bims-lifras Biomed News
on Li-Fraumeni syndrome
Issue of 2022–09–25
fiveteen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet
  1. Germline Testing for the Evaluation of Hereditary Cancer Predisposition.
  2. Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing.
  3. Incidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes.
  4. Pediatric Germline Predisposition to Myeloid Neoplasms.
  5. Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer.
  6. Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients.
  7. Targeted Sequencing of Germline Breast Cancer Susceptibility Genes for Discovering Pathogenic/Likely Pathogenic Variants in the Jakarta Population.
  8. Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer.
  9. Liquid Biopsy Revealed HBOC Pedigree and Led to Medical Management Among the Relatives.
  10. Hereditary Leiomyomatosis and Renal Cell Cancer-Recognizing Patterns May Save Lives.
  11. BAP1 Tumour Predisposition Syndrome Due to Whole BAP1 Gene Deletion.
  12. Multifocal Neuroblastoma and Central Hypoventilation in An Infant with Germline ALK F1174I Mutation.
  13. Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2.
  14. Bilateral Ovarian Sertoli-Leydig Cell Tumors Harboring DICER1 Germline and Distinct Somatic Mutations: Case Report and Literature Review.
  15. Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk.
  1. Clin Lab Med. 2022 Sep;pii: S0272-2712(22)00029-4. [Epub ahead of print]42(3): 497-506
    Germline Testing for the Evaluation of Hereditary Cancer Predisposition.
    Ozge Ceyhan-Birsoy.
      Germline testing for hereditary cancer predisposition has become increasingly important in the management of patients with cancer. Recent studies have demonstrated that hereditary cancer predisposition is more common than previously recognized and germline pathogenic variants may be actionable for patient treatment strategies. This article reviews the significance of hereditary cancer predisposition assessment and highlights the current practices in germline genetic testing approaches.
    Keywords:  Cancer; Genetic testing; Germline testing; Hereditary cancer predisposition
    DOI:  https://doi.org/10.1016/j.cll.2022.04.007
  2. Cancer Genet. 2022 Sep 06. pii: S2210-7762(22)00116-8. [Epub ahead of print]268-269 22-27
    Somatic tumor mutations in moderate risk cancer genes: Targets for germline confirmatory testing.
    Hannah Llorin, Madeline Graf, Nicolette Chun, James Ford.
       BACKGROUND: Recent changes in oncology practice guidelines indicate that mutations in cancer susceptibility genes identified on tumor genomic profiling (TGP) should prompt confirmatory germline testing. Our study aimed to determine the proportion of patients with TGP-identified mutations in moderate risk breast and ovarian cancer genes who previously would not have been considered for germline testing.
    METHODS: From January 2013 to September 2020, 7468 adult Stanford Health Care patients underwent TGP on solid tumor samples and 166 had TGP-identified mutations in moderate risk breast and ovarian cancer susceptibility genes (ATM, BRIP1, CHEK2, PALB2, RAD51C and RAD51D). Retrospective chart reviews were performed on 160 patients. Cases were analyzed to determine eligibility for germline testing using established NCCN criteria, and somatic and germline results were compared where both were available.
    RESULTS: Nearly half (45.3% [73/160]) of patients would not have been eligible for germline testing if not for a TGP-identified mutation in a moderate risk breast or ovarian cancer gene. Of the 64 cases that underwent germline testing, about half (51.5% [33/64]) had results that confirmed germline origin of the TGP finding. High rates of germline confirmation were found in PALB2 (100% [5/5]), ATM (40% [14/35]), CHEK2 (61.5% [8/13]), and BRIP1 (57.1% [4/7]).
    CONCLUSION: Our study shows that the presence of TGP-identified mutations in moderate risk breast and ovarian cancer genes increases eligibility for germline testing beyond those that would be eligible based largely on personal and family history criteria alone. Additionally, results of germline testing in these newly eligible cases supports that this expanded eligibility captures individuals with hereditary cancer syndromes that would not have otherwise been identified.
    Keywords:  Cancer genetics; Cancer genomics; Germline; Somatic
    DOI:  https://doi.org/10.1016/j.cancergen.2022.09.001
  3. Clin Genitourin Cancer. 2022 Aug 29. pii: S1558-7673(22)00177-X. [Epub ahead of print]
    Incidence of Germline Variants in Familial Bladder Cancer and Among Patients With Cancer Predisposition Syndromes.
    Matthew Mossanen, Amin H Nassar, Samantha M Stokes, Nieves Martinez-Chanza, Vivek Kumar, Pier Vitale Nuzzo, David J Kwiatkowski, Judy E Garber, Catherine Curran, Dory Freeman, Mark Preston, Kent W Mouw, Adam Kibel, Toni K Choueiri, Guru Sonpavde, Huma Q Rana.
       BACKGROUND: The familial aggregation of bladder cancers has been observed, but the incidence and association of familial bladder cancer with germline pathogenic and likely pathogenic (P/LP) variants is unknown.
    PATIENTS AND METHODS: A retrospective analysis was conducted of patients with bladder cancer treated at the Dana-Farber Cancer Institute to identify those with a first-degree relative with bladder cancer. A second cohort of patients referred to DFCI for suspicion of a cancer predisposition syndrome was analyzed for candidate P/LP germline variants. Descriptive statistics were generated.
    RESULTS: Among 885 patients with bladder cancer, 38 patients (4.3%) had a family history of bladder cancer in a first-degree relative. No significant association of age of diagnosis was observed between patients with and without a first-degree family history of bladder cancer (P = .3). In the second cohort, 27 of 80 (34%) patients with bladder cancer evaluated for cancer predisposition syndromes harbored a P/LP germline variant. P/LP variants were identified most commonly in the following genes: BRCA1 (n = 5), MSH2 (n = 5), MLH1 (n = 4), ATM (n = 3), and CHEK2 (n = 2). Of the 27 patients with identified germline P/LP variants, 20 (74%) had a family history of a tumor component syndrome in a first- or second-degree relative and 3 were subsequently diagnosed with another genetically-linked associated cancer.
    CONCLUSION: Familial bladder cancer defined as bladder cancer in the proband and a first-degree relative, was present in 4.3% of patients with bladder cancer and was not associated with age of diagnosis. Additionally, among patients suspected to have a familial cancer syndrome, one-third harbored a germline P/LP variant. Further study of germline variants in patients with familial bladder cancer including somatic testing for loss of heterozygosity may provide insights regarding disease pathogenesis and inform therapy.
    Keywords:  Bladder cancer; Clinical genetics; Familial; Germline variants; Urothelial carcinoma
    DOI:  https://doi.org/10.1016/j.clgc.2022.08.009
  4. Curr Hematol Malig Rep. 2022 Sep 19.
    Pediatric Germline Predisposition to Myeloid Neoplasms.
    Christineil Thompson, Sydney Ariagno, Mira A Kohorst.
       PURPOSE OF REVIEW: Advances in the understanding of germline predisposition to pediatric cancers, particularly myeloid neoplasms, have increased rapidly over the last 20 years. Here, we highlight the most up-to-date knowledge regarding known pathogenic germline variants that contribute to the development of myeloid neoplasms in children.
    RECENT FINDINGS: This discussion enumerates the most notable myeloid neoplasm-causing germline mutations. These mutations may be organized based on their molecular underpinnings-transcriptional control, splicing and signal transduction control, and a group of heterogeneous bone marrow failure syndromes. We review recent findings related to the biochemical mechanisms that predispose to malignant transformation in each condition. Key genetic discoveries such as novel mutations, degrees of penetrance, principles of the two-hit hypothesis, and co-occurrence of multiple mutations are shared. Clinical pearls, such as information regarding epidemiology, natural history, or prognosis, are also discussed. Germline mutations predisposing to pediatric myeloid neoplasms are frequent, but underrecognized. They hold major clinical implications regarding prognosis, treatment strategies, and screening for other malignancies. Further research is warranted to better characterize each of these conditions, as well as identify additional novel germline pathogenic variants of interest.
    Keywords:  GATA2; Germline predisposition; Inherited bone marrow failure; Myeloid neoplasms; Pediatric; SMAD9 or SMAD9L
    DOI:  https://doi.org/10.1007/s11899-022-00681-5
  5. Eur Urol. 2022 Sep 14. pii: S0302-2838(22)02619-7. [Epub ahead of print]
    Gene-based Confirmatory Germline Testing Following Tumor-only Sequencing of Prostate Cancer.
    Hong Truong, Kelsey Breen, Subhiksha Nandakumar, Daniel D Sjoberg, Yelena Kemel, Nikita Mehta, Andrew T Lenis, Peter A Reisz, Jessica Carruthers, Nicole Benfante, Vijai Joseph, Aliya Khurram, Anuradha Gopalan, Samson W Fine, Victor E Reuter, Andrew J Vickers, Ozge Birsoy, Ying Liu, Michael Walsh, Alicia Latham, Diana Mandelker, Zsofia K Stadler, Eugene Pietzak, Behfar Ehdaie, Karim A Touijer, Vincent P Laudone, Susan F Slovin, Karen A Autio, Daniel C Danila, Dana E Rathkopf, James A Eastham, Yu Chen, Michael J Morris, Kenneth Offit, David B Solit, Howard I Scher, Wassim Abida, Mark E Robson, Maria I Carlo.
       BACKGROUND: Tumor-only genomic profiling is an important tool in therapeutic management of men with prostate cancer. Since clinically actionable germline variants may be reflected in tumor profiling, it is critical to identify which variants have a higher risk of being germline in origin to better counsel patients and prioritize genetic testing.
    OBJECTIVE: To determine when variants found on tumor-only sequencing of prostate cancers should prompt confirmatory germline testing.
    DESIGN, SETTING, AND PARTICIPANTS: Men with prostate cancer who underwent both tumor and germline sequencing at Memorial Sloan Kettering Cancer Center from January 1, 2015 to January 31, 2020 were evaluated.
    OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Tumor and germline profiles were analyzed for pathogenic and likely pathogenic ("pathogenic") variants in 60 moderate- or high-penetrance genes associated with cancer predisposition. The germline probability (germline/germline + somatic) of a variant was calculated for each gene. Clinical and pathologic factors were analyzed as potential modifiers of germline probability.
    RESULTS AND LIMITATIONS: Of the 1883 patients identified, 1084 (58%) had a somatic or germline pathogenic variant in one of 60 cancer susceptibility genes, and of them, 240 (22%) had at least one germline variant. Overall, the most frequent variants were in TP53, PTEN, APC, BRCA2, RB1, ATM, and CHEK2. Variants in TP53, PTEN, or RB1 were identified in 746 (40%) patients and were exclusively somatic. Variants with the highest germline probabilities were in PALB2 (69%), MITF (62%), HOXB13 (60%), CHEK2 (55%), BRCA1 (55%), and BRCA2 (47%), and the overall germline probability of a variant in any DNA damage repair gene was 40%. Limitations were that most of the men included in the cohort had metastatic disease, and different thresholds for pathogenicity exist for somatic and germline variants.
    CONCLUSIONS: Of patients with pathogenic variants found on prostate tumor sequencing, 22% had clinically actionable germline variants, for which the germline probabilities varied widely by gene. Our results provide an evidenced-based clinical framework to prioritize referral to genetic counseling following tumor-only sequencing.
    PATIENT SUMMARY: Patients with advanced prostate cancer are recommended to have germline genetic testing. Genetic sequencing of a patient's prostate tumor may also identify certain gene variants that are inherited. We found that patients who had variants in certain genes, such as ones that function in DNA damage repair, identified in their prostate tumor sequencing, had a high risk for having an inherited cancer syndrome.
    Keywords:  Advanced prostate cancer; DNA damage repair genes; Germline testing; Tumor-only sequencing
    DOI:  https://doi.org/10.1016/j.eururo.2022.08.028
  6. Cancers (Basel). 2022 Sep 13. pii: 4447. [Epub ahead of print]14(18):
    Clinical Significance of Germline Pathogenic Variants among 51 Cancer Predisposition Genes in an Unselected Cohort of Italian Pancreatic Cancer Patients.
    Alberto Puccini, Marta Ponzano, Bruna Dalmasso, Irene Vanni, Annalice Gandini, Silvia Puglisi, Roberto Borea, Malvina Cremante, William Bruno, Virginia Andreotti, Eleonora Allavena, Valentino Martelli, Fabio Catalano, Massimiliano Grassi, Maria Laura Iaia, Chiara Pirrone, Alessandro Pastorino, Giuseppe Fornarini, Stefania Sciallero, Paola Ghiorzo, Lorenza Pastorino.
      Multigene germline panel testing is recommended for Pancreatic Cancer (PC) patients; however, for non-BRCA1/2 genes, the clinical utility is unclear. A comprehensive multi-gene assessment in unselected Italian PC patients is missing. We evaluated the prevalence and impact of Pathogenic Variants (PV) in 51 PC susceptibility genes in a real-world series of 422 Italian PC patients unselected for Family History (FH), compared the clinical characteristics and conducted survival analyses. 17% of patients had PVs (70/422), mainly in BRCA1/2 (4.5%, all <70 y), CDKN2A (4.5%, all >50 y), ATM (2.1%). PV carriers were younger (64 vs. 67; p = 0.02) and had more frequent personal/FH of PC, melanoma and breast/ovarian cancer (all p < 0.05). The Overall Survival (OS) was longer in patients carrying PVs (HR 0.78; p = 0.090), comprising ATM carriers (HR 0.33; p = 0.054). In the oxaliplatin-treated subset, PV carriers showed better control of the disease, although this was not statistically significant (67% vs. 56%). CDKN2A, BRCA2 and ATM were the most frequently altered genes. ATM PVs were positively associated with OS in 41% of PV carriers, 60% of whom carried CDKN2A,BRCA2 or ATM PVs, had negative FH and would have been missed by traditional referral. Thus, CDKN2A and ATM should be added to BRCA1/2 testing regardless of FH.
    Keywords:  BRCA; CDKN2A; DNA Damage Repair—Homologous Recombination Deficiency (DDR-HRD); genetics; germline; hereditary cancer syndromes; multigene panel testing; overall survival; pancreatic cancer
    DOI:  https://doi.org/10.3390/cancers14184447
  7. Diagnostics (Basel). 2022 Sep 16. pii: 2241. [Epub ahead of print]12(9):
    Targeted Sequencing of Germline Breast Cancer Susceptibility Genes for Discovering Pathogenic/Likely Pathogenic Variants in the Jakarta Population.
    Sonar Soni Panigoro, Rafika Indah Paramita, Kristina Maria Siswiandari, Fadilah Fadilah.
      Germline predisposition plays an important role in breast cancer. Different ethnic populations need respective studies on cancer risks pertinent to germline variants. We aimed to discover the pathogenic and likely pathogenic variants (P/LP-Vs) of germline breast cancer susceptibility genes and to evaluate their correlation with the clinical characteristics in Jakarta populations. The pure DNA was extracted from the blood buffy coat, using reagents from the QIAamp DNA Mini Kit® (Qiagen, Hilden, Germany). The DNA libraries were prepared using the TargetRich™ Hereditary Cancer Panel (Kailos Genetics®, Huntsville, AL, USA). The barcoded DNA libraries were sequenced using the Illumina NextSeq 500 platform. In-house bioinformatics pipelines were used to analyze the gene variants. We identified 35 pathogenic and likely pathogenic (P/LP-Vs) variants (28 frameshift, 5 nonsense, and 2 splice-site variants). The P/LP-Vs group was statistically significantly different in luminal B status (p < 0.05) compared with the non-P/LP-Vs group. The P/LP-Vs found both in BRCA1/2 genes and non-BRCA genes may increase the risk of breast cancer and alter drug responses. The screening of multigene variants is suggested, rather than BRCA testing only. Prior knowledge of the germline variants status is important for optimal breast cancer diagnosis and optimal therapy.
    Keywords:  NGS; breast cancer; germline variants; sequencing; young women
    DOI:  https://doi.org/10.3390/diagnostics12092241
  8. JAMA Netw Open. 2022 Sep 01. 5(9): e2232787
    Clinical Utility of Universal Germline Genetic Testing for Patients With Breast Cancer.
    Pat W Whitworth, Peter D Beitsch, Rakesh Patel, Barry Rosen, Gia Compagnoni, Paul L Baron, Rache Simmons, Eric A Brown, Linsey Gold, Dennis Holmes, Linda Ann Smith, Michael Kinney, Ian Grady, Patricia Clark, Karen Barbosa, Samuel Lyons, Lee Riley, Cynara Coomer, Lisa Curcio, Antonio Ruiz, Sadia Khan, Heather MacDonald, Kevin Hughes, Mary Kay Hardwick, Brandie Heald, Sandra B Munro, Sarah M Nielsen, Edward D Esplin.
       Importance: National Comprehensive Cancer Network guidelines currently recommend germline testing for high-risk genes in selected patients with breast cancer. The clinical utility of recommending testing all patients with breast cancer with multigene panels is currently under consideration.
    Objective: To examine the implications of universal testing of patients with breast cancer with respect to clinical decision-making.
    Design, Setting, and Participants: Patients from a previously reported cohort were assessed as in-criteria or out-of-criteria according to the 2017 guidelines and underwent testing with a multigene germline panel between 2017 to 2018. Patients were women and men aged 18 to 90 years, with a new and/or previous diagnosis of breast cancer who had not undergone either single or multigene testing. Clinicians from 20 community and academic sites documented patient clinical information and changes to clinical recommendations made according to test findings. Association between prevalence of pathogenic or likely pathogenic germline variants and previously unreported clinical features, including scores generated by the BRCAPRO statistical model, was determined. Data were analyzed from April 2020 to May 2022.
    Exposure: New and/or previous diagnosis of breast cancer.
    Main Outcomes and Measures: Disease management recommendations that were changed as a result of genetic testing results are reported.
    Results: Clinicians were asked to assess changes to clinical management as a result of germline genetic testing for 952 patients. Informative clinician-reported recommendations were provided for 939 (467 in-criteria and 472 out-of-criteria) of the patients with breast cancer (936 [99.7%] female; 702 [74.8%] White; mean [SD] age at initial diagnosis, 57.6 [11.5] years). One or more changes were reported for 31 of 37 (83.8%) in-criteria patients and 23 of 34 (67.6%) out-of-criteria patients with a pathogenic or likely pathogenic variant. Recommendations were changed as a result of testing results for 14 of 22 (63.6%) out-of-criteria patients who had a variant in a breast cancer predisposition gene. Clinicians considered testing beneficial for two-thirds of patients with pathogenic or likely pathogenic variants and for one-third of patients with either negative results or variants of uncertain significance. There was no difference in variant rate between patients meeting the BRCAPRO threshold (≥10%) and those who did not (P = .86, Fisher exact test). No changes to clinical recommendations were made for most patients with negative results (345 of 349 patients [98.9%]) or variants of uncertain significance (492 of 509 patients [96.7%]).
    Conclusions and Relevance: In this cohort study, germline genetic testing was used by clinicians to direct treatment for most out-of-criteria patients with breast cancer with pathogenic or likely pathogenic germline variants, including those with moderate-risk variants. Universal germline testing informs clinical decision-making and provides access to targeted treatments and clinical trials for all patients with breast cancer.
    DOI:  https://doi.org/10.1001/jamanetworkopen.2022.32787
  9. Acta Med Okayama. 2022 Aug;76(4): 479-483
    Liquid Biopsy Revealed HBOC Pedigree and Led to Medical Management Among the Relatives.
    Chikako Ogawa, Akira Hirasawa, Reimi Sogawa, Kayoko Hasuoka, Shuta Tomida, Mashu Futagawa, Yusaku Urakawa, Mariko Kochi, Hideki Yamamoto, Keiichiro Nakamura, Hisashi Masuyama.
      A hereditary breast and ovarian cancer (HBOC) pedigree was detected via liquid biopsy, and cancer prevention was initiated for the patient's daughter, after receiving a definitive result from BRCA genetic testing. A 48-yearold woman with ovarian cancer was administered precision medicine, which used cell-free DNA from plasma. The results revealed a pathogenic variant of BRCA1 as a presumed germline pathogenic mutation. We confirmed the germline pathological variant BRCA1 c.81-1G> A and suggested treatment with a PARP inhibitor. One of her three children had the variant, was diagnosed as an unaffected pathogenic variant carrier, and was advised to initiate surveillance.
    Keywords:  BRCA 1; cancer precision medicine; germline findings; hereditary breast and ovarian cancer (HBOC); presumed germline pathogenic variants (PGPV)
    DOI:  https://doi.org/10.18926/AMO/63908
  10. J Kidney Cancer VHL. 2022 ;9(2): 27-31
    Hereditary Leiomyomatosis and Renal Cell Cancer-Recognizing Patterns May Save Lives.
    Tavares Catarina, Maria Sofia Quental, José Ricardo Brandão, Miguel Silva-Ramos.
      In 2001, Finish investigators described a rare familiar syndrome characterized by an inherited susceptibility to cutaneous leiomyomas, uterine leiomyomas, and renal cell carcinoma (RCC). Hereditary leiomyomatosis and renal cell cancer (HLRCC) is now linked to a germline mutation in the fumarate hydratase (FH) gene that encodes a Krebs cycle enzyme, transforming fumarate to malate. The accumulation of fumarate, an oncometabolite, promotes tumorigenesis. We present a case of a 41-year-old female diagnosed with HLRCC after a radical nephrectomy due to renal cell cancer. Genetic analyses confirmed a novel FH mutation. Close follow-up allowed for a precocious diagnosis of a metachronous renal tumor and later a hepatic metastasis. Her family was also counseled and offered genetic testing. As observed in this case, the diagnosis of HLRCC is of paramount importance for patients and their families: there is a 15% cumulative lifetime risk of developing RCC, which frequently occurs in young patients and metastasizes at an early stage. Implementing a regular follow-up with adequate imaging examinations may help save lives.
    Keywords:  HLRCC; fumarate hydratase; hereditary renal cell cancer; renal cell carcinoma
    DOI:  https://doi.org/10.15586/jkcvhl.v9i2.222
  11. Case Rep Genet. 2022 ;2022 5503505
    BAP1 Tumour Predisposition Syndrome Due to Whole BAP1 Gene Deletion.
    Dinusha Pandithan, Sonja Klebe, Grace McKavanagh, Lesley Rawlings, Sui Yu, Jillian Nicholl, Nicola Poplawski.
      BRCA-1-associated protein-1 (BAP1) tumour predisposition syndrome (BAP1-TPDS) is a dominant hereditary cancer syndrome. The full spectrum of associated malignancies is yet to be fully characterised. We detail the phenotypic features of the first reported family with a whole BAP1 gene deletion. This report also adds to the emerging evidence that the rhabdoid subtype of meningioma is a part of the clinical spectrum of this tumour predisposition syndrome.
    DOI:  https://doi.org/10.1155/2022/5503505
  12. Diagnostics (Basel). 2022 Sep 19. pii: 2260. [Epub ahead of print]12(9):
    Multifocal Neuroblastoma and Central Hypoventilation in An Infant with Germline ALK F1174I Mutation.
    Anna Djos, Diana Treis, Susanne Fransson, Lena Gordon Murkes, Sandra Wessman, Jurate Ásmundsson, Agneta Markström, Per Kogner, Tommy Martinsson.
      A preterm infant with central hypoventilation was diagnosed with multifocal neuroblastoma. Congenital anomalies of the autonomic nervous system in association with neuroblastoma are commonly associated with germline mutations in PHOX2B. Further, the ALK gene is frequently mutated in both familial and sporadic neuroblastoma. Sanger sequencing of ALK and PHOX2B, SNP microarray of three tumor samples and whole genome sequencing of tumor and blood were performed. Genetic testing revealed a germline ALK F1174I mutation that was present in all tumor samples as well as in normal tissue samples from the patient. Neither of the patient's parents presented the ALK variant. Array profiling of the three tumor samples showed that two of them had only numerical aberrations, whereas one sample displayed segmental alterations, including a gain at chromosome 2p, resulting in two copies of the ALK-mutated allele. Whole genome sequencing confirmed the presence of the ALK variant and did not detect any aberrations in the coding or promotor region of PHOX2B. This study is to our knowledge the first to report a de novoALK F1174I germline mutation. This may not only predispose to congenital multifocal neuroblastoma but may also contribute to the respiratory dysfunction seen in this patient.
    Keywords:  ALK; PHOX2B; neuroblastoma; neurocristopathies
    DOI:  https://doi.org/10.3390/diagnostics12092260
  13. JAMA Oncol. 2022 Sep 22.
    Differences in Cancer Phenotypes Among Frequent CHEK2 Variants and Implications for Clinical Care-Checking CHEK2.
    Brittany L Bychkovsky, Nihat B Agaoglu, Carolyn Horton, Jing Zhou, Amal Yussuf, Parichehr Hemyari, Marcy E Richardson, Colin Young, Holly LaDuca, Deborah L McGuinness, Rochelle Scheib, Judy E Garber, Huma Q Rana.
       Importance: Germline CHEK2 pathogenic variants (PVs) are frequently detected by multigene cancer panel testing (MGPT), but our understanding of PVs beyond c.1100del has been limited.
    Objective: To compare cancer phenotypes of frequent CHEK2 PVs individually and collectively by variant type.
    Design, Setting, and Participants: This retrospective cohort study was carried out in a single diagnostic testing laboratory from 2012 to 2019. Overall, 3783 participants with CHEK2 PVs identified via MGPT were included. Medical histories of cancer in participants with frequent PVs, negative MGPT (wild type), loss-of-function (LOF), and missense were compared.
    Main Outcomes and Measures: Participants were stratified by CHEK2 PV type. Descriptive statistics were summarized including median (IQR) for continuous variables and proportions for categorical characteristics. Differences in age and proportions were assessed with Wilcoxon rank sum and Fisher exact tests, respectively. Frequencies, odds ratios (ORs), 95% confidence intervals were calculated, and P values were corrected for multiple comparisons where appropriate.
    Results: Of the 3783 participants with CHEK2 PVs, 3473 (92%) were female and most reported White race. Breast cancer was less frequent in participants with p.I157T (OR, 0.66; 95% CI, 0.56-0.78; P<.001), p.S428F (OR, 0.59; 95% CI. 0.46-0.76; P<.001), and p.T476M (OR, 0.74; 95% CI, 0.56-0.98; P = .04) PVs compared with other PVs and an association with nonbreast cancers was not found. Following the exclusion of p.I157T, p.S428F, and p.T476M, participants with monoallelic CHEK2 PV had a younger age at first cancer diagnosis (P < .001) and were more likely to have breast (OR, 1.83; 95% CI, 1.66-2.02; P < .001), thyroid (OR, 1.63; 95% CI, 1.26-2.08; P < .001), and kidney cancer (OR, 2.57; 95% CI, 1.75-3.68; P < .001) than the wild-type cohort. Participants with a CHEK2 PV were less likely to have a diagnosis of colorectal cancer (OR, 0.62; 95% CI, 0.51-0.76; P < .001) compared with those in the wild-type cohort. There were no significant differences between frequent CHEK2 PVs and c.1100del and no differences between CHEK2 missense and LOF PVs.
    Conclusions and Relevance: CHEK2 PVs, with few exceptions (p.I157T, p.S428F, and p.T476M), were associated with similar cancer phenotypes irrespective of variant type. CHEK2 PVs were not associated with colorectal cancer, but were associated with breast, kidney, and thyroid cancers. Compared with other CHEK2 PVs, the frequent p.I157T, p.S428F, and p.T476M alleles have an attenuated association with breast cancer and were not associated with nonbreast cancers. These data may inform the genetic counseling and care of individuals with CHEK2 PVs.
    DOI:  https://doi.org/10.1001/jamaoncol.2022.4071
  14. Fetal Pediatr Pathol. 2022 Sep 19. 1-7
    Bilateral Ovarian Sertoli-Leydig Cell Tumors Harboring DICER1 Germline and Distinct Somatic Mutations: Case Report and Literature Review.
    Caitlin E Hughes, Jiancong Liang, Vera Paulson, Huiying Wang.
      Background:DICER1 tumor predisposition syndrome is characterized by an increased risk for development of pleuropulmonary blastoma, pituitary blastoma, multinodular thyroid goiter, thyroid carcinoma, sex cord stromal tumor, cystic nephroma, embryonal rhabdomyosarcoma, and tumors of the CNS, amongst others. Of this list, only pituitary blastoma is recognized as pathognomonic for the syndrome. Case report: We describe a 15-year-old female with bilateral, asynchronous Sertoli-Leydig cell tumors (SLCT). Both tumors harbored an identical germline frameshift mutation as well as unique somatic DICER1 hot-spot point mutations. Discussion: A review of bilateral SLCTs demonstrates that all patients with available DICER1 mutation status carried a germline DICER1 mutation (100%, 9 of 9). In cases with known somatic DICER1 status on bilateral tumors, all harbored distinct somatic mutations (100%, 5 of 5). Our findings support the notion that bilateral ovarian SLCTs are indeed separate events and do not represent recurrent or metastatic disease.
    Keywords:  DICER1 syndrome; Ovary; Sertoli-Leydig cell tumor; germline; next generation sequencing; sex cord stromal tumor
    DOI:  https://doi.org/10.1080/15513815.2022.2120787
  15. Eur J Cancer Prev. 2022 Sep 12.
    Exome sequencing in a Swedish family with PMS2 mutation with varying penetrance of colorectal cancer: investigating the presence of genetic risk modifiers in colorectal cancer risk.
    Patrick Bryant, Sophie Walton Bernstedt, Jessada Thutkawkorapin, Ann-Sofie Backman, Annika Lindblom, Kristina Lagerstedt-Robinson.
       OBJECTIVE: Lynch syndrome is caused by germline mutations in the mismatch repair (MMR) genes, such as the PMS2 gene, and is characterised by a familial accumulation of colorectal cancer. The penetrance of cancer in PMS2 carriers is still not fully elucidated as a colorectal cancer risk has been shown to vary between PMS2 carriers, suggesting the presence of risk modifiers.
    METHODS: Whole exome sequencing was performed in a Swedish family carrying a PMS2 missense mutation [c.2113G>A, p.(Glu705Lys)]. Thirteen genetic sequence variants were further selected and analysed in a case-control study (724 cases and 711 controls).
    RESULTS: The most interesting variant was an 18 bp deletion in gene BAG1. BAG1 has been linked to colorectal tumour progression with poor prognosis and is thought to promote colorectal tumour cell survival through increased NF-κB activity.
    CONCLUSIONS: We conclude the genetic architecture behind the incomplete penetrance of PMS2 is complicated and must be assessed in a genome wide manner using large families and multifactorial analysis.
    DOI:  https://doi.org/10.1097/CEJ.0000000000000769
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