bims-lifras 2021-10-03 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–10–03
twenty-one papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Breast radiotherapy-related treatment outcomes in patients with or without germline mutations on multigene panel testing.
Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark.
A multicenter study assessing the prevalence of germline genetic alterations in Chinese gastric-cancer patients.
Germline variant screening with targeted next generation sequencing in prostate cancer: phenotype-genotype correlation.
Cancer Spectrum, Family History of Cancer and Overall Survival in Men with Germline BRCA1 or BRCA2 Mutations.
Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients.
Retrospective Analysis of Clinicopathological Features and Familial Cancer History of Synchronous Bilateral Breast Cancer.
Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.
Pretest Genetic Education Video Versus Genetic Counseling for Men Considering Prostate Cancer Germline Testing: A Patient-Choice Study to Address Urgent Practice Needs.
Genomic Determinants of Homologous Recombination Deficiency across Human Cancers.
The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families.
Germline variants in DNA repair genes are associated with young-onset head and neck cancer.
Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing.
Breast cancer characteristics and surgery among women with Li-Fraumeni syndrome in Germany-A retrospective cohort study.
Ovarian cancer specific BRCA-like copy number aberration classifiers detect mutations associated with homologous recombination deficiency in the AGO-TR1 trial.
Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies.
Risk-Reducing Bilateral Salpingo-Oophorectomy for Ovarian Cancer: A Review and Clinical Guide for Hereditary Predisposition Genes.
Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial.
Personalized Medicine for TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia.
Genomic Evolution in a Patient With Lung Adenocarcinoma With a Germline EGFR T790M Mutation.
Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome.

Int J Radiat Oncol Biol Phys. 2021 Sep 25. pii: S0360-3016(21)02830-3. [Epub ahead of print]

Breast radiotherapy-related treatment outcomes in patients with or without germline mutations on multigene panel testing.

Bhavana V Chapman, Diane Liu, Yu Shen, Oluwafikayo O Olamigoke, David S Lakomy, Angelica M Gutierrez Barrera, Shane R Stecklein, Gabriel O Sawakuchi, Scott J Bright, Isabelle Bedrosian, Jennifer K Litton, Benjamin D Smith, Wendy A Woodward, George H Perkins, Karen E Hoffman, Michael C Stauder, Eric A Strom, Banu K Arun, Simona F Shaitelman.

PURPOSE: Multigene panel testing has increased the detection of germline mutations in patients with breast cancer. The implications of using radiotherapy (RT) to treat patients with pathogenic variant (PV) mutations are not well understood and have been studied mostly in women with only BRCA1 or BRCA2 PVs. We analyzed oncologic outcomes and toxicity after adjuvant RT in a contemporary, diverse cohort of breast cancer patients who underwent genetic panel testing.
METHODS AND MATERIALS: We retrospectively reviewed the records of 286 women with clinical stage I-III breast cancer diagnosed 1995-2017 who underwent surgery, breast or chest wall RT with or without regional nodal irradiation, multigene panel testing, and evaluation at a large cancer center's genetic screening program. We evaluated rates of overall survival (OS), locoregional recurrence (LRR), disease-specific death (DSD), and radiation-related toxicities in three groups: BRCA1/2 PV carriers, non-BRCA1/2 PV carriers, and patients without PV mutations.
RESULTS: PVs were detected in 25.2% of the cohort (12.6% BRCA1/2 and 12.6% non-BRCA1/2). The most commonly detected non-BRCA1/2 mutated genes were ATM, CHEK2, PALB2, CDH1, TP53, and PTEN. The median follow-up time for the entire cohort was 4.4 years (95% confidence interval 3.8-4.9 years). No differences were found in OS, LRR, or DSD between groups (P>0.1 for all). Acute and late toxicities were comparable across groups.
CONCLUSION: Oncologic and toxicity outcomes after RT in women with PV germline mutations detected by multigene pane testing are similar to those in patients without detectable mutations, supporting the use of adjuvant RT as a standard of care when indicated.

DOI: https://doi.org/10.1016/j.ijrobp.2021.09.026
JCO Precis Oncol. 2021 ;pii: PO.21.00132. [Epub ahead of print]5

Underdiagnosis of Hereditary Colorectal Cancers Among Medicare Patients: Genetic Testing Criteria for Lynch Syndrome Miss the Mark.

Charles Muller, Sarah M Nielsen, Kathryn E Hatchell, Shan Yang, Scott T Michalski, Barbara Hamlington, Robert L Nussbaum, Edward D Esplin, Sonia S Kupfer.

PURPOSE: Strict clinical criteria used by Medicare for germline testing for Lynch syndrome (LS) could lead to missed diagnoses of hereditary cancer syndromes given variable individual and family phenotypes. The aim of this study was to compare rates and spectrum of pathogenic or likely pathogenic (P/LP) variants in LS and other hereditary cancer genes on the basis of meeting Medicare LS testing criteria.
METHODS: Retrospective review of Medicare beneficiaries who had multigene panel testing with an indication of personal or family history of colorectal cancer (CRC) was performed. Ordering providers determined if Medicare LS criteria were met. The results of genetic testing were compared on the basis of whether or not Medicare testing criteria were met.
RESULTS: Among 639 Medicare beneficiaries, 495 (77.5%) met testing criteria. Overall rates of P/LP variant identification were similar between those meeting and not meeting testing criteria (18.4% v 11.8%; P = .06). LS was diagnosed more frequently among those meeting testing criteria (10.1% v 4.9%; P = .05). No statistical differences were found in rates of P/LP variant identification for non-LS CRC genes (5.3% v 5.6%; P = .89) or non-CRC genes (4.2% v 2.1%; P = .23). PMS2, MUTYH, and ATM P/LP variants were found at higher rates among those outside of criteria.
CONCLUSION: Among Medicare beneficiaries undergoing genetic testing for suspected LS, rates of P/LP variants in actionable cancer genes were similar regardless of whether testing criteria were met. Current testing criteria fail to identify individuals with P/LP variants in PMS2 and other actionable cancer genes. Relaxing LS testing criteria could improve identification of individuals with hereditary cancer syndromes among Medicare beneficiaries.

DOI: https://doi.org/10.1200/PO.21.00132
Gastroenterol Rep (Oxf). 2021 Aug;9(4): 339-349

A multicenter study assessing the prevalence of germline genetic alterations in Chinese gastric-cancer patients.

Yin-Jie Zhang, Yang Yang, Qing Wei, Ting Xu, Xiao-Tian Zhang, Jing Gao, Si-Yi Tan, Bao-Rui Liu, Jing-Dong Zhang, Xiao-Bing Chen, Zhao-Jie Wang, Meng Qiu, Xin Wang, Lin Shen, Xi-Cheng Wang.

   Background: Approximately 10% of patients with gastric cancer (GC) have a genetic predisposition toward the disease. However, there is scant knowledge regarding germline mutations in predisposing genes in the Chinese GC population. This study aimed to determine the spectrum and distribution of predisposing gene mutations among Chinese GC patients known to have hereditary high-risk factors for cancer.
Methods: A total of 40 GC patients from 40 families were recruited from seven medical institutions in China. Next-generation sequencing was performed on 171 genes associated with cancer predisposition. For probands carrying pathogenic/likely pathogenic germline variants, Sanger sequencing was applied to validate the variants in the probands as well as their relatives.
Results: According to sequencing results, 25.0% (10/40) of the patients carried a combined total of 10 pathogenic or likely pathogenic germline variants involving nine different genes: CDH1 (n = 1), MLH1 (n = 1), MSH2 (n = 1), CHEK2 (n = 1), BLM (n = 1), EXT2 (n = 1), PALB2 (n = 1), ERCC2 (n = 1), and SPINK1 (n = 2). In addition, 129 variants of uncertain significance were identified in 27 patients.
Conclusions: This study indicates that approximately one in every four Chinese GC patients with hereditary high risk factors may harbor pathogenic/likely pathogenic germline alterations in cancer-susceptibility genes. The results further indicate a unique genetic background for GC among Chinese patients.

Keywords:  cancer-predisposition gene; familial gastric cancer; germline mutation; next-generation sequencing

DOI:  https://doi.org/10.1093/gastro/goab020
Turk J Med Sci. 2021 Sep 28.

Germline variant screening with targeted next generation sequencing in prostate cancer: phenotype-genotype correlation.

Ali Yavuz Çakir, Kuyaş Hekimler Öztürk, Alper Özorak.

   BACKGROUND/AIM: Next generation sequencing provides new information about the molecular pathogenesis of cancer. We used a targeted NGS-based multiple gene panel comprising prostate cancer (PCa) predisposing genes to assess the prevalence of germline mutations in PCa patients.
MATERIAL AND METHODS: In a cohort of twenty one PCa patients with a family history of cancer, a targeted multigene panel consisting of 39 genes associated with hereditary cancer was created and analyzed using the next generation sequencing method. The novel and pathogenic mutations detected were confirmed by Sanger sequencing method. Thereafter, the data obtained were evaluated using different genomic variant classifiers and databases.
RESULTS: With an incidence of less than 5% in different populations (MAF<0.05); a total of 81 variants were identified, including 41 missense, 16 synonymous, 3 splice-site, 11 intronic, 5 in-del and 5 novels. According to the ACMG criteria, 5 (6.2%) of these variants are pathogenic/likely pathogenic; 5 (6.2%) of them were classified as novel variants. In addition, variants having very low-frequency and unknown clinical significance (VUS) in the databases were detected.
CONCLUSION: The findings we obtained from this study contributed to the understanding the genetic pathogenesis of PCa, determining the frequency of mutations in the population, and revealing the genotype-phenotype correlations. Additionally, we demonstrated that using multigene panel-based genetic tests rather than single-gene tests in germline mutation screening in hereditary PCa will be more beneficial in terms of genetic counseling.

Keywords:  Next generation sequencing; bioinformatics; databases; germline mutations; prostate cancer

DOI:  https://doi.org/10.3906/sag-2105-348
J Pers Med. 2021 Sep 15. pii: 917. [Epub ahead of print]11(9):

Cancer Spectrum, Family History of Cancer and Overall Survival in Men with Germline BRCA1 or BRCA2 Mutations.

Florian Reichl, Daniela Muhr, Katharina Rebhan, Gero Kramer, Shahrokh F Shariat, Christian F Singer, Yen Y Tan.

   BACKGROUND: Men with germline BRCA1/2 mutations are not well studied compared to their female counterparts. This study evaluates the cancer characteristics, family history of cancer, and outcomes of male BRCA1/2 mutation carriers.
METHODS: All men with germline BRCA1/2 mutations who attended genetic assessment between October 1995 and October 2019 at the Medical University of Vienna were identified. Clinicohistopathological features, family history of cancer, and outcomes were assessed by mutation status.
RESULTS: Of the 323 men included, 45 (13.9%) had a primary cancer diagnosis, many of whom were BRCA2 carriers (75.5%). Breast cancer (BC) was the most common cancer (57.8%) followed by prostate cancer (15.6%). Invasive ductal carcinoma and hormone receptor positive tumors were the most common. Among 26 BC-affected patients, 42% did not have any relatives with cancer. Parent of origin was only known in half of the 26 men, with 42% of them inherited through the maternal lineage versus 8% through the paternal. BRCA2 carriers and those with a family history of BC had worse overall survival (20 y vs. 23 y BRCA1 carriers; P = 0.007; 19 y vs. 21 y for those without family history of BC; P = 0.036).
CONCLUSION: Male BRCA2 carriers were most likely to develop cancer and had worse prognosis. In our dataset, BC was the most common cancer, likely due to referral bias. Not all mutation carriers present with BC or have a family history of cancer to warrant genetic testing.

Keywords:  BRCA mutations; cancer spectrum; family history; hereditary cancer; men; parent of origin

DOI:  https://doi.org/10.3390/jpm11090917
Genes (Basel). 2021 Sep 18. pii: 1440. [Epub ahead of print]12(9):

Genetic Variants and Somatic Alterations Associated with MITF-E318K Germline Mutation in Melanoma Patients.

Elisabetta Vergani, Simona Frigerio, Matteo Dugo, Andrea Devecchi, Erika Feltrin, Loris De Cecco, Viviana Vallacchi, Mara Cossa, Lorenza Di Guardo, Siranoush Manoukian, Bernard Peissel, Andrea Ferrari, Gianfrancesco Gallino, Andrea Maurichi, Licia Rivoltini, Marialuisa Sensi, Monica Rodolfo.

  The MITF-E318K variant has been implicated in genetic predisposition to cutaneous melanoma. We addressed the occurrence of MITF-E318K and its association with germline status of CDKN2A and MC1R genes in a hospital-based series of 248 melanoma patients including cohorts of multiple, familial, pediatric, sporadic and melanoma associated with other tumors. Seven MITF-E318K carriers were identified, spanning every group except the pediatric patients. Three carriers showed mutated CDKN2A, five displayed MC1R variants, while the sporadic carrier revealed no variants. Germline/tumor whole exome sequencing for this carrier revealed germline variants of unknown significance in ATM and FANCI genes and, in four BRAF-V600E metastases, somatic loss of the MITF wild-type allele, amplification of MITF-E318K and deletion of a 9p21.3 chromosomal region including CDKN2A and MTAP. In silico analysis of tumors from MITF-E318K melanoma carriers in the TCGA Pan-Cancer-Atlas dataset confirmed the association with BRAF mutation and 9p21.3 deletion revealing a common genetic pattern. MTAP was the gene deleted at homozygous level in the highest number of patients. These results support the utility of both germline and tumor genome analysis to define tumor groups providing enhanced information for clinical strategies and highlight the importance of melanoma prevention programs for MITF-E318K patients.

Keywords:  MITF gene; MITF-E318K variant; MTAP gene; SKCM-TCGA Pan Cancer Atlas; copy number alterations; cutaneous melanoma; germline mutations; somatic mutations

DOI:  https://doi.org/10.3390/genes12091440
Healthcare (Basel). 2021 Sep 13. pii: 1203. [Epub ahead of print]9(9):

Retrospective Analysis of Clinicopathological Features and Familial Cancer History of Synchronous Bilateral Breast Cancer.

Kai-Ling Huang, Yu-Ling Liu, Ya-Ying Hsu, Wen-Ling Kuo.

  Bilateral breast cancer is a strong predictor of BRCA 1/2 mutation and hence one criterion indicated for hereditary genetic testing. The purpose of this study is to assess the characteristics of synchronous bilateral breast cancer (SBBC) and its association with personal and familial cancer traits. Patients diagnosed with SBBC in our institute between 1992 and 2018 were retrospectively reviewed, and the information of clinicopathological features, personal and family cancer history were analyzed. Of the 307 SBBCs enrolled, the growing case number generally aligned with the regional breast cancer incidence after the era of population-based mammography screening. SBBC patients had similar cancer stages but worse survival outcomes than those in the standard scenario. A total of 42.0% had mixed pathological diagnoses, and 22.8% had discordant immunohistochemistry (IHC) subtypes from both sides, which contributed to treatment challenges. The correlation of SBBC with hereditary breast and ovarian cancer (HBOC) syndrome was strongly implied, as 20.7% of our SBBC patients with known familial cancer histories had HOBC-related familial cancers (breast, ovarian, or prostate cancers). These findings highlight the need for genetic counseling and germline mutation testing in patients with SBBC. Early PARP inhibitor treatment should also be considered in high-risk cases for outcome improvement.

Keywords:  bilateral; breast cancer; cancer gene predisposition; genetic counseling; germline mutation; hereditary breast and ovarian cancer syndrome; synchronous

DOI:  https://doi.org/10.3390/healthcare9091203
Cancers (Basel). 2021 Sep 08. pii: 4515. [Epub ahead of print]13(18):

Transcriptome of Male Breast Cancer Matched with Germline Profiling Reveals Novel Molecular Subtypes with Possible Clinical Relevance.

Veronica Zelli, Valentina Silvestri, Virginia Valentini, Agostino Bucalo, Piera Rizzolo, Ines Zanna, Simonetta Bianchi, Anna Coppa, Giuseppe Giannini, Laura Cortesi, Daniele Calistri, Maria Grazia Tibiletti, Stephen B Fox, kCon Fab, Domenico Palli, Laura Ottini.

  Male breast cancer (MBC) is a rare and understudied disease compared with female BC. About 15% of MBCs are associated with germline mutation in BC susceptibility genes, mainly BRCA1/2 and PALB2. Hereditary MBCs are likely to represent a subgroup of tumors with a peculiar phenotype. Here, we performed a whole transcriptome analysis of MBCs characterized for germline mutations in the most relevant BC susceptibility genes in order to identify molecular subtypes with clinical relevance. A series of 63 MBCs, including 16 BRCA2, 6 BRCA1, 2 PALB2, 1 RAD50, and 1 RAD51D germline-mutated cases, was analyzed by RNA-sequencing. Differential expression and hierarchical clustering analyses were performed. Module signatures associated with central biological processes involved in breast cancer pathogenesis were also examined. Different transcriptome profiles for genes mainly involved in the cell cycle, DNA damage, and DNA repair pathways emerged between MBCs with and without germline mutations. Unsupervised clustering analysis revealed two distinct subgroups, one of which was characterized by a higher expression of immune response genes, high scores of gene-expression signatures suggestive of aggressive behavior, and worse overall survival. Our results suggest that transcriptome matched with germline profiling may be a valuable approach for the identification and characterization of MBC subtypes with possible relevance in the clinical setting.

Keywords:  BRCA1/2; germline mutations; male breast cancer; molecular subtypes; transcriptome profiling

DOI:  https://doi.org/10.3390/cancers13184515
JCO Precis Oncol. 2021 ;pii: PO.21.00238. [Epub ahead of print]5

Pretest Genetic Education Video Versus Genetic Counseling for Men Considering Prostate Cancer Germline Testing: A Patient-Choice Study to Address Urgent Practice Needs.

Jessica Russo, Carey McDougall, Nicholas Bowler, Ayako Shimada, Laura Gross, Colette Hyatt, William K Kelly, Anne Calvaresi, Nathan R Handley, Irvin H Hirsch, Joseph K Izes, Costas D Lallas, Mark Mann, James Ryan Mark, Patrick J Mille, Donald Preate, Edouard J Trabulsi, Miranda Tsang, Thenappan Chandrasekar, Perry R Weiner, Leonard G Gomella, Veda N Giri.

PURPOSE: Germline testing (GT) for prostate cancer (PCA) is now central to treatment and hereditary cancer assessment. With rising demand for and shortage of genetic counseling (GC), tools to deliver pretest informed consent across practice settings are needed to improve access to GT and precision care. Here, we report on Evaluation and Management for Prostate Oncology, Wellness, and Risk (EMPOWER), a patient-choice study for pretest video-based genetic education (VBGE) versus GC to inform urgent practice needs.
PATIENTS AND METHODS: Men with PCA or at risk for PCA (family history of PCA) were eligible and could choose pretest VBGE or GC. Outcomes included decisional conflict for GT, change in genetics knowledge, satisfaction, and intention to share results with family and/or providers. Descriptive statistics summarized results with counts and percentages for categorical variables and mean ± standard deviation for continuous variables. Data were compared with Fisher's exact, chi-squared, or Wilcoxon two-sample tests. Mean change in genetics knowledge was compared with t tests. The significance level was set a priori at .05.
RESULTS: Data on the first 127 participants were analyzed. Characteristics were White (85.8%), bachelor's degree (66.9%), and PCA diagnosis (90.6%). The majority chose VBGE (71%) versus GC (29%; P < .001). No differences were observed in decisional conflict for GT or satisfaction. Cancer genetics knowledge improved in both groups without significant difference (+0.9 VBGE, +1.8 GC, P = .056). Men who chose VBGE had higher intention to share GT results (96.4% VBGE v 86.4% GC, P = .02). Both groups had high rates of GT uptake (VBGE 94.4%, GC 92%).
CONCLUSION: A substantial proportion of men opted for pretest VBGE, with comparable patient-reported outcomes and uptake of GT. The results support the use of pretest video to address the critical GC shortage in the precision era.

DOI: https://doi.org/10.1200/PO.21.00238
Cancers (Basel). 2021 Sep 12. pii: 4572. [Epub ahead of print]13(18):

Genomic Determinants of Homologous Recombination Deficiency across Human Cancers.

Tao Qing, Xinfeng Wang, Tomi Jun, Li Ding, Lajos Pusztai, Kuanlin Huang.

  Germline BRCA1/2 mutations associated with HRD are clinical biomarkers for sensitivity to poly-ADP ribose polymerase inhibitors (PARPi) treatment in breast, ovarian, pancreatic, and prostate cancers. However, it remains unclear whether other mutations may also lead to HRD and PARPi sensitivity across a broader range of cancer types. Our goal was to determine the germline or somatic alterations associated with the HRD phenotype that might therefore confer PARPi sensitivity. Using germline and somatic genomic data from over 9000 tumors representing 32 cancer types, we examined associations between HRD scores and pathogenic germline variants, somatic driver mutations, and copy number deletions in 30 candidate genes involved in homologous recombination. We identified several germline and somatic mutations (e.g., BRCA1/2, PALB2, ATM, and ATR mutations) associated with HRD phenotype in ovarian, breast, pancreatic, stomach, bladder, and lung cancer. The co-occurrence of germline BRCA1 variants and somatic TP53 mutations was significantly associated with increasing HRD in breast cancer. Notably, we also identified multiple somatic copy number deletions associated with HRD. Our study suggests that multiple cancer types include tumor subsets that show HRD phenotype and should be considered in the future clinical studies of PARPi and synthetic lethality strategies exploiting HRD, which can be caused by a large number of genomic alterations.

Keywords:  DNA damage repair; copy number variation; germline and somatic; homologous recombination

DOI:  https://doi.org/10.3390/cancers13184572
Cancer Biol Med. 2021 Sep 28. pii: j.issn.2095-3941.2021.0011. [Epub ahead of print]

The mutation landscape of multiple cancer predisposition genes in Chinese familial/hereditary breast cancer families.

Li Dong, Hailian Zhang, Huan Zhang, Yingnan Ye, Yanan Cheng, Lijuan Li, Lijuan Wei, Lei Han, Yandong Cao, Shixia Li, Xishan Hao, Juntian Liu, Jinpu Yu.

   OBJECTIVE: Approximately 5%-10% of breast cancer (BC) patients display familial traits that are genetically inherited among the members of a family. The purpose of this study was to profile the germline mutations in 43 genes with different penetration rates and their correlations with phenotypic traits in Chinese familial BC families.
METHODS: Ion Torrent S5™-based next generation sequencing was conducted on 116 subjects from 27 Chinese familial BC families.
RESULTS: Eighty-one germline mutations in 27 BC predisposition genes were identified in 82.8% (96/116) of the cases. Among these, 80.8% of the mutated genes were related to DNA damage repair. Fourteen possible disease-causing variants were identified in 13 of 27 BC families. Only 25.9% (7/27) of the BC families exhibited hereditary deficiency in BRCA1/2 genes, while 22.2% of the BC families exhibited defects in non-BRCA genes. In all, 41.7% (40/96) of the mutation carriers had BRCA mutations, 88.5% (85/96) had non-BRCA mutations, and 30.2% (29/96) had both BRCA and non-BRCA mutations. The BC patients with BRCA mutations had a higher risk of axillary lymph node metastases than those without mutations (P < 0.05). However, the BC patients with non-BRCA mutations frequently had a higher occurrence of benign breast diseases than those without mutations (P < 0.05).
CONCLUSIONS: In addition to BRCA1/2, genetic variants in non-BRCA DNA repair genes might play significant roles in the development of familial/hereditary BC. Therefore, profiling of multiple BC predisposition genes should be more valuable for screening potential pathogenic germline mutations in Chinese familial/hereditary BC.

Keywords:  DNA damage repair genes; Familial breast cancer; clinical features; predisposition genes

DOI:  https://doi.org/10.20892/j.issn.2095-3941.2021.0011
Oral Oncol. 2021 Sep 28. pii: S1368-8375(21)00651-5. [Epub ahead of print]122 105545

Germline variants in DNA repair genes are associated with young-onset head and neck cancer.

Sarah Santiloni Cury, Priscila Mayrink de Miranda, Fabio Albuquerque Marchi, Luisa Matos do Canto, Thiago Celestino Chulam, Annabeth Høgh Petersen, Mads M Aagaard, Clóvis Antonio Lopes Pinto, Luiz Paulo Kowalski, Silvia Regina Rogatto.

  The genetic predisposition to head and neck carcinomas (HNSCC) and how the known risk factors (papillomavirus infection, alcohol, and tobacco consumption) contribute to the early-onset disease are barely explored. Although HNSCC at early onset is rare, its frequency is increasing in recent years. Germline and somatic variants were assessed to build a comprehensive genetic influence pattern in HNSCC predisposition and patient outcome. Whole-exome sequencing was performed in 45 oral and oropharynx carcinomas paired with normal samples of young adults (≤49 years). We found FANCG, CDKN2A, and TPP germline variants previously associated with HNSCC risk. At least one germline variant in DNA repair pathway genes was detected in 67% of cases. Germline and somatic variants (including copy number variations) in FAT1 gene were identified in 9 patients (20%) and 12 tumors (30%), respectively. Somatic variants were found in HNSCC associated genes, such as TP53, CDKN2A, and PIK3CA. To date, 55 of 521 cases from the large cohort of TCGA presented < 49 years old. A comparison between the somatic alterations of TCGA-HNSCC at early onset and our dataset revealed strong similarities. Protein-protein interaction analysis between somatic and germline altered genes revealed a central role of TP53. Altogether, germline alterations in DNA repair genes potentially contribute to an increased risk of developing HNSCC at early-onset, while FAT1 could impact the prognosis.

Keywords:  Cancer predisposition; Early-onset cancer; Oral cavity carcinomas; Oropharynx carcinomas; Risk factors; Whole-exome sequencing

DOI:  https://doi.org/10.1016/j.oraloncology.2021.105545
Cancers (Basel). 2021 Sep 21. pii: 4714. [Epub ahead of print]13(18):

Spectrum of Germline Pathogenic Variants in BRCA1/2 Genes in the Apulian Southern Italy Population: Geographic Distribution and Evidence for Targeted Genetic Testing.

Margherita Patruno, Simona De Summa, Nicoletta Resta, Mariapia Caputo, Silvia Costanzo, Maria Digennaro, Brunella Pilato, Rosanna Bagnulo, Antonino Pantaleo, Cristiano Simone, Maria Iole Natalicchio, Elisabetta De Matteis, Paolo Tarantino, Stefania Tommasi, Angelo Paradiso.

  BRCA1/2-associated hereditary breast and ovarian cancer is the most common form of hereditary breast and ovarian cancer and occurs in all ethnicities and racial populations. Different BRCA1/BRCA2 pathogenic variants (PVs) have been reported with a wide variety among populations. In this study, we retrospectively analyzed prevalence and geographic distribution of pathogenic germline BRCA1/2 variants in families from Apulia in southern Italy and evaluated the genotype-phenotype correlations. Data were collected from Oncogenetic Services present in Apulian hospitals and a shared database was built containing Apulian native probands (n = 2026) that had undergone genetic testing from 2004 to 2019. PVs were detected in 499 of 2026 (24.6%) probands and 68.5% of them (342 of 499) were in the BRCA1 gene. We found 65 different PVs in BRCA1 and 46 in BRCA2. There were 10 most recurrent PVs and their geographical distribution appears to be significantly specific for each province. We have assumed that these PVs are related to the historical and geopolitical changes that occurred in Apulia over time and/or to a "founder effect". Broader knowledge of BRCA1/2 prevalence and recurring PVs in specific geographic areas could help establish more flexible genetic testing strategies that may enhance our ability to detect high-risk subjects.

Keywords:  Apulian population; BRCA1; BRCA2; geographic distribution; hereditary breast and ovarian cancer; southern Italy

DOI:  https://doi.org/10.3390/cancers13184714
Cancer Med. 2021 Sep 26.

Breast cancer characteristics and surgery among women with Li-Fraumeni syndrome in Germany-A retrospective cohort study.

Nathalie Rippinger, Christine Fischer, Hans-Peter Sinn, Nicola Dikow, Christian Sutter, Kerstin Rhiem, Sabine Grill, Friedrich W Cremer, Huu P Nguyen, Nina Ditsch, Karin Kast, Simone Hettmer, Christian P Kratz, Sarah Schott.

   BACKGROUND: Women with Li-Fraumeni syndrome (LFS) have elevated breast cancer (BC) risk. Optimal BC treatment strategies in this population are yet unknown.
METHODS: BC subtypes and treatment were retrospectively investigated between December 2016 and January 2019 in a multicentre study. BC risks were evaluated according to the type of surgery.
RESULTS: Thirty-five women of our study population (35/44; 79.5%) had developed 36 breast lesions at first diagnosis at a mean age of 34 years. Those breast lesions comprised 32 invasive BCs (89%), three ductal carcinoma in situ alone (8%) and one malignant phyllodes tumour (3%). BCs were mainly high-grade (18/32), of no special type (NST; 31/32), HER2-enriched (11/32) or luminal-B-(like)-type (10/32). Affected women (n = 35) received breast-conserving surgery (BCS, n = 17) or a mastectomy (ME, n = 18) including seven women with simultaneous contralateral prophylactic mastectomy (CPM) at first diagnosis. Nineteen women suffered 20 breast or locoregional axillary lesions at second diagnosis with mean age of 36. Median time between first and second diagnosis was 57 months; median time to contra- and ipsilateral recurrence depended on surgical strategies (BCS: 46 vs. unilateral ME: 93 vs. bilateral ME > 140 months). Women with a primary treatment of solitaire therapeutic ME suffered from contralateral BC earlier compared to those with therapeutic ME and CPM (median: 93 vs. >140 months).
CONCLUSION: Aggressive BC subtypes occur among women with LFS. Surgical treatment, i.e. ME and CPM, may prolong time to a second BC diagnosis. Conclusion on long-term survival benefit is pending. Individual competing tumour risks and long-term outcomes need to be taken into consideration.

Keywords:   TP53 ; Li-Fraumeni syndrome; breast surgery; cancer predisposition; hereditary breast cancer; mastectomy; prophylactic surgery

DOI:  https://doi.org/10.1002/cam4.4300
Clin Cancer Res. 2021 Sep 30. pii: clincanres.CCR-21-1673-A.2021. [Epub ahead of print]

Ovarian cancer specific BRCA-like copy number aberration classifiers detect mutations associated with homologous recombination deficiency in the AGO-TR1 trial.

Philip C Schouten, Lisa K Richters, Daniel J Vis, Stefan Kommoss, Ewald van Dyk, Corinna Ernst, Roelof J C Kluin, Frederik Marme, Esther H Lips, Sandra Schmidt, Esther Scheerman, Katharina Prieske, Carolien H M van Deurzen, Alexander Burges, Patricia C Ewing-Graham, Dimo Dietrich, Agnes Jager, Nikolaus de Gregorio, Jan Hauke, Andreas du Bois, Petra M Nederlof, Lodewyk F Wessels, Eric Hahnen, Philipp Harter, Sabine C Linn, Rita K Schmutzler.

PURPOSE: Previously, we developed breast cancer BRCA1-like and BRCA2-like copy number profile shrunken centroid classifiers predictive for mutation status and response to therapy, targeting homologous recombination deficiency (HRD). Therefore, we investigated BRCA1- and BRCA2-like classification in ovarian cancer, aiming to acquire classifiers with similar properties as those in breast cancer.
EXPERIMENTAL DESIGN: We analyzed DNA copy number profiles of germline BRCA1- and BRCA2-mutant ovarian cancers and control tumors and observed that existing breast cancer classifiers did not sufficiently predict mutation status. Hence, we trained new shrunken centroid classifiers on this set and validated them in the independent TCGA dataset. Subsequently, we assessed BRCA1/2-like classification and obtained germline and tumor mutation and methylation status of cancer predisposition genes, among them several involved in homologous recombination (HR) repair, of 300 ovarian cancer samples derived from the consecutive cohort trial AGO-TR1 (NCT02222883).
RESULTS: The detection rate of the BRCA1-like classifier for BRCA1 mutations and promoter hypermethylation was 95.6 %. The BRCA2-like classifier performed less accurate, likely due to a smaller training set. Furthermore, three-quarters of the BRCA1/2-like tumors could be explained by (epi)genetic alterations in BRCA1/2, germline RAD51C mutations and alterations in other genes involved in HR. Around half of the non BRCA-mutated ovarian cancer cases displayed a BRCA-like phenotype.
CONCLUSIONS: The newly trained classifiers detected most BRCA-mutated and methylated cancers and all tumors harboring a RAD51C germline mutations. Beyond that, we found an additional substantial proportion of ovarian cancers to be BRCA-like.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-1673
Cancers (Basel). 2021 Sep 10. pii: 4538. [Epub ahead of print]13(18):

Histological and Somatic Mutational Profiles of Mismatch Repair Deficient Endometrial Tumours of Different Aetiologies.

Neil A J Ryan, Thomas D J Walker, James Bolton, Natalja Ter Haar, Tom Van Wezel, Mark A Glaire, David N Church, D Gareth Evans, Tjalling Bosse, Emma J Crosbie.

   BACKGROUND: Mismatch repair deficient (MMRd) tumours may arise from somatic events acquired during carcinogenesis or in the context of Lynch syndrome (LS), an inherited cancer predisposition condition caused by germline MMR pathogenic variants. Our aim was to explore whether sporadic and hereditary MMRd endometrial cancers (EC) display distinctive tumour biology.
METHODS: Clinically annotated LS-EC were collected. Histological slide review was performed centrally by two specialist gynaecological pathologists. Mutational analysis was by a bespoke 75- gene next-generation sequencing panel. Comparisons were made with sporadic MMRd EC. Multiple correspondence analysis was used to explore similarities and differences between the cohorts.
RESULTS: After exclusions, 135 LS-EC underwent independent histological review, and 64 underwent mutational analysis. Comparisons were made with 59 sporadic MMRd EC. Most tumours were of endometrioid histological subtype (92% LS-EC and 100% sporadic MMRd EC, respectively, p = NS). Sporadic MMRd tumours had significantly fewer tumour infiltrating lymphocytes (p ≤ 0.0001) and showed more squamous/mucinous differentiation than LS-EC (p = 0.04/p = 0.05). PTEN mutations were found in 88% sporadic MMRd and 61% LS-EC, respectively (p < 0.001). Sporadic MMRd tumours had significantly more mutations in PDGFRA, ALK, IDH1, CARD11, CIC, MED12, CCND1, PTPN11, RB1 and KRAS, while LS-EC showed more mutations affecting SMAD4 and ARAF. LS-EC showed a propensity for TGF-β signalling disruption. Cluster analysis found that wild type PTEN associates predominantly with LS-EC, whilst co-occurring mutations in PTEN, PIK3CA and KRAS predict sporadic MMRd EC.
CONCLUSIONS: Whilst MMRd EC of hereditary and sporadic aetiology may be difficult to distinguish by histology alone, differences in infiltrating immune cell counts and mutational profile may predict heterogenous responses to novel targeted therapies and warrant further study.

Keywords:  endometrial cancer; lynch syndrome; mismatch repair; somatic mutation

DOI:  https://doi.org/10.3390/cancers13184538
JCO Oncol Pract. 2021 Sep 28. OP2100382

Risk-Reducing Bilateral Salpingo-Oophorectomy for Ovarian Cancer: A Review and Clinical Guide for Hereditary Predisposition Genes.

Ying L Liu, Kelsey Breen, Amanda Catchings, Megha Ranganathan, Alicia Latham, Deborah J Goldfrank, Rachel N Grisham, Kara Long Roche, Melissa K Frey, Dennis S Chi, Nadeem Abu-Rustum, Carol Aghajanian, Kenneth Offit, Zsofia K Stadler.

Pathogenic germline variants underlie up to 20% of ovarian cancer (OC) and are associated with varying degrees of risk for OC. For mutations in high-penetrance genes such as BRCA1/2, the role of risk-reducing bilateral salpingo-oophorectomy (RRSO) in cancer prevention is well-established and improves mortality. However, in moderate-penetrance genes where the degree of risk for OC is less precisely defined, the role of RRSO is more controversial. Although national guidelines have evolved to incorporate gene-specific recommendations, studies demonstrate significant variations in practice. Given this, our multidisciplinary group has reviewed the available literature on risk estimates for genes associated with OC, incorporated levels of evidence, and set thresholds for consideration of RRSO. We found that the benefit of RRSO is well-established for pathogenic variants in BRCA1/2 as well as BRIP1 and RAD51C/D where the risk of OC is elevated beyond our threshold for RRSO. In PALB1, RRSO is particularly controversial as newer studies consistently demonstrate an increased risk of OC that is dependent on family history, making uniform recommendations challenging. Additionally, new guidelines for Lynch syndrome provide gene-specific risks, questioning the role of RRSO, and even hysterectomy, for MSH6 and PMS2 mutation carriers. Given these uncertainties, shared decision making should be used around RRSO with discussion of individual risk factors, family history, and adverse effects of surgery and premature menopause. Herein, we provide a clinical guide and counseling points.

DOI: https://doi.org/10.1200/OP.21.00382
JTO Clin Res Rep. 2020 Sep;1(3): 100068

Somatic and Germline BRCA 1 and 2 Mutations in Advanced NSCLC From the SAFIR02-Lung Trial.

Jordi Remon, Benjamin Besse, Alexandra Leary, Ivan Bièche, Bastien Job, Ludovic Lacroix, Aurélie Auguste, Marjorie Mauduit, Clarisse Audigier-Valette, Judith Raimbourg, Anne Madroszyk, Stefan Michels, Mohammed Amine Bayar, Marta Jimenez, Jean-Charles Soria, Etienne Rouleau, Fabrice Barlesi.

   Introduction: Molecular profiling is considered a standard of care in advanced NSCLC. A comprehensive next-generation sequencing panel can discover somatic or germline BRCA1/2 mutations that are new druggable molecular alterations. However, the phenotypic and potential therapeutic relevance of BRCA1/2 mutation in NSCLC remains poorly defined.
Methods: From April 2014 to March 2017, 600 newly diagnosed, EGFR/ALK negative patients with advanced NSCLC were enrolled in the SAFIR02-Lung trial. Molecular profiling was done at study entry on archival tissue or frozen tissue collected from a new biopsy specimen before the third cycle of platinum-based chemotherapy. The prevalence of BRCA1/2 variants and its biological relevance were assessed. A homologous recombinant deficiency (HRD) score was based on the copy number variation data, and the germline status was determined by blood analysis. The BRCA Share database and the French CGG consortium were the references for the variant classification.
Results: Of 379 patients with a molecular profile discussed in a tumor molecular board, BRCA1/2 variants were identified in 20 patients (5.3%), including eight patients (2.1%) with a confirmed pathogenic BRCA mutation. Two patients (0.5%) harbored a germline BRCA2 mutation, and for six others, a somatic BRCA mutation was identified (1.6%). All were men and mainly smokers (88%). The overall response rate to chemotherapy was 13%. BRCA variants of unknown significance were detected in 12 patients (3.2%), achieving an 8.3% overall response rate with chemotherapy. One-third of tumors carrying pathogenic BRCA mutations or variants of unknown significance had biallelic inactivation and high HRD score. Overall survival of this cohort was 12.8 months.
Conclusions: Pathogenic BRCA1/2 mutations occur in 2.1% of patients with advanced NSCLC. The predictive role of BRCA mutation for making treatment decisions in NSCLC seems limited based on clinical response (low platinum sensitivity) and molecular features (discrepancy between biallelic inactivation and high HRD score).

Keywords:  Advanced non–small cell lung cancer; BRCA mutation; Next-generation sequencing; PARP inhibitors; SAFIR trial

DOI:  https://doi.org/10.1016/j.jtocrr.2020.100068
Int J Mol Sci. 2021 Sep 18. pii: 10105. [Epub ahead of print]22(18):

Personalized Medicine for TP53 Mutated Myelodysplastic Syndromes and Acute Myeloid Leukemia.

Thomas Cluzeau, Michael Loschi, Pierre Fenaux, Rami Komrokji, David A Sallman.

  Targeting TP53 mutated myelodysplastic syndromes and acute myeloid leukemia remains a significant unmet need. Recently, new drugs have attempted to improve the outcomes of this poor molecular subgroup. The aim of this article is to review all the current knowledge using active agents including hypomethylating agents with venetoclax, eprenetapopt or magrolimab. We include comprehensive analysis of clinical trials to date evaluating these drugs in TP53 myeloid neoplasms as well as discuss future novel combinations for consideration. Additionally, further understanding of the unique clinicopathologic components of TP53 mutant myeloid neoplasms versus wild-type is critical to guide future study. Importantly, the clinical trajectory of patients is uniquely tied with the clonal burden of TP53, which enables serial TP53 variant allele frequency analysis to be a critical early biomarker in investigational studies. Together, significant optimism is now possible for improving outcomes in this patient population.

Keywords:  AML; MDS; TP53; eprenetapopt; magrolimab

DOI:  https://doi.org/10.3390/ijms221810105
JTO Clin Res Rep. 2021 Apr;2(4): 100146

Genomic Evolution in a Patient With Lung Adenocarcinoma With a Germline EGFR T790M Mutation.

Netta Mäkinen, Meng Zhou, Meredith Bemus, Julius Nevin, Anwesha Nag, Ruthia Chen, Yolonda L Colson, Aaron R Thorner, Geoffrey R Oxnard, Matthew Meyerson, Lynette M Sholl.

   Introduction: A subset of lung adenocarcinomas (ADs) has been found to have somatic activating mutations in the tyrosine kinase domain of the EGFR gene, associated with response to EGFR tyrosine kinase inhibitor therapy. Rare germline mutations within this domain, including EGFR T790M, have been associated with genetic susceptibility to lung ADs. Using high-throughput sequencing, we elucidate the genomic evolution in tissues from a patient with lung AD carrying a germline EGFR T790M mutation.
Methods: We performed microdissection, targeted panel, and whole-exome sequencing to molecularly characterize multiple foci of atypical adenomatous hyperplasia (AAH), in situ and invasive components of AD, normal lung tissue, and whole blood from the patient. Normal lung tissue was analyzed for potential acquired somatic genome alterations ("field effect").
Results: All lesions harbored a secondary somatic EGFR mutation, either L858R or L861Q, in addition to the germline T790M mutation. Clear overlap was observed between the somatic profiles of in situ and invasive AD components, confirming clonal relatedness. AAH lesions shared few to no somatic alterations with the AD, suggesting clonal independence. No robust evidence of field effect was identified in the normal lung tissue.
Conclusions: Somatic EGFR mutations are early events in the pathogenesis of lung ADs arising in the context of germline EGFR T790M. Synchronous AAH lesions seem to be independent. Stepwise genomic evolution is observed in association with invasiveness of the neoplastic cell population.

Keywords:  EGFR germline mutation; Genome evolution; High-throughput sequencing; Lung adenocarcinoma; NSCLC

DOI:  https://doi.org/10.1016/j.jtocrr.2021.100146
NPJ Genom Med. 2020 Sep 29. 5(1): 40

Early-onset renal cell carcinoma in PTEN harmatoma tumour syndrome.

Raymond H Kim, Xiangling Wang, Andrew J Evans, Steven C Campbell, Jane K Nguyen, Kirsten M Farncombe, Charis Eng.

Individuals with PTEN hamartoma tumour syndrome (PHTS), including Cowden syndrome (CS), are susceptible to multiple benign hamartomas and an increased risk of cancer, particularly breast, endometrial, and thyroid. As a result, individuals undergo enhanced surveillance for early detection of these cancers. However, less commonly occurring cancers, such as colorectal and kidney, have insufficient guidelines for early detection. Currently, screening for kidney cancer via renal ultrasound begins at 40 years of age, because there were only rare cases of elevated risk in prospective series under 40. There have, however, been accumulating reports of kidney cancer in individuals with CS in their 30s, illustrating a need to lower the age of surveillance. We present additional evidence of renal cell carcinoma in two individuals with CS in their early twenties, and propose a reassessment of the abdominal surveillance in patients with PHTS. We propose biannual screening for kidney cancer beginning at 20 years of age.

DOI: https://doi.org/10.1038/s41525-020-00148-7