathogenic variant; Hereditary diffuse gastric cancer; Second-hit mechanism; Signet ring carcinoma; Synthetic lethality

DOI:  https://doi.org/10.1186/s13046-023-02622-3
Res Sq. 2023 Feb 20. pii: rs.3.rs-2592107. [Epub ahead of print]

Genomic Analyses of Germline and Somatic Variation in High-Grade Serous Ovarian Cancer.

Aaron W Adamson, Yuan Chun Ding, Linda Steele, Lucile A Leong, Robert Morgan, Mark T Wakabayashi, Ernest S Han, Thanh H Dellinger, Paul S Lin, Amy A Hakim, Sharon Wilczynski, Charles D Warden, Shu Tao, Victoria Bedell, Mihaela C Cristea, Susan L Neuhausen.

Background High-grade serous ovarian cancers (HGSCs) display a high degree of complex genetic alterations. In this study, we identified germline and somatic genetic alterations in HGSC and their association with relapse-free and overall survival. Using a targeted capture of 577 genes involved in DNA damage response and PI3K/AKT/mTOR pathways, we conducted next-generation sequencing of DNA from matched blood and tumor tissue from 71 HGSC participants. In addition, we performed the OncoScan assay on tumor DNA from 61 participants to examine somatic copy number alterations. Results Approximately one-third of tumors had loss-of-function germline (18/71, 25.4%) or somatic (7/71, 9.9%) variants in the DNA homologous recombination repair pathway genes BRCA1, BRCA2, CHEK2, MRE11A, BLM , and PALB2 . Loss-of-function germline variants also were identified in other Fanconi anemia genes and in MAPK and PI3K/AKT/mTOR pathway genes. Most tumors harbored somatic TP53 variants (65/71, 91.5%). Using the OncoScan assay on tumor DNA from 61 participants, we identified focal homozygous deletions in BRCA1, BRCA2, MAP2K4, PTEN, RB1, SLX4, STK11, CREBBP , and NF1 . In total, 38% (27/71) of HGSC patients harbored pathogenic variants in DNA homologous recombination repair genes. For patients with multiple tissues from the primary debulking or from multiple surgeries, the somatic mutations were maintained with few newly acquired point mutations suggesting that tumor evolution was not through somatic mutations. There was a significant association of loss-of-function variants in homologous recombination repair pathway genes and high-amplitude somatic copy number alterations. Using GISTIC analysis, we identified NOTCH3, ZNF536 , and PIK3R2 in these regions that were significantly associated with an increase in cancer recurrence and a reduction in overall survival. Conclusions From 71 patients with HGCS, we performed targeted germline and tumor sequencing and provided a comprehensive analysis of these 577 genes. We identified germline and somatic genetic alterations including somatic copy number alterations and analyzed their associations with relapse-free and overall survival. This single-site long-term follow-up study provides additional information on genetic alterations related to occurrence and outcome of HGSC. Our findings suggest that targeted treatments based on both variant and SCNA profile potentially could improve relapse-free and overall survival.

DOI: https://doi.org/10.21203/rs.3.rs-2592107/v1
JCO Oncol Pract. 2023 Mar 03. OP2200341

Improving Rates of Germline BRCA Mutation Testing for Patients With Ovarian Cancer in Vancouver Island, British Columbia, Canada.

Laurie Barnhardt, Farouk S Nathoo, Jennifer M Rauw.

PURPOSE: Despite more than a decade of endorsement from multiple international cancer authorities advocating all women with ovarian cancer be offered germline breast cancer (BRCA) gene testing, British Columbia Cancer Victoria was not meeting this target. A quality improvement project was undertaken with the aim of increasing completed BRCA testing rates for all eligible patients seen at British Columbia Cancer Victoria to > 90% by 1 year from April 2016.
METHODS: A current state analysis was completed, and multiple change ideas were developed, including education of medical oncologists, referral process update, initiating a group consenting seminar, and engagement of a nurse practitioner to lead the seminar. We used a retrospective chart audit from December 2014 to February 2018. On April 15, 2016, we initiated our Plan, Do, Study, Act (PDSA) cycles and completed them on February 28, 2018. We evaluated sustainability through an additional retrospective chart audit from January 2021 to August 2021.
RESULTS: Patients with completed germline BRCA genetic testing climbed from an average of 58%-89% per month. Before our project, patients waited on average 243 days (± 214) for their genetic test results. After implementation, patients received results within 118 days (± 98). This was sustained with an average of 83% of patients per month having completed germline BRCA testing almost 3 years after project completion.
CONCLUSION: Our quality improvement initiative resulted in a sustained increase in germline BRCA test completion for eligible patients with ovarian cancer.

DOI: https://doi.org/10.1200/OP.22.00341