bims-lifras 2021-07-18 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–07–18
23 papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome.
A systematic review of the prevalence of germline pathogenic variants in patients with pancreatic cancer.
Lung Cancer in Li-Fraumeni Syndrome.
Multigene Panel Testing in Individuals With Hepatocellular Carcinoma Identifies Pathogenic Germline Variants.
Next-generation sequencing of BRCA1 and BRCA2 genes in Moroccan prostate cancer patients with positive family history.
Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion.
Case-case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer.
Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer.
Cancer predisposition genes in Japanese children with rhabdomyosarcoma.
Germline and tumor BRCA1/2 pathogenic variants in Chinese triple-negative breast carcinomas.
Expanding Germline Testing to All Patients With Esophagogastric Cancers-Easy to Do, Harder to Justify.
Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.
Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.
A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer.
Results from London Regional Clinical Genetics services over a 5-year period on germline TP53 testing in women diagnosed with breast cancer at <30 years.
Implications of Multigene Panel Testing on Psychosocial Outcomes: A Comparison of Patients With Pancreatic and Breast or Ovarian Cancer.
Targeted Next-generation Sequencing for Reliable Detection of Genetic Status in Breast Cancer.
Tolerability of Breast Radiotherapy Among Carriers of ATM Germline Variants.
Malignant gliomas with H3F3A G34R mutation or MYCN amplification in pediatric patients with Li Fraumeni syndrome.
BRCA-mutant pancreatic ductal adenocarcinoma.
The Common Thread: A Case of Synchronous Lung Cancers and a Germline CHEK2 Mutation.
Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.
Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development.

JCO Glob Oncol. 2021 Jul;7 1141-1150

Identification of the TP53 p.R337H Variant in Tumor Genomic Profiling Should Prompt Consideration of Germline Testing for Li-Fraumeni Syndrome.

Renata Lazari Sandoval, Cibele Masotti, Mariana Petaccia de Macedo, Maurício Fernando Silva Almeida Ribeiro, Ana Carolina Rathsam Leite, Sibele Inacio Meireles, Rodrigo Medeiros Bovolin, Fernando Costa Santini, Rodrigo Ramella Munhoz, Denis Leonardo Fontes Jardim, Artur Katz, Anamaria Aranha Camargo, Gustavo Dos Santos Fernandes, Maria Isabel Achatz.

PURPOSE: Li-Fraumeni syndrome (LFS) is rare in the worldwide population, but it is highly prevalent in the Brazilian population because of a founder mutation, TP53 p.R337H, accounting for 0.3% of south and southeastern population. Clinical criteria for LFS may not identify all individuals at risk of carrying the Brazilian founder mutation because of its lower penetrance and variable expressivity. This variant is rarely described in databases of somatic mutations. Somatic findings in tumor molecular profiling may give insight to identify individuals who might be carriers of LFS and allow the adoption of risk reduction strategies for cancer.
MATERIALS AND METHODS: We determined the frequency of the TP53 p.R337H variant in tumor genomic profiling from 755 consecutive Brazilian patients with pan-cancer. This is a retrospective cohort from January 2013 to March 2020 at a tertiary care center in Brazil.
RESULTS: The TP53 p.R337H variant was found in 2% (15 of 755) of the samples. The mutation allele frequency ranged from 30% to 91.7%. A total of seven patients were referred for genetic counseling and germline testing after tumor genomic profiling results were disclosed. All the patients who proceeded with germline testing (6 of 6) confirmed the diagnosis of LFS. Family history was available in 12 cases. Nine patients (9 of 12) did not meet LFS clinical criteria.
CONCLUSION: The identification of the TP53 p.R337H variant in tumor genomic profiling should be a predictive finding of LFS in the Brazilian population and should prompt testing for germline status confirmation.

DOI: https://doi.org/10.1200/GO.21.00097
J Gastroenterol. 2021 Jul 13.

A systematic review of the prevalence of germline pathogenic variants in patients with pancreatic cancer.

Esteban Astiazaran-Symonds, Alisa M Goldstein.

  The genetics of pancreatic ductal adenocarcinoma (PDAC) is complex with patients reported to harbor germline pathogenic variants (PVs) in many different genes. PDAC patients with familial pancreatic cancer (FPC) are more likely to carry germline PVs but there is no consensus main gene involved in FPC. We performed a systematic review of publications from PubMed and Scopus reporting PVs in patients with FPC, sporadic pancreatic cancer (SPC) and unselected cohorts of PDAC patients undergoing genetic testing and calculated a cumulative prevalence of PVs for each gene evaluated across these three groups of patients. When available, variants in the selected publications were reclassified according to the American College of Medical Genetics and Genomics classification system and used for prevalence calculations if classified as pathogenic or likely pathogenic. We observed an increased prevalence of PVs in FPC compared to SPC or unselected PDAC patients for most of the 41 genes reported. The genes with the highest prevalence of carriers of PVs in FPC were ATM, BRCA2, and CDKN2A. BRCA2 and ATM showed the highest prevalence of PVs in both SPC and unselected PDAC cohorts. Several genes with the highest prevalence of PVs are involved in breast and ovarian cancer suggesting strong overlap with underlying genetics in these disorders but no single gene was predominant. More research is needed to further understand the risk of PDAC associated with these many diverse genes.

Keywords:  Mutation; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Pathogenic variant; Prevalence

DOI:  https://doi.org/10.1007/s00535-021-01806-y
JCO Precis Oncol. 2021 ;pii: PO.20.00468. [Epub ahead of print]5

Lung Cancer in Li-Fraumeni Syndrome.

Kathleen Kerrigan, Jessica Chan, Jennie Vagher, Wendy Kohlmann, Anne Naumer, Jo Anson, Sara Low, Joshua Schiffman, Luke Maese.

DOI: https://doi.org/10.1200/PO.20.00468
JCO Precis Oncol. 2021 ;pii: PO.21.00079. [Epub ahead of print]5

Multigene Panel Testing in Individuals With Hepatocellular Carcinoma Identifies Pathogenic Germline Variants.

Anya Mezina, Neil Philips, Zoe Bogus, Noam Erez, Rui Xiao, Ruoming Fan, Kim M Olthoff, K Rajender Reddy, N Jewel Samadder, Sarah M Nielsen, Kathryn E Hatchell, Edward D Esplin, Anil K Rustgi, Bryson W Katona, Maarouf A Hoteit, Katherine L Nathanson, Kirk J Wangensteen.

Hepatocellular carcinoma (HCC) has well-defined environmental risk factors. In addition, epidemiologic studies have suggested hereditary risk factors. The goals of this study were to determine the rate of pathogenic and likely pathogenic (P/LP) germline variants in cancer predisposition genes in patients with HCC, possible enrichment of P/LP variants in particular genes, and potential impact on clinical management.
MATERIALS AND METHODS: A prospective study at a tertiary medical center enrolled 217 patients with a personal history of HCC. Multigene panel testing was performed for 134 cancer predisposition genes in all patients. The rate of P/LP variants was compared with population rates. A separate retrospective cohort included 219 patients with HCC who underwent testing at a commercial laboratory.
RESULTS: In the prospective cohort, P/LP germline variants were identified in 25 of 217 patients with HCC (11.5%). Four patients (1.8%) had P/LP variants in the highly penetrant cancer genes BRCA2 (n = 2), MSH6 (n = 1), and PMS2 (n = 1). In addition, multiple patients had P/LP variants in FANCA (n = 5) and BRIP1 (n = 4), which were significantly enriched in HCC compared with the general population. Detection of P/LP variants led to changes in clinical management in regard to therapy selection, screening recommendations, and cascade testing of relatives. In a separate retrospective analysis of 219 patients with HCC, 30 (13.7%) were positive for P/LP variants including 13 (5.9%) with highly penetrant genes APC (n = 2), BRCA1 (n = 1), BRCA2 (n = 6), MSH2 (n = 2), or TP53 (n = 2).
CONCLUSION: P/LP germline variants in cancer predisposition genes were detected in 11%-14% of patients with HCC. Inherited genetics should not be overlooked in HCC as there are important implications for precision treatment, future risk of cancers, and familial cancer risk.

DOI: https://doi.org/10.1200/PO.21.00079
PLoS One. 2021 ;16(7): e0254101

Next-generation sequencing of BRCA1 and BRCA2 genes in Moroccan prostate cancer patients with positive family history.

Fatiha Salmi, Fatima Maachi, Amal Tazzite, Rachid Aboutaib, Jamal Fekkak, Houssine Azeddoug, Hassan Jouhadi.

Prostate cancer is the most common male cancer in Morocco. Although sporadic forms account for a large proportion of patients, familial forms of prostate cancer are observed in 20% of cases and about 5% are due to hereditary transmission. Indeed, germline mutations in BRCA1/2 genes have been associated with prostate cancer risk. However, the spectrum of these mutations was not investigated in Moroccan Prostate cancer patients. Thereby, the aim of this study was to characterize and to estimate the prevalence of germline BRCA1/2 mutations and large rearrangements in Moroccan patients with familial prostate cancer. The entire coding regions and intron/exon boundaries of BRCA1 and BRCA2 genes have been analyzed by next generation sequencing (NGS) in a total of 30 familial prostate cancer patients. Three pathogenic mutations were detected in four unrelated patients (13.3%). One BRCA1 mutation (c.1953_1956delGAAA) and two BRCA2 mutations (c.7234_7235insG and BRCA2ΔE12). In addition, sixty-three distinct polymorphisms and unclassified variants have been found. Early identification of germline BRCA1/2 mutations may be relevant for the management of Moroccan prostate cancer patients.

DOI: https://doi.org/10.1371/journal.pone.0254101
JCO Precis Oncol. 2021 ;pii: PO.20.00432. [Epub ahead of print]5

Clinical Germline Testing Results of Men With Prostate Cancer: Patient-Level Factors and Implications of NCCN Guideline Expansion.

Samantha E Greenberg, Trevor C Hunt, Jacob P Ambrose, William T Lowrance, Christopher B Dechet, Brock B O'Neil, Jonathan D Tward.

Germline likely pathogenic or pathogenic variants (PVs) have been identified in up to 17% of men with prostate cancer (PC) and may drive disease severity or be targetable by novel therapies. National Comprehensive Cancer Network (NCCN) guidelines encouraging germline testing in metastatic PC were recently expanded to include all men with high-risk, very high-risk, or regional PC. Our aim was to assess the impact of expanded NCCN guidelines on the detection rate of germline PVs and to determine patient-level factors associated with a PV germline testing result.
PATIENTS AND METHODS: Men with PC underwent multigene germline genetic testing for PVs from June 2016 to December 2018, and trends were compared. The association of patient-level factors with a PV germline testing result, where ≥ 1 PV was identified, was assessed using analysis of variance and univariate logistic regression. Sensitivity analyses were limited to clinically actionable variants and those associated with disease severity or progression (BRCA1/2 and ATM).
RESULTS: Of 408 men undergoing germline testing, 42 (10.3%) men had PVs and 366 (89.7%) men did not have PVs identified. The proportion of men identified with a germline PV remained stable following testing criteria expansion (9.4% v 10.6%, P = .73). No patient-level factors were significantly associated with increased odds of a PV germline testing result, including age at diagnosis, race, pretreatment prostate-specific antigen, Gleason grade group, NCCN risk group, and family history of cancer (breast and/or ovarian, prostate, or any cancer).
CONCLUSION: This study demonstrated a stable PV detection rate in men with PC using expanded criteria aligned to the updated NCCN testing guidelines. However, we did not find strong evidence to suggest that patient-level factors are associated with PV germline testing results. These findings support the recent expansion of NCCN germline testing guidelines in PC.

DOI: https://doi.org/10.1200/PO.20.00432
Hum Mutat. 2021 Jul 10.

Case-case analysis addressing ascertainment bias for multigene panel testing implicates BRCA1 and PALB2 in endometrial cancer.

Sharon E Johnatty, Tina Pesaran, Jill Dolinsky, Amal Yussuf, Holly La Duca, Paul A James, Tracy A O' Mara, Amanda B Spurdle.

  Hereditary endometrial cancer (EC) is most commonly attributed to pathogenic variants in mismatch repair (MMR) genes. Evidence supports existence of additional genetic risk factors in the context of multiple cancer diagnoses and/or family history of EC. EC patients (n=5292) referred for diagnostic multi-gene cancer panel testing were annotated for: presence of a pathogenic gene variant; personal history of prior, concurrent or subsequent cancer of another type; reported family history of Lynch syndrome or endometrial cancer. The Pearson χ2 test was used to assess differences in gene variant prevalence between case sub-groups defined by personal and/or family history of cancer/s, using cases with no family history of Lynch/EC as reference. Another cancer diagnosis was reported for 55% of EC cases. EC cases with prior and reported family history of Lynch cancer were enriched for variants in MLH1 (p=3.5x10-7 ), MSH2 (p=3.1x10-7 ), and PMS2 (p=0.02). Consistent with expectations for a breast cancer (BC) gene also predisposing to EC, variant frequency was increased in EC patients with prior BC and family history of EC for BRCA1 (p=1.7x10-5 ) and PALB2 (p=0.0002). Strategic case-case analyses to address cohort ascertainment bias has provided rationale to direct future studies of candidate hereditary EC genes. This article is protected by copyright. All rights reserved.

Keywords:  Endometrial cancer; ascertainment; family history; gene; multi-gene panel tests

DOI:  https://doi.org/10.1002/humu.24256
JAMA Netw Open. 2021 Jul 01. 4(7): e2114753

Prevalence of Germline Alterations on Targeted Tumor-Normal Sequencing of Esophagogastric Cancer.

Geoffrey Y Ku, Yelena Kemel, Steve B Maron, Joanne F Chou, Vignesh Ravichandran, Zarina Shameer, Anna Maio, Elizabeth S Won, David P Kelsen, David H Ilson, Marinela Capanu, Vivian E Strong, Daniela Molena, Smita Sihag, David R Jones, Daniel G Coit, Yaelle Tuvy, Kendall Cowie, David B Solit, Nikolaus Schultz, Jaclyn F Hechtman, Kenneth Offit, Vijai Joseph, Diana Mandelker, Yelena Y Janjigian, Zsofia K Stadler.

Importance: Among patients with esophagogastric cancers, only individuals who present with known features of heritable cancer syndromes are referred for genetic testing. Broader testing might identify additional patients with germline alterations.
Objectives: To examine the prevalence of likely pathogenic or pathogenic (LP/P) germline alterations among patients with esophagogastric cancer and to assess associations between germline variant prevalence and demographic and clinicopathologic features.
Design, Setting, and Participants: This cross-sectional study was performed at a tertiary referral cancer center from January 1, 2014, to December 31, 2019, in 515 patients with esophagogastric cancer who consented to tumor and blood sequencing.
Main Outcomes and Measures: Presence or absence of LP/P variants in up to 88 genes associated with cancer predisposition syndromes as identified by targeted sequencing (Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets).
Results: Among 515 patients (median age, 59 years; range, 18-87 years; 368 [71.5%] male; 398 [77.3%] White), 243 (47.2%) had gastric cancer, 111 (21.6%) had gastroesophageal junction (GEJ) cancer, and 161 (31.3%) had esophageal cancer. A total of 48 patients with gastric cancer (19.8%), 16 (14.4%) with GEJ cancer, and 17 (10.6%) with esophageal cancer had LP/P germline variants. The number of LP/P variants in high- and moderate-penetrance genes was significantly higher in patients with gastric cancer (29 [11.9%]; 95% CI, 8.1%-16.7%) vs patients with esophageal cancer (8 [5.0%]; 95% CI, 2.2%-9.6%; P = .03), and the difference was greater for high-penetrance germline alterations in patients with gastric cancer (25 [10.3%]; 95% CI, 6.8%-14.8%) vs in patients with esophageal cancer (3 [1.9%]; 95% CI, 0.38%-5.3%; P = .001). The most frequent high- and moderate-penetrance LP/P alterations were in BRCA1/2 (14 [2.7%]), ATM (11 [2.1%]), CDH1 (6 [1.2%]), and MSH2 (4 [0.8%]). Those with early-onset disease (≤50 years of age at diagnosis) were more likely to harbor an LP/P germline variant (29 [21.0%]; 95% CI, 14.5%-28.8%) vs those with late-onset disease (patients >50 years of age at diagnosis) (52 [13.8%]; 95% CI, 10.5%-17.7%; P = .046). ATM LP/P variants occurred in 6 patients (4.3%; 95% CI, 1.6%-9.1%) with early-onset esophagogastric cancer vs 5 (1.3%; 95% CI, 0.4%-3.1%; P = .08) of those with late-onset esophagogastric cancer.
Conclusions and Relevance: These results suggest that pathogenic germline variants are enriched in gastric and early-onset esophagogastric cancer and that germline testing should be considered in these populations. The role of ATM alterations in esophagogastric cancer risk warrants further investigation.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.14753
J Hum Genet. 2021 Jul 14.

Cancer predisposition genes in Japanese children with rhabdomyosarcoma.

Hiroko Fukushima, Ryoko Suzuki, Yuni Yamaki, Sho Hosaka, Masako Inaba, Wataru Morii, Emiko Noguchi, Hidetoshi Takada.

Rhabdomyosarcoma (RMS) is one of the most common soft tissue sarcomas in children. Germline mutations in cancer-predisposition genes have been detected in approximately 10% of pediatric cancers. However, the genetic background of RMS is still unclear, especially in Asian children. DNA was extracted from the peripheral blood of children with RMS and cancer-associated genes analyzed using targeted re-sequencing. Twenty patients participated in this study. There were three deaths due to RMS. One patient developed a second neoplasm. Nine patients had long-term co-morbidities. Six pathogenic variants were found in five patients: one nonsense variant of DICER1, one exon deletion of TP53, and three missense variants of BUB1B, LIG4, and MEN1. Two of the five patients had a family history of cancer. Two patients with missense variants of LIG4 had long-term co-morbidities of drug-induced cardiomyopathy. The missense variants of LIG4, essential for DNA double-strand break repair, were detected in two unrelated patients. While this is the first report of the germline genetic analysis of Japanese children with RMS with detailed clinical information, the frequency of the variant was almost equivalent to that of previous reports from western countries. Unbiased exon sequencing may be useful to clarify the pathogenesis of RMS in children and in predicting the clinical course of these patients.

DOI: https://doi.org/10.1038/s10038-021-00961-7
J Cancer Res Clin Oncol. 2021 Jul 13.

Germline and tumor BRCA1/2 pathogenic variants in Chinese triple-negative breast carcinomas.

Gang Ji, Longlong Bao, Qianlan Yao, Jing Zhang, Xiaoli Zhu, Qianming Bai, Zhiming Shao, Wentao Yang, Xiaoyan Zhou.

   PURPOSE: BRCA1/2 screening for all triple-negative breast cancer (TNBC) patients younger than 60 years may still be an economic burden in China. Further evidences that include incidence and outcome of BRCA1/2 pathogenic variants (PV) screened based on younger age or family history (FH) are worth discussing for improving the cost-effectiveness of BRCA1/2 testing in Chinese TNBC. We aimed to investigate the prevalence of germline and tumor BRCA1/2 PV based on age screening in Chinese TNBC patients.
METHODS: Paired blood and tumor DNA from 124 unselected Chinese TNBC patients with less than or equal to 55 years were collected and analyzed for BRCA1/2 PV. Clinicopathological characteristics including age at diagnosis, FH and follow-up data were collected for further analysis.
RESULTS: The entire frequency of germline and tumor BRCA1/2 PV was 21.0 and 25%, respectively. Among them, 20 (16.1%) germline and 5 (4.0%) somatic BRCA1/2 single-nucleotide variant/insertion/deletions were found by NGS testing, 6 (4.8%) BRCA1 large genomic rearrangements were detected in blood DNA by MPLA. There was significant correlation between FH of HBOC and germline BRCA1/2 PVs among these patients. Patients with tumor BRCA1/2 PVs had significant improvements than non-carriers in PFS (p = 0.047). No significant impacts were found between various mutation status in OS outcomes. No significant differences were found between BRCA1 or BRCA2 and non-carriers in PFS or OS.
CONCLUSION: There is a high incidence of germline and tumor BRCA1/2 PVs in Chinese TNBC patients with less than or equal to 55 years old. Tumor BRCA1/2 PV carriers showed an improved survival outcome. Our results suggest that BRCA1/2 PVs testing addressed within each specific clinical scenario could be more cost-effective for patients.

Keywords:  BRCA1/2; Large genomic rearrangement (LRG); Somatic mutation; Triple-negative breast cancer (TNBC)

DOI:  https://doi.org/10.1007/s00432-021-03696-2
JAMA Netw Open. 2021 Jul 01. 4(7): e2114789

Expanding Germline Testing to All Patients With Esophagogastric Cancers-Easy to Do, Harder to Justify.

Thomas L Holden, Catherine Neumann, Michael J Hall.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.14789
Prostate. 2021 Jul 12.

Observed evidence for guideline-recommended genes in predicting prostate cancer risk from a large population-based cohort.

Jun Wei, Wancai Yang, Zhuqing Shi, Lucy Lu, Qiang Wang, W Kyle Resurreccion, Valentina Engelmann, S Lilly Zheng, Peter J Hulick, Kathleen A Cooney, William B Isaacs, Brian T Helfand, Jim Lu, Jianfeng Xu.

   BACKGROUND: Germline testing for prostate cancer (PCa) is now recommended by the National Comprehensive Cancer Network. While multi-gene testing has been proposed, evidence for their association with PCa risk is not well established.
METHODS: We tested associations of pathogenic/likely pathogenic mutations in 10 guideline-recommended genes (ATM, BRCA1, BRCA2, CHEK2, PALB2, MLH1, MSH2, MSH6, PMS2, and HOXB13) with PCa risk in the UK Biobank, a population-based cohort. Mutations were annotated based on prostate-specific transcripts using the American College of Medical Genetics and Genomics standards. Associations were tested in 4399 PCa cases and 85,403 unaffected male controls using logistic regression adjusting for age and genetic background. p < .005 was considered significant based on Bonferroni correction.
RESULTS: Among the 10 tested genes, significantly higher mutation carrier rates in PCa cases versus controls were found for four genes at p < .005; HOXB13, BRCA2, ATM, and CHEK2, with odds ratios (95% confidence interval) estimated at 4.96 (3.62-6.69), 3.23 (2.23-4.56), 2.95 (2.01-4.22), 1.94 (1.43-2.58), respectively. No significant association was found between mutation carrier status and age at PCa diagnosis or family history of PCa. Despite the large sample size of this study, statistical power remains limited, especially for genes where pathogenic mutation carrier rates are extremely rare (<0.03%).
CONCLUSION: Observed evidence for PCa risk was found for four of the 10 guideline-recommended genes in this large population-based study. Mutations in these four genes can be interpreted with confidence in genetic counseling for PCa risk assessment. Evidence for the remaining six genes needs to be further evaluated in larger studies.

Keywords:  germline mutation; guidelines; prostate cancer; risk

DOI:  https://doi.org/10.1002/pros.24195
JCO Precis Oncol. 2021 ;pii: PO.20.00525. [Epub ahead of print]5

Prospective Statewide Study of Universal Screening for Hereditary Colorectal Cancer: The Ohio Colorectal Cancer Prevention Initiative.

Rachel Pearlman, Wendy L Frankel, Benjamin J Swanson, Dan Jones, Weiqiang Zhao, Ahmet Yilmaz, Kristin Miller, Jason Bacher, Christopher Bigley, Lori Nelsen, Paul J Goodfellow, Richard M Goldberg, Electra Paskett, Peter G Shields, Jo L Freudenheim, Peter P Stanich, Ilene Lattimer, Mark Arnold, Thomas W Prior, Mitchell Haut, Matthew F Kalady, Brandie Heald, Ian Paquette, David J Draper, Joanna M Brell, Sameer Mahesh, Kisa Weeman, Shyamal Bastola, Jeffrey Zangmeister, Aruna Gowda, Filix Kencana, Albert Malcolm, Yinong Liu, Sharon Cole, Charles Bane, Chaoyang Li, Esther Rehmus, Colin C Pritchard, Brian H Shirts, Angela Jacobson, Shelly A Cummings, Albert de la Chapelle, Heather Hampel.

Hereditary cancer syndromes infer high cancer risks and require intensive surveillance. Identification of high-risk individuals among patients with colorectal cancer (CRC) needs improvement.
METHODS: Three thousand three hundred ten unselected adults who underwent surgical resection for primary invasive CRC were prospectively accrued from 51 hospitals across Ohio between January 1, 2013, and December 31, 2016. Universal Tumor screening (UTS) for mismatch repair (MMR) deficiency was performed for all, and pathogenic germline variants (PGVs) were identified using multigene panel testing (MGPT) in those who met at least one inclusion criterion: MMR deficiency, diagnosed < 50 years, multiple primary tumors (CRC or endometrial cancer), or with a first-degree relative with CRC or endometrial cancer.
RESULTS: Five hundred twenty-five patients (15.9%) had MMR deficiency. Two hundred thirty-four of 3,310 (7.1%; 16% of the 1,462 who received MGPT) had 248 PGVs in cancer susceptibility genes. One hundred forty-two (4.3%) had a PGV in an MMR gene, and 101 (3.1%) had a PGV in a non-MMR gene. Ten with Lynch syndrome (LS) also had a non-MMR PGV and were included in both groups. Two (0.06%) had constitutional MLH1 hypermethylation. Of unexplained MMR-deficient patients, 88.4% (76 of 86) had double somatic MMR mutations. Testing for only MMR genes in MMR-deficient patients would have missed 18 non-MMR gene PGVs (7.3% of total PGVs identified). Had UTS been the only method used to screen for hereditary cancer syndromes, 38.6% (91 of 236) would have been missed, including 6.3% (9 of 144) of those with LS. These results have treatment implications as 5.3% (175 of 3,310) had PGVs in genes with therapeutic targets.
CONCLUSION: UTS alone is insufficient for identifying a large proportion of CRC patients with hereditary syndromes, including some with LS. At a minimum, 7.1% of individuals with CRC have a PGV and pan-cancer MGPT should be considered for all patients with CRC.

DOI: https://doi.org/10.1200/PO.20.00525
J Cancer Res Ther. 2021 Jul;17(3): 790-796

A practical screening strategy for Lynch syndrome and Lynch syndrome mimics in colorectal cancer.

Zhi-Gang Yao, Bei-Bei Lv, Hai-Yan Jing, Wen-Jing Su, Jia-Mei Li, Hui Fan, Miao-Qing Zhao, Ye-Jun Qin, Xi-Chao Sun.

   Objectives: The objective of the study is to provide an efficient and practical screening strategy to distinguish a broader spectrum of Lynch syndrome (LS) and LS mimics-associated colorectal cancer (CRC), including Lynch-like syndrome (LLS), constitutional mismatch repair-deficiency, familial CRC type X (FCCTX), and polymerase proofreading-associated polyposis syndrome.
Materials and Methods: 1294 cases of CRC samples were detected mismatch repair (MMR) status using immunohistochemistry (IHC) staining, in which the cases with MLH1-deficient CRC underwent BRAF mutation analysis by IHC. Following the personal and/or family history survey, next-generation sequencing (NGS) was used to detect gene variants.
Results: 1294 CRC patients were dichotomized into tumors caused by a deficient MMR (dMMR) system and a proficient MMR (pMMR) system after MMR status analysis. 45 patients with suspected sporadic dMMR CRC were then separated from MLH1-deficient CRC though BRAF mutation status analysis by IHC. Following the personal and/or family history survey for 1294 patients, as well as germline genetic testing by NGS, 34 patients were diagnosed as LS (8 cases), SLS (13 cases), LLS ( 6 cases), FCCTX (3 cases), and sporadic CRC (4 cases).
Conclusions: Our screening strategy, which consists of clinical and molecular analyses, is expected to improve the screening efficiency and management for the LS and LS mimics.

Keywords:  DNA mismatch repair; Lynch syndrome; Lynch-like syndrome; familial colorectal cancer; hereditary nonpolyposis colorectal cancer

DOI:  https://doi.org/10.4103/jcrt.jcrt_214_21
J Med Genet. 2021 Jul 15. pii: jmedgenet-2021-107742. [Epub ahead of print]

Results from London Regional Clinical Genetics services over a 5-year period on germline TP53 testing in women diagnosed with breast cancer at <30 years.

Alice Garrett, Sabrina Talukdar, Louise Izatt, Angela F Brady, Sinead Whyte, Katherine S Josephs, Monisha Shanmugasundaram, Li Shan Guillemot, Dara Vakili, Shevaun Ey, Munaza Ahmed.

   BACKGROUND: The most common cancer diagnosed in germline TP53 pathogenic variant (PV) carriers is premenopausal breast cancer. An increased rate of breast tumour HER2 positivity has been reported in this group. Screening for breast/other cancers is recommended in PV carriers.
OBJECTIVES: 1. To assess the frequency of germline TP53 PVs reported diagnostically in women with breast cancer at <30 years of age.2. To evaluate the impact of personal/family history and HER2 status on the likelihood of germline TP53 pathogenic/likely pathogenic variant (PV/LPV) identification.
METHODS: Genetic test results from patients undergoing diagnostic germline TP53 tests between 2012 and 2017 in the four London Regional Clinical Genetics Services were reviewed. Clinical/pathology data and family history were extracted from genetics files for women diagnosed with breast cancer at <30 years.
RESULTS: The overall germline TP53 PV/LPV variant detection rate was 9/270=3.3% in all women diagnosed with breast cancer at <30 years and 2/171=1.2% in those with no second/subsequent cancer diagnosis or family history of TP53-spectrum cancers. Breast cancers were significantly more likely to be HER2-positive in TP53 PV/LPV carriers than in non-carriers (p=0.00006).
CONCLUSIONS: Germline TP53 PVs/LPVs are uncommon among women diagnosed with breast cancer aged <30 years without other relevant personal or family cancer history but have an important clinical impact when identified.

Keywords:  genetic testing; genetics; germ-line mutation; medical; sequence analysis

DOI:  https://doi.org/10.1136/jmedgenet-2021-107742
JCO Precis Oncol. 2021 ;pii: PO.20.00199. [Epub ahead of print]5

Implications of Multigene Panel Testing on Psychosocial Outcomes: A Comparison of Patients With Pancreatic and Breast or Ovarian Cancer.

Cathryn Koptiuch, Whitney F Espinel, Wendy K Kohlmann, Jingsong Zhao, Kimberly A Kaphingst.

PURPOSE: National Comprehensive Cancer Network guidelines for germline genetic testing have included pancreatic cancer in the context of additional family cancer history for many years but this was not recommended for patients with pancreatic ductal adenocarcinoma (PDAC) independent of a family history until 2019. This hypothesis-generating study reports the results from multigene panel testing for PDAC patients at an academic medical center.
PATIENTS AND METHODS: This prospective longitudinal feasibility study examined responses to genetic counseling and multigene panel testing among PDAC and breast or ovarian cancer (BrOv) patients between October 2016 and November 2017. Pre- and post-test surveys assessed perceptions of genetic risk and testing, recall, comprehension, and emotional reactions to results using open-ended and closed-ended items.
RESULTS: Forty-six BrOv and 33 PDAC patients were enrolled, and 44 BrOv and 31 PDAC participants underwent genetic testing. Seven pathogenic variants were identified in six BrOv participants (13.6%), and three pathogenic variants were identified in three PDAC participants (9.7%). The majority of both cohorts expressed similar attitudes about the importance of genetic testing for their personal and family medical management and expressed accurate understanding of implications of their results. Although sample size was small, there were no significant differences between the BrOv and PDAC cohorts for positive or negative emotions.
CONCLUSION: This study points to high rates of positive emotions and low rates of negative emotions following genetic test results, suggesting that the emotional reactions to genetic test results are similar for patients with BrOv and PDAC, despite poor prognosis with PDAC diagnoses. Because of the unique needs of the PDAC population following diagnosis, a multidisciplinary approach to germline genetic testing following diagnosis may result in best patient and family member outcomes.

DOI: https://doi.org/10.1200/PO.20.00199
J Coll Physicians Surg Pak. 2021 Jul;30(7): 837-840

Targeted Next-generation Sequencing for Reliable Detection of Genetic Status in Breast Cancer.

Hassan Tariq, Asma Gul, Muhammad Zubair, Syed Raza Jaffer, Nadeem Zafar, Ghazala Sadaf.

OBJECTIVE: To test the germline oncogenic mutations in BRCA1 and BRCA2 genes, associated with triple-negative breast cancer (TNBC) patients under study, by targeted sequencing of their DNA with next-generation sequencing (NGS) platform.
STUDY DESIGN: Cross-sectional observational study.
PLACE AND DURATION OF STUDY: Histopathology Department, Armed Forces Institute of Pathology (AFIP) Rawalpindi, Pakistan from May to June 2020.
METHODOLOGY: Peripheral blood of 14 women (aged ≤60) with triple negative breast carcinoma (TNBC) was taken with the consent of performing germline genetic testing. Targeted NGS was performed for all coding regions and splicing sites of BRCA1 and BRCA2 genes, using AmpliSeq for Illumina BRCA Panel and Illumina MiSeq sequencer (placed at AFIP). Analysis and interpretation of the sequencing results have been done by using Illumina bioinformatics tools and external databases.
RESULTS: Two hundred and fifty-four variants were detected in BRCA1 and BRCA2 genes, having variant quality score of 100 in all cases under study. As a result, two pathogenic variants and three variants of uncertain significance were interpreted in this germline pipeline. Cases with pathogenic variants had early onset breast cancer with age less than 35.
CONCLUSION: Germline variants in BRCA were detected in the known cases of TNBC, which will not only identify the most prevalent mutations in this region; but will also make them a candidate to receive targeted therapies, which was previously not possible without genetic testing. Moreover, this study further validates the importance of early BRCA genetic screening in young patients, who have positive family history of breast carcinoma. Key Words: Breast cancer, Triple negative, Next-generation sequencing, BRCA1, BRCA2.

DOI: https://doi.org/10.29271/jcpsp.2021.07.837
JCO Precis Oncol. 2021 ;pii: PO.20.00334. [Epub ahead of print]5

Tolerability of Breast Radiotherapy Among Carriers of ATM Germline Variants.

Leslie A Modlin, Jessica Flynn, Zhigang Zhang, Oren Cahlon, Boris Mueller, Atif J Khan, Erin F Gillespie, Beryl McCormick, Zsofia K Stadler, Mark E Robson, Simon N Powell, Lior Z Braunstein.

ATM, a gene that controls repair of DNA double-strand breaks, confers an excess lifetime risk of breast cancer among carriers of germline pathogenic variants (PV). ATM PV homozygotes are particularly sensitive to DNA damage caused by ionizing radiation. Consequently, there is concern that adjuvant radiotherapy (RT) may cause excess morbidity among heterozygous carriers of ATM PV. We evaluated the tolerability of breast RT among carriers of ATM germline variants.
METHODS: Of 167 patients with ATM germline variants presenting to our institution with breast cancer, 91 received RT. Treatment-related toxicity was ascertained from medical records and graded across organ systems. Toxicities grade > 2 were recorded from the end of treatment to last evaluable follow-up and were analyzed according to ATM variant pathogenicity.
RESULTS: Of 91 evaluable carriers of ATM variants, with a median follow-up of 32 months following RT, 25% (n = 23) harbored a PV, whereas 75% (n = 68) harbored a variant of uncertain significance (VUS). Prevalence of grade ≥ 2 toxicity unrelated to post-mastectomy reconstruction among patients with ATM PV was: 32% at the end of treatment (v 34% for VUS carriers), 11% at 1 year of follow-up (v 4% for VUS carriers), and 8% at the last follow-up (v 13% for VUS carriers), consistent with previous studies of RT among unselected populations. No grade 4 or 5 toxicities were observed. ATM variant pathogenicity was not associated with local toxicity, contralateral breast cancer, or secondary malignancy in this limited cohort of patients who received breast RT.
CONCLUSION: We found no evidence of excess RT-associated toxicity among carriers of pathogenic ATM germline variants. Breast-conserving therapy and adjuvant RT may be safely considered among appropriately selected carriers of ATM germline variants.

DOI: https://doi.org/10.1200/PO.20.00334
Acta Neuropathol. 2021 Jul 15.

Malignant gliomas with H3F3A G34R mutation or MYCN amplification in pediatric patients with Li Fraumeni syndrome.

Melanie Schoof, Uwe Kordes, Alexander E Volk, Sina Al-Kershi, Catena Kresbach, Ulrich Schüller.

DOI: https://doi.org/10.1007/s00401-021-02346-8
Br J Cancer. 2021 Jul 14.

BRCA-mutant pancreatic ductal adenocarcinoma.

Eleonora Lai, Pina Ziranu, Dario Spanu, Marco Dubois, Andrea Pretta, Simona Tolu, Silvia Camera, Nicole Liscia, Stefano Mariani, Mara Persano, Marco Migliari, Clelia Donisi, Laura Demurtas, Valeria Pusceddu, Marco Puzzoni, Mario Scartozzi.

Despite continued research, pancreatic ductal adenocarcinoma (PDAC) remains one of the main causes of cancer death. Interest is growing in the role of the tumour suppressors breast cancer 1 (BRCA1) and BRCA2-typically associated with breast and ovarian cancer-in the pathogenesis of PDAC. Indeed, both germline and sporadic mutations in BRCA1/2 have been found to play a role in the development of PDAC. However, data regarding BRCA1/2-mutant PDAC are lacking. In this review, we aim to outline the specific landscape of BRCA-mutant PDAC, focusing on heritability, clinical features, differences between BRCA1 and 2 mutations and between germline and sporadic alterations, as well as established therapeutic strategies and those that are still under evaluation.

DOI: https://doi.org/10.1038/s41416-021-01469-9
Clin Lung Cancer. 2021 Jun 12. pii: S1525-7304(21)00147-9. [Epub ahead of print]

The Common Thread: A Case of Synchronous Lung Cancers and a Germline CHEK2 Mutation.

Edward T Carey, Virginia Ferreira, Elaine Shum, Fang Zhou, Joshua K Sabari.

  Patients with one form of cancer are at increased risk for another, and this is true for lung cancer, where synchronous primary lung cancers are an increasing multifaceted challenge.1,2 Here, we present the case of a middle age woman who was found to have bilateral lung masses. Biopsy and subsequent testing revealed unique synchronous lung adenocarcinomas, each with unique genetic signatures. Despite having two unique tumors, she was found to have CHEK2 mutations in both tumors and in germline testing. Because of this extensive testing that showed unique tumors, she was ultimately diagnosed with stage IIIb and IA2 lung cancers, and this changed her treatment options. Consideration of unique primary tumors leads to thorough diagnostics, which changed this patient's diagnosis, prognosis, and treatment. We hope this case raises awareness for multiple primary tumors, as well as CHEK2 as an important oncogene.

Keywords:  ChEK2 mutations; Germline mutations; KRAS; Lung adenocarcinoma; Multiple primary tumors

DOI:  https://doi.org/10.1016/j.cllc.2021.05.011
Genet Med. 2021 Jul 14.

Germline ATM variants predispose to melanoma: a joint analysis across the GenoMEL and MelaNostrum consortia.

GenoMEL

PURPOSE: Ataxia-Telangiectasia Mutated (ATM) has been implicated in the risk of several cancers, but establishing a causal relationship is often challenging. Although ATM single-nucleotide polymorphisms have been linked to melanoma, few functional alleles have been identified. Therefore, ATM impact on melanoma predisposition is unclear.
METHODS: From 22 American, Australian, and European sites, we collected 2,104 familial, multiple primary (MPM), and sporadic melanoma cases who underwent ATM genotyping via panel, exome, or genome sequencing, and compared the allele frequency (AF) of selected ATM variants classified as loss-of-function (LOF) and variants of uncertain significance (VUS) between this cohort and the gnomAD non-Finnish European (NFE) data set.
RESULTS: LOF variants were more represented in our study cohort than in gnomAD NFE, both in all (AF = 0.005 and 0.002, OR = 2.6, 95% CI = 1.56-4.11, p < 0.01), and familial + MPM cases (AF = 0.0054 and 0.002, OR = 2.97, p < 0.01). Similarly, VUS were enriched in all (AF = 0.046 and 0.033, OR = 1.41, 95% CI = 1.6-5.09, p < 0.01) and familial + MPM cases (AF = 0.053 and 0.033, OR = 1.63, p < 0.01). In a case-control comparison of two centers that provided 1,446 controls, LOF and VUS were enriched in familial + MPM cases (p = 0.027, p = 0.018).
CONCLUSION: This study, describing the largest multicenter melanoma cohort investigated for ATM germline variants, supports the role of ATM as a melanoma predisposition gene, with LOF variants suggesting a moderate-risk.

DOI: https://doi.org/10.1038/s41436-021-01240-8
Am J Cancer Res. 2021 ;11(6): 3271-3284

Inhibition of P53-mediated cell cycle control as the determinant in dedifferentiated liposarcomas development.

Mossane Stocker, Louis-Romée Le Nail, Hubert De Belenet, Jay S Wunder, Irene L Andrulis, Nalan Gokgoz, Nicolas Levy, Jean-Camille Mattei, Sylviane Olschwang.

Liposarcomas are a heterogeneous group of sarcomas, including well-differentiated and dedifferentiated liposarcoma, myxoid/round cell liposarcoma, and pleomorphic liposarcoma. Complete surgical resection is the key of treatment. Radiotherapy, based on the tumor grade and the vicinity of critical structures with the tumor, can be used to prevent local recurrence. The group of dedifferentiated liposarcomas (DDLS) is poorly sensitive to adjuvant chemotherapy. Improved understanding of the genetic aberrations that lead to liposarcoma initiation is necessary for the development of targeted therapies to improve tumor control and survival. DDLS share genetic abnormalities with other groups, exhibiting high-level amplifications of chromosome 12, including the MDM2 and CDK4 genes, and harbor additional amplifications of chromosomes 6 and 1. Novel therapies targeted at the gene products of chromosome 12 are currently considered in clinical trials. Our work consisted in a genomic characterization of DDLS to draw up a complete picture of alterations, including genomic signatures, tumor mutation burden, gene mutations, copy number variations, translocations, gene fusions and methylation modifications. Analysis of translocations helped to understand the mechanisms underlying the amplification processes. Combination of mutations and loss of heterozygosity or homozygous deletions were detected and led to inactivate tumor suppressor genes (TSG). In contrast, methylation anomalies seemed not linked to any particular genomic profile. All identified anomalies, whether amplifications and/or TSG inactivation, involve genes playing a role in p53 regulation, that appears to be the epicenter of the initiation process in DDLS tumorigenesis, as is also known to be responsible for Li-Fraumeni syndrome, a family cancer syndrome highly predisposing to sarcomas.

Keywords: Dedifferentiated liposarcoma; genetic profile; p53 pathway; targeted therapy