bims-lifras 2022-04-24 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2022‒04‒24
23 papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective.
Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer.
Pancreatic Ductal Carcinoma Risk Associated with Hereditary Cancer-Risk Genes.
Evaluation of a Four-Gene Panel for Hereditary Cancer Risk Assessment.
Germline testing and genetic counselling in prostate cancer.
Identification of a Cancer-Predisposing Germline POT1 p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma.
Principles of molecular testing for hereditary cancer.
Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.
Hereditary Diffuse Gastric Cancer-Update Based on the Current Consort Recommendations.
Identifying patients with Lynch syndrome using a universal tumor screening program in an integrated healthcare system.
Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.
Genetic Testing for All: Overcoming Disparities in Ovarian Cancer Genetic Testing.
MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma.
Ipilimumab/Nivolumab Therapy in Patients With Metastatic Pancreatic or Biliary Cancer With Homologous Recombination Deficiency Pathogenic Germline Variants.
Study protocol for a multi-institutional prospective surveillance study among kindreds with familial pancreatic cancer and individuals with hereditary pancreatic cancer syndrome: The Diamond Study.
Prenatal genetic counseling practices regarding recommendations for cancer genetic counseling: A retrospective chart review from two academic institutions.
A Phenome-Wide Association Study and the Discovery of a New Clinical Spectrum of Hereditary Cancer Genes.
SMARCB1-deficient and SMARCA4-deficient Malignant Brain Tumors With Complex Copy Number Alterations andTP53Mutations May Represent the First Clinical Manifestation of Li-Fraumeni Syndrome.
Lynch syndrome: An unusal case of familial cancer unearthed.
Radiotherapy and radiosensitivity syndromes in DNA repair gene mutations.
Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study.
Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases.
Identification and Somatic Characterization of the Germline PTEN Promoter Variant rs34149102 in a Family with Gastrointestinal and Breast Tumors.

Mol Genet Genomics. 2022 Apr 22.

Identification of hereditary breast and ovarian cancer germline variants in Granada (Spain): NGS perspective.

María Molina-Zayas, Carmen Garrido-Navas, Jose Luis García-Puche, Julian Barwell, Susana Pedrinaci, Margarita Martínez Atienza, Susana García-Linares, Tomás de Haro-Muñoz, Jose Antonio Lorente, M Jose Serrano, Antonio Poyatos-Andújar.

  The aim of this study was to assess the prevalence of germline variants in cancer-predisposing genes by either targeted (BRCA1/2) or multigene NGS panel in a high-risk Hereditary Breast and Ovarian Cancer (HBOC) cohort. Samples from 824 Caucasian probands were retrospectively collected and the impact of genetic diagnosis and genetic variants epidemiology in this cohort was evaluated. Performance of risk-reducing prophylactic measures, such as prophylactic mastectomy and/or prophylactic oophorectomy, was assessed through clinical follow-up of patients with a positive genetic result. Pathogenic variants predisposing to HBOC were identified in 11.9% (98/824) individuals at BRCA2 (47/98), BRCA1 (24/98), PALB2 (8/51), ATM (7/51), CHEK2 (6/51) MSH6, (2/51), RAD51C (2/51) and TP53 (2/386). Of them, 11 novel pathogenic variants and 12 VUS were identified, characterized, and submitted to ClinVar. Regarding clinical impact, the risk of developing basal or Her2 breast cancer was increased 15.7 times or 37.5 times for BRCA1 and MSH6 pathogenic variants respectively. On the contrary, the risk of developing basal or luminal A breast cancer was reduced to 81% or 77% for BRCA2 and BRCA1 pathogenic variants, respectively. Finally, 53.2% of individuals testing positive for class IV/V variants underwent prophylactic surgery (mastectomy, oophorectomy or both) being significantly younger at the cancer diagnosis than those undertaking prophylactic measures (p = 0.008). Of them, 8 carried a pathogenic/likely pathogenic variant in other genes different from BRCA1 and BRCA2, and the remaining (46.7%) decided to continue with clinical follow-up. No differences in pathogenicity or risk of developing cancer were found for BRCA1/2 between targeted and multigene sequencing strategies; however, NGS was able to resolve a greater proportion of high-risk patients.

Keywords:  BRCA1; BRCA2; Hereditary breast and ovarian cancer (HBOC); Multigene panel; NGS

DOI:  https://doi.org/10.1007/s00438-022-01891-5
Salud Publica Mex. 2022 Feb 25. 64(1): 41-48

Germline pathogenic variants in Mexican patients with hereditary triple-negative breast cancer.

Yanin Chavarri-Guerra, Cynthia Villarreal-Garza, Ana S Ferrigno, Alejandro Mohar, Dione Aguilar, Rosa M Alvarez-Gomez, Lenny Gallardo-Alvarado, Azucena Del Toro-Valero, Gregorio Quintero-Beulo, Francisco Gutierrez-Delgado, José Luis Rodriguez-Olivares, Maria Fernanda Ochoa-Chavez, Gubidxa Gutierrez-Seymour, Danielle Castillo, Josef Herzog, Jeffrey N Weitzel.

OBJECTIVE: Describe the prevalence of breast cancer (BC)- associated germline pathogenic variants (PVs) among Mexican patients with triple-negative BC (TNBC).MATERIALS AND METHODS: The spectrum of PVs identified among patients with TNBC who were enrolled in a prospective registry and underwent genetic testing was analyzed.
RESULTS: Of 387 patients with invasive TNBC and a median age at diagnosis of 39 years (range 21-72), 113 (29%) were carriers of PVs in BC-susceptibility genes: BRCA1 (79%), BRCA2 (15%), and other (6%: ATM, BRIP1, PALB2, PTEN, RAD51C, and TP53). PV carriers were younger at BC diagnosis (37 vs. 40 years, p=0.004) than non-carriers.
CONCLUSION: A large proportion of TNBC in Mexican patients is associated with germline PVs, the vast majority in BRCA. The incremental yield of PVs in other BC-susceptibility genes was modest, and a stepwise approach starting with BRCA testing may be justified if it is more cost-effective than multigene panel testing.

DOI: https://doi.org/10.21149/12704
J Natl Cancer Inst. 2022 Apr 21. pii: djac069. [Epub ahead of print]

Pancreatic Ductal Carcinoma Risk Associated with Hereditary Cancer-Risk Genes.

Anna Gardiner, John Kidd, Maria C Elias, Kayla Young, Brent Mabey, Nassim Taherian, Shelly Cummings, Mokenge Malafa, Eric Rosenthal, Jennifer B Permuth.

BACKGROUND: Although several hereditary cancer predisposition genes have been implicated in pancreatic ductal adenocarcinoma (PDAC) susceptibility, gene-specific risks are not well defined, and are potentially biased due to the design of previous studies. More precise and unbiased risk estimates can result in screening and prevention better tailored to genetic findings.METHODS: This is a retrospective analysis of 676,667 individuals, 2,445 of whom had a personal diagnosis of PDAC, who received multigene panel testing between 2013-2020 from a single laboratory. Clinical data were obtained from test requisition forms. Multivariable logistic regression models determined the increased risk of PDAC due to pathogenic variants (PVs) in various genes as adjusted odds ratios (ORs) with 95% confidence intervals (CIs). Multivariable odds ratios were adjusted for age, personal/family cancer history, and ancestry.
RESULTS: Overall, 11.1% of patients with PDAC had a PV. Significantly elevated PDAC risk (two-sided P < .05) was observed for CDK2NA (p16INK4a) (OR 8.69, 95% CI 4.69-16.12), ATM (OR 3.44, 95% CI 2.58-4.60), MSH2 (OR 3.17, 95% CI 1.70-5.91), PALB2 (OR 3.09, 95% CI 2.02-4.74), BRCA2 (OR 2.55, 95% CI 1.99-3.27), and BRCA1 (OR 1.62, 95% CI 1.07-2.43).
CONCLUSIONS: This study provides PDAC risk estimates for 6 genes commonly included in multigene panel testing for hereditary cancer risk. These estimates are lower than those from previous studies, possibly due to adjustment for family history, and support current recommendations for germline testing in all PDAC patients, regardless of a personal or family history of cancer.

DOI: https://doi.org/10.1093/jnci/djac069
Genes (Basel). 2022 Apr 13. pii: 682. [Epub ahead of print]13(4):

Evaluation of a Four-Gene Panel for Hereditary Cancer Risk Assessment.

Angela Secondino, Flavio Starnone, Iolanda Veneruso, Maria Antonietta Di Tella, Serena Conato, Carmine De Angelis, Sabino De Placido, Valeria D'Argenio.

  BRCA1/2 are tumor suppressor genes involved in DNA double-strand break repair. They are the most penetrant genes for hereditary breast and ovarian cancers, but pathogenic variants in these two genes can be identified only in a fraction of hereditary cases. Following the diffusion of BRCA molecular testing and the availability of specific therapeutic strategies for the management of pathogenic variant carriers, the demand for the analysis of additional predisposing genetic factors has increased. Indeed, there is accumulating evidence regarding the role of other genes, including CHEK2 and PALB2. Both of them are involved in the same molecular pathway as BRCA genes, with CHEK2 being responsible for cell cycle stopping to allow the repair of DNA double-strand breaks and PALB2 being able to interact with BRCA1 and activate BRCA2. Thus, their role as additional hereditary cancer predisposing factors is intriguing. Accordingly, guidelines for hereditary cancer risk assessment have been updated to include the criteria for additional genes testing. In this context, we validated a commercially available kit allowing for the simultaneous analysis of BRCA1, BRCA2, CHEK2 and PALB2. Forty-eight patients, already tested for BRCA mutational status, were re-analyzed in the present study. Results comparison showed that the tested method was able to correctly identify all the variants previously detected in the same patients. In particular, all single-nucleotide variants and small indels were correctly identified. Moreover, two copy number variants, included to assess the software's performance in detecting this kind of gene alteration, were also detected. Even if copy number variant estimation still requires confirmation by a molecular technique to avoid false positive results, it is able to reduce the number of patients requiring multiplex ligation probe amplification analysis, positively impacting the test's turnaround time. Finally, since the time and costs of the analysis are similar to those required just for BRCA genes, this strategy may be affordable for providing a more comprehensive test for hereditary cancer risk assessment.

Keywords:  BRCA1; BRCA2; CHEK2; PALB2; breast cancer; hereditary cancers; multigene panel testing; next generation sequencing; ovarian cancer

DOI:  https://doi.org/10.3390/genes13040682
Nat Rev Urol. 2022 Apr 21.

Germline testing and genetic counselling in prostate cancer.

Jessica Russo, Veda N Giri.

Genetic testing for prostate cancer is rapidly growing and is increasingly being driven by precision medicine. Rates of germline pathogenic variants have been reported in up to 15% of men with prostate cancer, particularly in metastatic disease, and results of genetic testing could uncover options for precision therapy along with a spectrum of hereditary cancer-predisposition syndromes with unique clinical features that have complex management options. Thus, the pre-test discussion, whether delivered by genetic counsellors or by health-care professionals in hybrid models, involves information on hereditary cancer risk, extent of gene testing, purpose of testing, medical history and family history, potential types of results, additional cancer risks that might be uncovered, genetically based management and effect on families. Understanding precision medicine, personalized cancer risk management and syndrome-related cancer risk management is important in order to develop collaborative strategies with genetic counselling for optimal care of patients and their families.

DOI: https://doi.org/10.1038/s41585-022-00580-7
Genes (Basel). 2022 Mar 26. pii: 591. [Epub ahead of print]13(4):

Identification of a Cancer-Predisposing Germline POT1 p.Ile49Metfs*7 Variant by Targeted Sequencing of a Splenic Marginal Zone Lymphoma.

Audrey N Jajosky, Anna L Mitchell, Mahmut Akgul, Shashirekha Shetty, Jennifer M Yoest, Stanton L Gerson, Navid Sadri, Kwadwo A Oduro.

  Germline disruptive variants in Protection of Telomeres 1 (POT1) predispose to a wide variety of cancers, including melanoma, chronic lymphocytic leukemia (CLL), Hodgkin lymphoma, myeloproliferative neoplasms, and glioma. We report the first case of splenic marginal zone lymphoma (SMZL) arising in a patient with a germline POT1 variant: a 65-year-old male with an extensive history of cancer, including melanoma and papillary thyroid carcinoma, who presented with circulating atypical lymphocytosis. Bone marrow biopsy revealed 20% involvement by a CD5-CD10- B-cell lymphoma that was difficult to classify. During the clinical workup of his low-grade lymphoma, targeted next-generation sequencing (NGS) identified POT1 p.I49Mfs*7 (NM_015450:c. 147delT) at a variant allele frequency (VAF) of 51%. NGS of skin fibroblasts confirmed the POT1 variant was germline. This likely pathogenic POT1 loss-of-function variant has only been reported once before as a germline variant in a patient with glioma and likely represents one of the most deleterious germline POT1 variants ever linked to familial cancer. The spectrum of cancers associated with germline pathogenic POT1 variants (i.e., autosomal dominant POT1 tumor predisposition syndrome) should potentially be expanded to include SMZL, a disease often associated with the loss of chromosome 7q: the location of the POT1 genetic locus (7q31.33).

Keywords:  cancer genetics; germline POT1 alteration; hereditary cancer predisposition; splenic marginal zone lymphoma

DOI:  https://doi.org/10.3390/genes13040591
Genes Chromosomes Cancer. 2022 Apr 18.

Principles of molecular testing for hereditary cancer.

Chloe Mighton, Jordan Lerner-Ellis.

Molecular testing for hereditary cancers has rapidly advanced over the past two decades. Next-generation sequencing has been widely adopted, which has made molecular testing increasingly accessible, and large gene panels are now routinely used in clinical care. Effectively using molecular testing as a tool for the management of patients with hereditary cancer involves understanding various basic principles. In this article, we provide an overview of general principles for molecular germline testing for hereditary cancer syndromes. We overview hereditary cancer etiology, clinical indications for molecular testing, test methodologies and limitations, interpretation and reporting of test results, the evolving nature of gene-disease relationships and penetrance, and resources related to the clinical management of hereditary cancer syndromes.

DOI: https://doi.org/10.1002/gcc.23048
Hum Mol Genet. 2022 Apr 20. pii: ddac089. [Epub ahead of print]

Frequency of pathogenic germline variants in cancer susceptibility genes in 1336 renal cell carcinoma cases.

Bryndis Yngvadottir, Avgi Andreou, Laia Bassaganyas, Alexey Larionov, Alex J Cornish, Daniel Chubb, Charlie N Saunders, Philip Smith, Huairen Zhang, Yasemin Cole, Genomics England Research Consortium, James Larkin, Lisa Browning, Samra Turajlic, Kevin Litchfield, Richard S Houlston, Eamonn R Maher.

BACKGROUND: Renal cell carcinoma (RCC) occurs in a number of cancer predisposition syndromes but the genetic architecture of susceptibility to RCC is not well defined. We investigated the frequency of pathogenic germline variants in cancer susceptibility genes (CSGs) within a large series of unselected RCC participants.METHODS: Whole genome sequencing data on 1336 RCC participants and 5834 controls recruited to the UK 100000 Genomes Project, a nationwide multicentre study, was analysed to identify rare pathogenic or likely pathogenic (P/LP) short variants (SNVs and INDELs) and structural variants in 121 CSGs.
RESULTS: Among 1336 RCC participants (mean 61.3 years [±12SD], range 13-88 years; 64% male), 85 participants (6.4%; 95% CI [5.1, 7.8]) had one or more P/LP germline variant in a wider range of CSGs than previously recognised. A further 64 intragenic variants in CSGs previously associated with RCC were classified as a variant of uncertain significance (VUS) (24 'hot VUSs') and were considered to be of potential clinical relevance as further evaluation might result in their reclassification. Most patients with pathogenic variants in well-established RCC-CSGs were aged < 50 years. Burden test analysis for filtered variants in CSGs demonstrated a significant excess of CHEK2 variants RCC European participants compared to the healthy European controls (P = 0.0019).
CONCLUSIONS: Approximately 6% of patients with RCC unselected for family history have a germline variant requiring additional follow-up analysis. To improve diagnostic yield we suggest expanding the panel of RCC-CSGs tested to include CHEK2 and all SDHx subunits and raising the eligibility criteria for age-based testing.

DOI: https://doi.org/10.1093/hmg/ddac089
Curr Oncol. 2022 Mar 30. 29(4): 2454-2460

Hereditary Diffuse Gastric Cancer-Update Based on the Current Consort Recommendations.

Christoph Treese, Britta Siegmund, Severin Daum.

  Hereditary diffuse gastric cancer (HDGC) is an autosomal dominant inherited cancer syndrome that has been associated with a mutation of the CDH1, and rarely the CTNNA1 gene, respectively. HDGC is characterized histologically by multifocal growth and signet ring cells in the gastric mucosa and lobular type breast cancer. In cases of a proven pathogenic CDH1 mutation, a prophylactic gastrectomy, or alternatively, an annual surveillance gastroscopy in expert centers is recommended. Additionally, MR imaging of the breast should be performed annually starting from the age of 30, to detect lobular breast cancer. In 2020, the International Gastric Cancer Linkage Consortium (IGCLC) additionally defined new clinical groups with specific recommendations: (1) the group of patients with a proven mutation in the CDH1 gene, but exclusive manifestation as lobular breast cancer, was defined as hereditary lobular breast cancer (HLBC); (2) the group, which clinically fulfills familial HDGC criteria, in the absence of a relevant mutation, was designated as HDGC-like. This update summarizes relevant aspects of hereditary gastric cancer and the current recommendation criteria of the IGCLC published in 2020.

Keywords:  CDH1 mutation; CTNNA1 mutation; familial intestinal gastric cancer; hereditary diffuse gastric cancer; hereditary diffuse gastric cancer-like; hereditary lobular breast cancer; prophylactic gastrectomy; screening endoscopy

DOI:  https://doi.org/10.3390/curroncol29040199
Hered Cancer Clin Pract. 2022 Apr 18. 20(1): 17

Identifying patients with Lynch syndrome using a universal tumor screening program in an integrated healthcare system.

Philip R Crain, Jamilyn M Zepp, Sara Gille, Lindsay Jenkins, Tia L Kauffman, Elizabeth Shuster, Katrina A B Goddard, Benjamin S Wilfond, Jessica Ezzell Hunter.

  INTRODUCTION: Lynch syndrome (LS) is associated with an increased risk of colorectal (CRC) and endometrial (EC) cancers. Universal tumor screening (UTS) of all individuals diagnosed with CRC and EC is recommended to increase identification of LS. Kaiser Permanente Northwest (KPNW) implemented a UTS program for LS among individuals newly diagnosed with CRC in January 2016 and EC in November 2016. UTS at KPNW begins with immunohistochemistry (IHC) of tumor tissue to determine loss of mismatch repair proteins associated with LS (MLH1, MSH2, MSH6, and PMS2)., IHC showing loss of MLH1 is followed by reflex testing (automatic testing) to detect the presence of the BRAF V600E variant (in cases of CRC) and MLH1 promoter hypermethylation to rule out likely sporadic cases.MATERIALS AND METHODS: Individuals newly diagnosed with CRC and EC were identified between the initiation of the respective UTS programs and July 2018. Electronic medical records were reviewed to extract patient data related to UTS, including IHC and reflex testing results, date of referrals to the genetics department, and results of germline genetic testing for LS.
RESULTS: 313 out of 362 individuals diagnosed with CRC and 61 out of 64 individuals diagnosed with EC who were eligible were screened by IHC for LS. Most (47/52 or 90%, including 46/49 CRC and 1/3 EC) individuals that were not screened by IHC only had a biopsy sample available. Fourteen individuals (3.7% overall, including 13/313 CRC and 1/61 EC) received an abnormal result after reflex testing and were referred for genetic counseling. Of these, 10 individuals (71% overall, including 9/13 CRC and 1/1 EC) underwent germline genetic testing for LS. Five individuals diagnosed with CRC were found to have pathogenic variants. in PMS2 (n = 3), MLH1 (n = 1), and MSH6 (n = 1). No pathogenic variants were identified in individuals diagnosed with EC.
CONCLUSIONS: UTS identified individuals at risk for LS. Most individuals who screened positive for LS had follow-up germline genetic testing for LS. The consistent use of biopsy samples is an opportunity to improve UTS.

Keywords:  Colorectal cancer; Genetic screening; Genetic testing; HNPCC; Lynch syndrome; Microsatellite instability

DOI:  https://doi.org/10.1186/s13053-022-00217-1
NPJ Breast Cancer. 2022 Apr 21. 8(1): 52

Clinical relevance of pathogenic germline variants in mismatch repair genes in Chinese breast cancer patients.

Li Hu, Jie Sun, Zhongwu Li, Ziwei Qu, Yan Liu, Qiting Wan, Jiaming Liu, Xinyun Ding, Fan Zang, Juan Zhang, Lu Yao, Ye Xu, Yin Wang, Yuntao Xie.

The prevalence and clinical relevance of pathogenic germline variants in MMR genes have not been investigated in large series of breast cancers. In this study, we screened the germline variants in MMR genes in 8085 consecutive Chinese breast cancer patients, and investigated the MMR/PD-L1 protein expression and tumor mutation burden (TMB) of breast tumors from MMR variant carriers. We found that 15 of 8085 patients (0.19%) carried a pathogenic germline variant in MMR genes. Compared with non-carriers, MMR variant carriers might have worse recurrence-free survival (unadjusted hazard ratios [HR] = 2.70, 95% CI: 1.12-6.49, P = 0.027) and distant recurrence-free survival (unadjusted HR = 3.24, 95% CI: 1.45-7.22, P = 0.004). More importantly, some of the breast cancers from MMR carriers displayed MMR protein loss (5/13), TMB-high (2/10), and PD-L1 positive expression (9/13). This study showed that MMR variant carriers were rare in breast cancer. They might have worse survival and part of them might benefit from immunotherapy.

DOI: https://doi.org/10.1038/s41523-022-00417-x
Am Soc Clin Oncol Educ Book. 2022 Apr;42 1-12

Genetic Testing for All: Overcoming Disparities in Ovarian Cancer Genetic Testing.

Melissa K Frey, Amy Finch, Amita Kulkarni, Mohammad R Akbari, Eloise Chapman-Davis.

Nearly 3% of the population carries genetic variants that lead to conditions that include hereditary breast and ovarian cancer and Lynch syndrome. These pathogenic variants account for approximately 20% of ovarian cancer cases, and those with germline pathogenic variants have an odds ratio between 4 and 40 for developing ovarian cancer compared with noncarriers. Given the high prevalence of genetic variants, multiple organizations, including ASCO, recommend universal genetic counseling and testing for women diagnosed with epithelial ovarian cancer. Unfortunately, most individuals with a hereditary ovarian cancer syndrome are unaware of their underlying mutation, and racial and ethnic minority individuals as well as patients of low socioeconomic status experience disproportionate rates of underrecognition, leading to late and missed diagnoses. In this article, we review the current understanding of disparities in genetic testing for people with ovarian cancer, the role of population-based genetic testing, and innovative strategies to overcome the critical inequities present in current cancer genetic medicine. Underuse and disparities related to accessing recommended genetic services are complex and multifactorial, requiring improvements in processes related to provider identification, genetic counseling and testing referral, and patient uptake/adherence. Through the expansion of remote genetic counseling, offering online strategies for genetic testing, and reaching at-risk relatives through direct relative contact cascade testing and population-based genetic testing, there are a growing number of innovations in the field of genetic medicine, many of which emphasize health equity and offer promising alternatives to the current paradigm of genetic testing.

DOI: https://doi.org/10.1200/EDBK_350292
Clin Cancer Res. 2022 Apr 20. pii: clincanres.4183.2021. [Epub ahead of print]

MAPK pathway genetic alterations are associated with prolonged overall survival in low-grade serous ovarian carcinoma.

Beryl Manning-Geist, Sushmita Gordhandas, Ying L Liu, Qin Zhou, Alexia Iasonos, Arnaud Da Cruz Paula, Diana Mandelker, Kara Long Roche, Oliver Zivanovic, Anna Maio, Yelena Kemel, Dennis S Chi, Roisin E O'Cearbhaill, Carol Aghajanian, Britta Weigelt, M Herman Chui, Rachel N Grisham.

PURPOSE: To characterize the somatic mutational landscape, investigate associations between genetic alterations and clinical outcomes, and determine the prevalence of pathogenic germline mutations in low-grade serous ovarian carcinomas (LGSCs).EXPERIMENTAL DESIGN: Patients with LGSC tumors that underwent panel-based sequencing of up to 505 genes were identified. Data on somatic and germline mutations, copy number alterations, and clinicopathologic features, including age at diagnosis, platinum sensitivity, and overall survival (OS), were collected.
RESULTS: Following central pathology re-review, 119 patients with LGSC were identified for analysis. One hundred ten (92%) had advanced-stage disease (stages III/IV). Somatic KRAS (33%), NRAS (11%), EIF1AX (10%), and BRAF (11%) alterations were the most common; mitogen-activated protein kinase (MAPK) pathway alterations were found in 60% (n=71) of LGSCs. KRAS mutations were significantly associated with age at diagnosis >50 years (p=0.02) and platinum-sensitive disease (p=0.03). On multivariate analysis, MAPK pathway alterations (p=0.02) and platinum sensitivity (p=0.005) were significantly associated with improved OS. Seventy-nine patients (66%) underwent germline genetic testing; 7 pathogenic germline mutations, including 1 bi-allelic MUTYH mutation (c.1187G>A (p.Gly396Asp)) and 6 mono-allelic alterations, were identified. Somatic loss of the wildtype allele (loss of heterozygosity) in the tumor at the locus of the germline mutation was only observed in the bi-allelic MUTYH mutation carrier. There were no germline BRCA1/2 mutations.
CONCLUSIONS: This study showed MAPK pathway alterations in LGSC, including KRAS mutations, are independently associated with platinum sensitivity and prolonged survival. Germline data, which were limited, identified few pathogenic germline mutations in patients with LGSC.

DOI: https://doi.org/10.1158/1078-0432.CCR-21-4183
JAMA Oncol. 2022 Apr 21.

Ipilimumab/Nivolumab Therapy in Patients With Metastatic Pancreatic or Biliary Cancer With Homologous Recombination Deficiency Pathogenic Germline Variants.

Gretel Terrero, Jashodeep Datta, Jessica Dennison, Daniel A Sussman, Ines Lohse, Nipun B Merchant, Peter J Hosein.

DOI: https://doi.org/10.1001/jamaoncol.2022.0611
Pancreatology. 2022 Apr 15. pii: S1424-3903(22)00142-9. [Epub ahead of print]

Study protocol for a multi-institutional prospective surveillance study among kindreds with familial pancreatic cancer and individuals with hereditary pancreatic cancer syndrome: The Diamond Study.

Susumu Hijioka, Chigusa Morizane, Kyoichi Takaori, Takuji Okusaka.

  BACKGROUND: Family history of pancreatic cancer (PC) and some hereditary cancer syndromes are risk factors for PC. Previous studies suggest that conducting surveillance for kindreds at high risk for familial PC may be useful for diagnoses at the stage where resections can still be implemented; however, there is insufficient evidence linking surveillance and increased rates of resectable PC.METHODS: We launched a surveillance study for kindreds with familial PC and individuals with hereditary PC syndrome, titled the "Diamond Study," in June 2020. This Japanese national multi-institutional prospective intervention study has been initiated to conduct evaluations within a prospective clinical trial format.
RESULTS: The primary endpoint is the fraction of patients with resectable PC among patients with PC found through surveillance interventions. Endoscopic ultrasound and magnetic resonance imaging combined with magnetic resonance cholangiopancreatography will be performed alternatively every 6 months for up to 15 years, with 400 as the predicted number of registered participants and a predicted registration period of 10 years.
CONCLUSION: We intend to scientifically prove the usefulness of surveillance for kindreds with familial PC and individuals with hereditary PC syndrome to improve PC prognoses.

Keywords:  Family history; Hereditary cancer syndromes; Pancreatic cancer; Surveillance study

DOI:  https://doi.org/10.1016/j.pan.2022.04.006
J Genet Couns. 2022 Apr 18.

Prenatal genetic counseling practices regarding recommendations for cancer genetic counseling: A retrospective chart review from two academic institutions.

Lisa F Saba, Cathy M Sullivan, Tamara Solomon, Sarah Huguenard, Salma A Nassef.

  Prenatal and preconception genetic counselors are trained to take patient pedigrees to evaluate for potential risks for genetic conditions, including hereditary cancer syndromes. However, little research has been published on how often prenatal/preconception genetic counselors provide recommendations for cancer genetic counseling solely based on a family history of cancer. Therefore, this study sought to (a) characterize the types of cancers recognized for a cancer genetic counseling recommendation, (b) analyze appointment indications associated with discussion documentation, and (c) investigate how often National Comprehensive Cancer Center (NCCN) genetic testing criteria for Hereditary Breast and Ovarian Cancer syndrome (HBOC) and Lynch syndrome were met and how often a recommendation for cancer genetic counseling was made. A retrospective chart review and pedigree analysis were performed for prenatal/preconception genetic counseling patients with a family history of cancer seen at two academic institutions between August 10, 2019, and December 1, 2019. In the 170 charts included, a recommendation for cancer genetic counseling was documented in 40% of all genetic counseling summaries and in 59.2% of summaries when NCCN genetic testing criteria for HBOC and/or Lynch syndrome was met. Using chi-squared and logistic regression analysis, these data support that individuals were significantly more likely to receive a recommendation when NCCN genetic testing criteria were met (OR = 5.01, p < .001) or when the family history contained two or more types of cancer (OR = 2.24, p = .02). Overall, this study identified the NCCN genetic testing criteria for HBOC and Lynch syndrome for which recommendations for cancer genetic counseling were commonly missed. This characterization suggests that continuing education for prenatal and preconception genetic counselors on updated NCCN guidelines may be helpful for improving rates of cancer genetic counseling referrals, uptake of genetic testing, and cancer screening recommendations.

Keywords:  family history; hereditary cancer; pedigree analysis; prenatal genetic counseling; referral practices; risk assessment

DOI:  https://doi.org/10.1002/jgc4.1577
JAMA Oncol. 2022 Apr 21.

A Phenome-Wide Association Study and the Discovery of a New Clinical Spectrum of Hereditary Cancer Genes.

Kailin Yang, Jacob G Scott.

DOI: https://doi.org/10.1001/jamaoncol.2022.0361
Am J Surg Pathol. 2022 Apr 22.

SMARCB1-deficient and SMARCA4-deficient Malignant Brain Tumors With Complex Copy Number Alterations andTP53Mutations May Represent the First Clinical Manifestation of Li-Fraumeni Syndrome.

Martin Hasselblatt, Christian Thomas, Aniello Federico, Karolina Nemes, Pascal D Johann, Brigitte Bison, Susanne Bens, Sonja Dahlum, Uwe Kordes, Antje Redlich, Lienhard Lessel, Kristian W Pajtler, Christian Mawrin, Ulrich Schüller, Kay Nolte, Christof M Kramm, Felix Hinz, Felix Sahm, Caterina Giannini, Judith Penkert, Christian P Kratz, Stefan M Pfister, Reiner Siebert, Werner Paulus, Marcel Kool, Michael C Frühwald.

Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant central nervous system tumor predominantly affecting infants. Mutations ofSMARCB1or (rarely)SMARCA4causing loss of nuclear SMARCB1 or SMARCA4 protein expression are characteristic features, but further recurrent genetic alterations are lacking. Most AT/RTs occur de novo, but secondary AT/RTs arising from other central nervous system tumors have been reported. Malignant gliomas, IDH wild-type, arising in patients with Li-Fraumeni syndrome typically show somatic mutations ofTP53as well as complex copy number alterations, but little is known about the loss of SMARCB1 or SMARCA4 protein expression in this context. Here, we report 2 children in whom malignant supratentorial brain tumors with SMARCB1 deficiency, complex copy number alterations, and somaticTP53mutations lead to the discovery of pathogenic/likely pathogenicTP53variants in the germline. Screening of the molecularneuropathology.org dataset for cases with similar genetic and epigenetic alterations yielded another case with SMARCA4 deficiency in a young adult with Li-Fraumeni syndrome. In conclusion, SMARCB1-deficient or SMARCA4-deficient malignant brain tumors with complex copy number alterations and somaticTP53mutations in children and young adults may represent the first clinical manifestation of Li-Fraumeni syndrome and should prompt genetic counseling and investigation forTP53germline status.

DOI: https://doi.org/10.1097/PAS.0000000000001905
Indian J Pathol Microbiol. 2022 Apr-Jun;65(2):65(2): 465-467

Lynch syndrome: An unusal case of familial cancer unearthed.

Subhra Dhar, Ashraf U Mannan, J Jaya Singh, Sandipan Dhar, Swetalina Pradhan.

  Lynch syndrome or hereditary nonpolyposis colorectal cancer (HNPCC) is a type of inherited cancer syndrome with a genetic predisposition to different types of cancer. There is an increased predisposition to cancers in the endometrium, colon, stomach, ovary, uterus, skin, kidney, and brain in patients of Lynch syndrome. We are reporting a 48-year-old male who presented with a pea-sized growth in his left arm which was found to be sebaceoma on histopathology. On further detailed history, examination, and genetic study, it was proved to be a familial case of Lynch syndrome. The case is being reported to stress the importance of knowledge about clinical manifestation, associated neoplasms, and molecular genetic profile of Lynch syndrome which will enable physicians and pathologists to provide highly targeted surveillance and management for patients with high cancer risk.

Keywords:  Familial cancer; Lynch syndrome; genetic testing; sebaceoma; sebaceous neoplasms

DOI:  https://doi.org/10.4103/IJPM.IJPM_809_19
Klin Onkol. 2022 ;35(2): 119-127

Radiotherapy and radiosensitivity syndromes in DNA repair gene mutations.

R Lohynská, Z Pechačová, E Mazaná, J Čejková, A Nováková-Jirešová, J Hornová, M Langová.

  BACKGROUND: Ionizing radiation DNA damage is the main mechanism of radiotherapy (RT) action and the outcome of treatment and healthy tissue toxicity is influenced by a number of external and internal factors, including mutations in DNA damage recognition and repair. Disorders of DNA repair may result in increased sensitivity to cancer treatment.PURPOSE: The mechanism of DNA repair and an overview of genetic syndromes with mutations in genes involved in DNA repair clarify the accelerated carcinogenesis and increased radiosensitivity in RT cancers. Most radiosensitivity syndromes are autosomal recessively inherited; examples are ataxia teleangiectasia, Nijmegen breakage syndrome, xeroderma pigmentosum, Cockayne syndrome, Bloom syndrome and Werner syndrome.
CONCLUSION: Radiotherapy is contraindicated in most homozygous patients with recessive radiosensitivity syndromes. Asymptomatic heterozygotes may have an increased risk of tumor incidence and a small part of them slightly increased risk of RT intolerance; however, this does not limit RT treatment. The high risk of secondary malignancies after radiotherapy is a contraindication to adjuvant RT in Li-Fraumeni syndrome.

Keywords:  DNA repair; radiosensitivity; radiotherapy

DOI:  https://doi.org/10.48095/ccko2022119
Blood. 2022 Apr 20. pii: blood.2021015328. [Epub ahead of print]

Prognostic impact of DDX41 germline mutations in intensively treated acute myeloid leukemia patients: an ALFA-FILO study.

Nicolas Duployez, Laetitia Largeaud, Matthieu Duchmann, Rathana Kim, Julie Rieunier, Juliette Lambert, Audrey Bidet, Lise Larcher, Jean Lemoine, Francois Delhommeau, Pierre Hirsch, Laurène Fenwarth, Olivier Kosmider, Justine Decroocq, Anne Bouvier, Yannick Le Bris, Marlène Ochmann, Alberto Santagostino, Lionel Adès, Pierre Fenaux, Xavier Thomas, Jean-Baptiste Micol, Claude J Gardin, Raphaël A Itzykson, Jean Soulier, Emmanuelle Clappier, Christian Récher, Claude Preudhomme, Arnaud Pigneux, Hervé Dombret, Eric Delabesse, Marie Sébert.

DDX41 germline mutations (DDX41MutGL) are the most common genetic predisposition to myelodysplastic syndrome and acute myeloid leukemia (AML). Recent reports suggest that DDX41MutGL myeloid malignancies could be considered as a distinct entity, even if their specific presentation and outcome remain to be defined. We described here the clinical and biological features of 191 patients with DDX41MutGL AML. Baseline characteristics and outcome of 86 of them, treated with intensive chemotherapy in 5 prospective ALFA/FILO trials were compared with those of 1604 DDX41 wild-type (DDX41WT) AML patients, representing a prevalence of 5%. DDX41MutGL AML patients were mostly males (75%) in their seventh decade, with low leukocyte count (median, 2x109/L), low bone marrow blast infiltration (median, 33%), normal cytogenetics (75%) and few additional somatic mutations (median, 2). A second somatic DDX41 mutation (DDX41MutSom) was found in 82% of patients and clonal architecture inference suggested that it could be the main driver for AML progression. DDX41MutGL patients displayed higher complete remission (CR) rates (94% vs. 69%, p<0.0001) and longer restricted mean overall survival (OS) censored at hematopoietic stem cell transplantation (HSCT) than ELN-2017 intermediate/adverse (Int/Adv) DDX41WT patients (5-year ΔRMST of 13.6 months, p < 0.001). Relapse rates censored at HSCT were lower at 1 year in DDX41MutGL patients (15% vs. 44%) but later increased to join that of Int/Adv DDX41WT patients at 3 years (82% vs 75%). HSCT in first CR was associated with prolonged relapse-free survival (RFS; HR, 0.43 [95%CI, 0.21-0.88]; p = 0.02) but not with longer OS (HR=0.77 [95%CI, 0.35-1.68], p=0.5).

DOI: https://doi.org/10.1182/blood.2021015328
JAMA Oncol. 2022 Apr 21.

Association of Pathogenic Variants in Hereditary Cancer Genes With Multiple Diseases.

Chenjie Zeng, Lisa A Bastarache, Ran Tao, Eric Venner, Scott Hebbring, Justin D Andujar, Sarah T Bland, David R Crosslin, Siddharth Pratap, Ayorinde Cooley, Jennifer A Pacheco, Kurt D Christensen, Emma Perez, Carrie L Blout Zawatsky, Leora Witkowski, Hana Zouk, Chunhua Weng, Kathleen A Leppig, Patrick M A Sleiman, Hakon Hakonarson, Marc S Williams, Yuan Luo, Gail P Jarvik, Robert C Green, Wendy K Chung, Ali G Gharavi, Niall J Lennon, Heidi L Rehm, Richard A Gibbs, Josh F Peterson, Dan M Roden, Georgia L Wiesner, Joshua C Denny.

Importance: Knowledge about the spectrum of diseases associated with hereditary cancer syndromes may improve disease diagnosis and management for patients and help to identify high-risk individuals.Objective: To identify phenotypes associated with hereditary cancer genes through a phenome-wide association study.
Design, Setting, and Participants: This phenome-wide association study used health data from participants in 3 cohorts. The Electronic Medical Records and Genomics Sequencing (eMERGEseq) data set recruited predominantly healthy individuals from 10 US medical centers from July 16, 2016, through February 18, 2018, with a mean follow-up through electronic health records (EHRs) of 12.7 (7.4) years. The UK Biobank (UKB) cohort recruited participants from March 15, 2006, through August 1, 2010, with a mean (SD) follow-up of 12.4 (1.0) years. The Hereditary Cancer Registry (HCR) recruited patients undergoing clinical genetic testing at Vanderbilt University Medical Center from May 1, 2012, through December 31, 2019, with a mean (SD) follow-up through EHRs of 8.8 (6.5) years.
Exposures: Germline variants in 23 hereditary cancer genes. Pathogenic and likely pathogenic variants for each gene were aggregated for association analyses.
Main Outcomes and Measures: Phenotypes in the eMERGEseq and HCR cohorts were derived from the linked EHRs. Phenotypes in UKB were from multiple sources of health-related data.
Results: A total of 214 020 participants were identified, including 23 544 in eMERGEseq cohort (mean [SD] age, 47.8 [23.7] years; 12 611 women [53.6%]), 187 234 in the UKB cohort (mean [SD] age, 56.7 [8.1] years; 104 055 [55.6%] women), and 3242 in the HCR cohort (mean [SD] age, 52.5 [15.5] years; 2851 [87.9%] women). All 38 established gene-cancer associations were replicated, and 19 new associations were identified. These included the following 7 associations with neoplasms: CHEK2 with leukemia (odds ratio [OR], 3.81 [95% CI, 2.64-5.48]) and plasma cell neoplasms (OR, 3.12 [95% CI, 1.84-5.28]), ATM with gastric cancer (OR, 4.27 [95% CI, 2.35-7.44]) and pancreatic cancer (OR, 4.44 [95% CI, 2.66-7.40]), MUTYH (biallelic) with kidney cancer (OR, 32.28 [95% CI, 6.40-162.73]), MSH6 with bladder cancer (OR, 5.63 [95% CI, 2.75-11.49]), and APC with benign liver/intrahepatic bile duct tumors (OR, 52.01 [95% CI, 14.29-189.29]). The remaining 12 associations with nonneoplastic diseases included BRCA1/2 with ovarian cysts (OR, 3.15 [95% CI, 2.22-4.46] and 3.12 [95% CI, 2.36-4.12], respectively), MEN1 with acute pancreatitis (OR, 33.45 [95% CI, 9.25-121.02]), APC with gastritis and duodenitis (OR, 4.66 [95% CI, 2.61-8.33]), and PTEN with chronic gastritis (OR, 15.68 [95% CI, 6.01-40.92]).
Conclusions and Relevance: The findings of this genetic association study analyzing the EHRs of 3 large cohorts suggest that these new phenotypes associated with hereditary cancer genes may facilitate early detection and better management of cancers. This study highlights the potential benefits of using EHR data in genomic medicine.

DOI: https://doi.org/10.1001/jamaoncol.2022.0373
Genes (Basel). 2022 Apr 05. pii: 644. [Epub ahead of print]13(4):

Identification and Somatic Characterization of the Germline PTEN Promoter Variant rs34149102 in a Family with Gastrointestinal and Breast Tumors.

Vittoria Disciglio, Paola Sanese, Candida Fasano, Claudio Lotesoriere, Anna Maria Valentini, Giovanna Forte, Martina Lepore Signorile, Katia De Marco, Valentina Grossi, Ivan Lolli, Filomena Cariola, Cristiano Simone.

  Genetic variants located in non-coding regions can affect processes that regulate protein expression, functionally contributing to human disease. Germline heterozygous mutations in the non-coding region of the PTEN gene have been previously identified in patients with PTEN hamartoma tumor syndrome (PHTS) diagnosed with breast, thyroid, and/or endometrial cancer. In this study, we report a PTEN promoter variant (rs34149102 A allele) that was identified by direct sequencing in an Italian family with a history of gastroesophageal junction (GEJ) adenocarcinoma and breast cancer. In order to investigate the putative functional role of the rs34149102 A allele variant, we evaluated the status of PTEN alterations at the somatic level. We found that PTEN protein expression was absent in the GEJ adenocarcinoma tissue of the index case. Moreover, we detected the occurrence of copy number loss involving the PTEN rs34149102 major C allele in tumor tissue, revealing that the second allele was somatically inactivated. This variant is located within an active regulatory region of the PTEN core promoter, and in silico analysis suggests that it may affect the binding of the nuclear transcription factor MAZ and hence PTEN expression. Overall, these results reveal the functional role of the PTEN promoter rs34149102 A allele variant in the modulation of PTEN protein expression and highlight its contribution to hereditary cancer risk.

Keywords:  PTEN hamartoma tumor syndrome (PHTS); PTEN promoter; breast cancer; gastroesophageal junction adenocarcinoma

DOI:  https://doi.org/10.3390/genes13040644