bims-lifras 2021-08-08 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021–08–08
seventeen papers selected by
Joanna Zawacka-Pankau, Karolinska Institutet

Somatic reversion impacts evolution of myelodysplastic syndromes and acute myeloid leukemia in the short telomere disorders.
Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location.
POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.
The Future of Parallel Tumor and Germline Genetic Testing: Is There a Role for All Patients With Cancer?
Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer.
Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement.
Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants.
Germline Alterations in Patients With IBD-associated Colorectal Cancer.
Gene of the month: FH.
Early detection of duodenal cancer by upper GI-endoscopy in Lynch syndrome.
Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling.
The Distinct Performances of Ultrasound, Mammograms, and MRI in Detecting Breast Cancer in Patients With Germline Pathogenic Variants in Cancer Predisposition Genes.
Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data.
EUS-based pancreatic cancer surveillance in BRCA1/BRCA2/PALB2/ATM carriers without a family history of pancreatic cancer.
Somatic Tumor Profile Analysis in a Patient with Germline PMS2 Mutation and Synchronous Ovarian and Uterine Carcinomas.
Benefits and burdens of risk management for young people with inherited cancer: A focus on Li-Fraumeni syndrome.
The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis and seminoma development.

J Clin Invest. 2021 Aug 03. pii: 147598. [Epub ahead of print]

Somatic reversion impacts evolution of myelodysplastic syndromes and acute myeloid leukemia in the short telomere disorders.

Kristen E Schratz, Valeriya Gaysinskaya, Zoe L Cosner, Emily A DeBoy, Zhimin Xiang, Laura Kasch-Semenza, Liliana Florea, Pali D Shah, Mary Armanios.

   BACKGROUND: Germline mutations in telomerase and other telomere maintenance genes manifest in the premature aging short telomere syndromes. Myelodysplastic syndromes and acute myeloid leukemia (MDS/AML) account for 75% of associated malignancies, but how these cancers overcome the inherited telomere defect is unknown.
METHODS: We used ultra-deep targeted sequencing to detect somatic reversion mutations in 17 candidate telomere lengthening genes among controls and short telomere syndrome patients with and without MDS/AML and we tested the functional significance of these mutations.
RESULTS: While no controls carried somatic mutations in telomere maintenance genes, 29% (16 of 56) of adults with germline telomere maintenance defects carried at least one (P<0.001) and 13% (7 of 56) had 2 or more. In addition to TERT promoter mutations which were present in 19%, we identified POT1 and TERF2IP mutations in 13%. POT1 mutations impaired telomere binding in vitro and some mutations were identical to ones seen in familial melanoma associated with longer telomere length. Exclusively in patients with germline defects in telomerase RNA (TR), we identified somatic mutations in nuclear RNA exosome genes, RBM7, SKIV2L2, and DIS3, where loss-of-function upregulates mature TR levels. Somatic reversion events in six telomere-related genes were more prevalent in patients who were MDS/AML-free (P = 0.02, RR 4.4, 95% CI 1.2-16.7), and no MDS/AML patient had more than one reversion mutation.
CONCLUSIONS: Our data identify diverse adaptive somatic mechanisms in the short telomere syndrome; they raise the possibility that their presence alleviates the telomere crisis that promotes transformation to MDS/AML.

Keywords:  Clonal selection; Genetics; Leukemias; Oncology; Telomeres

DOI:  https://doi.org/10.1172/JCI147598
Genes (Basel). 2021 Jul 08. pii: 1050. [Epub ahead of print]12(7):

Differences in Ovarian and Other Cancers Risks by Population and BRCA Mutation Location.

Masayuki Sekine, Koji Nishino, Takayuki Enomoto.

  Hereditary breast and ovarian cancer is caused by a germline mutation in BRCA1 or BRCA2 genes. The frequency of germline BRCA1/2 gene mutation carriers and the ratio of germline BRCA1 to BRCA2 mutations in BRCA-related cancer patients vary depending on the population. Genotype and phenotype correlations have been reported in BRCA mutant families, however, the correlations are rarely used for individual risk assessment and management. BRCA genetic testing has become a companion diagnostic for PARP inhibitors, and the number of families with germline BRCA mutation identified is growing rapidly. Therefore, it is expected that analysis of the risk of developing cancer will be possible in a large number of BRCA mutant carriers, and there is a possibility that personal and precision medicine for the carriers with specific common founder mutations will be realized. In this review, we investigated the association of ovarian cancer risk and BRCA mutation location, and differences of other BRCA-related cancer risks by BRCA1/2 mutation, and furthermore, we discussed the difference in the prevalence of germline BRCA mutation in ovarian cancer patients. As a result, although there are various discussions, there appear to be differences in ovarian cancer risk by population and BRCA mutation location. If it becomes possible to estimate the risk of developing BRCA-related cancer for each BRCA mutation type, the age at risk-reducing salpingo-oophorectomy can be determined individually. The decision would bring great benefits to young women with germline BRCA mutations.

Keywords:  BRCA-related cancer; BRCA1/2; hereditary breast and ovarian cancer; risk-reducing salpingo-oophorectomy

DOI:  https://doi.org/10.3390/genes12071050
Oncogene. 2021 Aug 06.

POLE, POLD1, and NTHL1: the last but not the least hereditary cancer-predisposing genes.

Luigi Magrin, Daniele Fanale, Chiara Brando, Alessia Fiorino, Lidia Rita Corsini, Roberta Sciacchitano, Clarissa Filorizzo, Alessandra Dimino, Antonio Russo, Viviana Bazan.

POLE, POLD1, and NTHL1 are involved in DNA replication and have recently been recognized as hereditary cancer-predisposing genes, because their alterations are associated with colorectal cancer and other tumors. POLE/POLD1-associated syndrome shows an autosomal dominant inheritance, whereas NTHL1-associated syndrome follows an autosomal recessive pattern. Although the prevalence of germline monoallelic POLE/POLD1 and biallelic NTHL1 pathogenic variants is low, they determine different phenotypes with a broad tumor spectrum overlapping that of other hereditary conditions like Lynch Syndrome or Familial Adenomatous Polyposis. Endometrial and breast cancers, and probably ovarian and brain tumors are also associated with POLE/POLD1 alterations, while breast cancer and other unusual tumors are correlated with NTHL1 pathogenic variants. POLE-mutated colorectal and endometrial cancers are associated with better prognosis and may show favorable responses to immunotherapy. Since POLE/POLD1-mutated tumors show a high tumor mutational burden producing an increase in neoantigens, the identification of POLE/POLD1 alterations could help select patients suitable for immunotherapy treatment. In this review, we will investigate the role of POLE, POLD1, and NTHL1 genetic variants in cancer predisposition, discussing the potential future therapeutic applications and assessing the utility of performing a routine genetic testing for these genes, in order to implement prevention and surveillance strategies in mutation carriers.

DOI: https://doi.org/10.1038/s41388-021-01984-2
J Natl Compr Canc Netw. 2021 07 28. pii: jnccn20489. [Epub ahead of print]19(7): 871-878

The Future of Parallel Tumor and Germline Genetic Testing: Is There a Role for All Patients With Cancer?

Ying L Liu, Zsofia K Stadler.

Under the traditional paradigm of genetic testing in cancer, the role of germline testing was to assess for the inherited risk of cancer, whereas the role of tumor testing was to determine therapeutic selection. Parallel tumor-normal genetic testing uses simultaneous genetic testing of the tumor and normal tissue to identify mutations and allows their classification as either germline or somatic. The increasing adoption of parallel testing has revealed a greater number of germline findings in patients who otherwise would not have met clinical criteria for testing. This result has widespread implications for the screening and further testing of at-risk relatives and for gene discovery. It has also revealed the importance of germline testing in therapeutic actionability. Herein, we describe the pros and cons of tumor-only versus parallel tumor-normal testing and summarize the data on the prevalence of incidental actionable germline findings. Because germline testing in patients with cancer continues to expand, it is imperative that systems be in place for the proper interpretation, dissemination, and counseling for patients and at-risk relatives. We also review new therapeutic approvals with germline indications and highlight the increasing importance of germline testing in selecting therapies. Because recommendations for universal genetic testing are increasing in multiple cancer types and the number of approved therapies with germline indications is also increasing, a gradual transition toward parallel tumor-normal genetic testing in all patients with cancer is foreseeable.

DOI: https://doi.org/10.6004/jnccn.2021.7044
J Pers Med. 2021 Jul 02. pii: 631. [Epub ahead of print]11(7):

Combinations of Low-Frequency Genetic Variants Might Predispose to Familial Pancreatic Cancer.

Emily P Slater, Lisa M Wilke, Lutz Benedikt Böhm, Konstantin Strauch, Manuel Lutz, Norman Gercke, Elvira Matthäi, Kari Hemminki, Asta Försti, Matthias Schlesner, Nagarajan Paramasivam, Detlef K Bartsch.

  Familial pancreatic cancer (FPC) is an established but rare inherited tumor syndrome that accounts for approximately 5% of pancreatic ductal adenocarcinoma (PDAC) cases. No major causative gene defect has yet been identified, but germline mutations in predisposition genes BRCA1/2, CDKN2A and PALB2 could be detected in 10-15% of analyzed families. Thus, the genetic basis of disease susceptibility in the majority of FPC families remains unknown. In an attempt to identify new candidate genes, we performed whole-genome sequencing on affected patients from 15 FPC families, without detecting BRCA1/2, CDKN2A or PALB2 mutations, using an Illumina based platform. Annotations from CADD, PolyPhen-2, SIFT, Mutation Taster and PROVEAN were used to assess the potential impact of a variant on the function of a gene. Variants that did not segregate with pancreatic disease in respective families were excluded. Potential predisposing candidate genes ATM, SUFU, DAB1, POLQ, FGFBP3, MAP3K3 and ACAD9 were identified in 7 of 15 families. All identified gene mutations segregated with pancreatic disease, but sometimes with incomplete penetrance. An analysis of up to 46 additional FPC families revealed that the identified gene mutations appeared to be unique in most cases, despite a potentially deleterious ACAD9 Ala326Thr germline variant, which occurred in 4 (8.7%) of 46 FPC families. Notably, affected PDAC patients within a family carried identical germline mutations in up to three different genes, e.g., DAB1, POLQ and FGFBP3. These results support the hypothesis that FPC is a highly heterogeneous polygenetic disease caused by low-frequency or rare variants.

Keywords:  WGS; familial pancreatic cancer; genetic variants

DOI:  https://doi.org/10.3390/jpm11070631
Cancer. 2021 Aug 03.

Genetic risk assessment for hereditary renal cell carcinoma: Clinical consensus statement.

Gennady Bratslavsky, Neil Mendhiratta, Michael Daneshvar, James Brugarolas, Mark W Ball, Adam Metwalli, Katherine L Nathanson, Phillip M Pierorazio, Ronald S Boris, Eric A Singer, Maria I Carlo, Mary B Daly, Elizabeth P Henske, Colette Hyatt, Lindsay Middleton, Gloria Morris, Anhyo Jeong, Vivek Narayan, W Kimryn Rathmell, Ulka Vaishampayan, Bruce H Lee, Dena Battle, Michael J Hall, Khaled Hafez, Michael A S Jewett, Christina Karamboulas, Sumanta K Pal, A Ari Hakimi, Alexander Kutikov, Othon Iliopoulos, W Marston Linehan, Eric Jonasch, Ramaprasad Srinivasan, Brian Shuch.

   BACKGROUND: Although renal cell carcinoma (RCC) is believed to have a strong hereditary component, there is a paucity of published guidelines for genetic risk assessment. A panel of experts was convened to gauge current opinions.
METHODS: A North American multidisciplinary panel with expertise in hereditary RCC, including urologists, medical oncologists, clinical geneticists, genetic counselors, and patient advocates, was convened. Before the summit, a modified Delphi methodology was used to generate, review, and curate a set of consensus questions regarding RCC genetic risk assessment. Uniform consensus was defined as ≥85% agreement on particular questions.
RESULTS: Thirty-three panelists, including urologists (n = 13), medical oncologists (n = 12), genetic counselors and clinical geneticists (n = 6), and patient advocates (n = 2), reviewed 53 curated consensus questions. Uniform consensus was achieved on 30 statements in specific areas that addressed for whom, what, when, and how genetic testing should be performed. Topics of consensus included the family history criteria, which should trigger further assessment, the need for risk assessment in those with bilateral or multifocal disease and/or specific histology, the utility of multigene panel testing, and acceptance of clinician-based counseling and testing by those who have experience with hereditary RCC.
CONCLUSIONS: In the first ever consensus panel on RCC genetic risk assessment, 30 consensus statements were reached. Areas that require further research and discussion were also identified, with a second future meeting planned. This consensus statement may provide further guidance for clinicians when considering RCC genetic risk assessment.
LAY SUMMARY: The contribution of germline genetics to the development of renal cell carcinoma (RCC) has long been recognized. However, there is a paucity of guidelines to define how and when genetic risk assessment should be performed for patients with known or suspected hereditary RCC. Without guidelines, clinicians struggle to define who requires further evaluation, when risk assessment or testing should be done, which genes should be considered, and how counseling and/or testing should be performed. To this end, a multidisciplinary panel of national experts was convened to gauge current opinion on genetic risk assessment in RCC and to enumerate a set of recommendations to guide clinicians when evaluating individuals with suspected hereditary kidney cancer.

Keywords:  clinical consensus; genetic risk assessment; genetic testing; germline mutations; hereditary kidney cancer; recommendations; renal cell carcinoma

DOI:  https://doi.org/10.1002/cncr.33679
Cancers (Basel). 2021 Jul 31. pii: 3857. [Epub ahead of print]13(15):

Non-Lynch Familial and Early-Onset Colorectal Cancer Explained by Accumulation of Low-Risk Genetic Variants.

Pilar Mur, Nuria Bonifaci, Anna Díez-Villanueva, Elisabet Munté, Maria Henar Alonso, Mireia Obón-Santacana, Gemma Aiza, Matilde Navarro, Virginia Piñol, Joan Brunet, Ian Tomlinson, Gabriel Capellá, Victor Moreno, Laura Valle.

  A large proportion of familial and/or early-onset cancer patients do not carry pathogenic variants in known cancer predisposing genes. We aimed to assess the contribution of previously validated low-risk colorectal cancer (CRC) alleles to familial/early-onset CRC (fCRC) and to serrated polyposis. We estimated the association of CRC with a 92-variant-based weighted polygenic risk score (wPRS) using 417 fCRC patients, 80 serrated polyposis patients, 1077 hospital-based incident CRC patients, and 1642 controls. The mean wPRS was significantly higher in fCRC than in controls or sporadic CRC patients. fCRC patients in the highest (20th) wPRS quantile were at four-fold greater CRC risk than those in the middle quantile (10th). Compared to low-wPRS fCRC, a higher number of high-wPRS fCRC patients had developed multiple primary CRCs, had CRC family history, and were diagnosed at age ≥50. No association with wPRS was observed for serrated polyposis. In conclusion, a relevant proportion of mismatch repair (MMR)-proficient fCRC cases might be explained by the accumulation of low-risk CRC alleles. Validation in independent cohorts and development of predictive models that include polygenic risk score (PRS) data and other CRC predisposing factors will determine the implementation of PRS into genetic testing and counselling in familial and early-onset CRC.

Keywords:  cancer predisposition; hereditary colorectal cancer; polygenic risk score; serrated polyposis

DOI:  https://doi.org/10.3390/cancers13153857
Inflamm Bowel Dis. 2021 Aug 04. pii: izab195. [Epub ahead of print]

Germline Alterations in Patients With IBD-associated Colorectal Cancer.

Giuseppe Biscaglia, Anna Latiano, Stefano Castellana, Rosanna Fontana, Annamaria Gentile, Tiziana Latiano, Giuseppe Corritore, Anna Panza, Marianna Nardella, Giuseppina Martino, Fabrizio Bossa, Francesco Perri, Tommaso Mazza, Angelo Andriulli, Orazio Palmieri.

   BACKGROUND: Patients with inflammatory bowel diseases (IBD), both ulcerative colitis (UC) and Crohn's disease (CD), are at risk of developing a colorectal cancer (CRC). No information is available on the contribution of patients' genetic background to CRC occurrence. This study investigates germline alterations in patients with IBD-associated CRC.
METHODS: We profiled a panel of 39 genes potentially involved in cancer predisposition and searched for germline variants in IBD patients with CRC or high-grade dysplasia.
RESULTS: After clinical exclusion of genetic cancer syndromes, 25 IBD patients (4 CD and 21 UC) with CRC or high-grade dysplasia were studied. After excluding variants with low likelihood of pathogenicity (classes 1 or 2 according the International Agency for Research on Cancer [IARC]), the panel identified pathogenic variants, likely pathogenic, or variants with unknown significance in 18 patients (72%). Six patients (24%) carried pathogenic or likely variants (IARC class 5 or 4). Of the identified variants, 4 encompassed the APC region, 3 the MLH1 gene, and the remaining ones the MSH2, MSH3, monoallelic MUTYH, EPCAM, BRCA1, CHEK2, POLD1, POLE, CDKN2A, and PDGFRA genes. Four patients carried at least 2 variants in different genes. Duration of IBD was significantly shorter in carriers of 4 or 5 IARC variants (7 years; range 0-21; P = .002) and in those with variants with unknown significance (12 years; range 0-22; P = .005) compared with patients without or with only benign variations (23.5 years; range 15-34).
CONCLUSIONS: In silico analysis and sequence-based testing of germline DNA from IBD patients with CRC or high-grade dysplasia detected 24% of variants positioned in pathogenic classes. In patients with type 3, 4, and 5 variants, the onset of high-grade dysplasia or CRC was significantly earlier than in patients with benign or unidentified variants. The screening for these genes could identify IBD patients requiring a more intensive endoscopic surveillance for earlier detection of dysplastic changes.

Keywords:  Crohn’s disease; colorectal cancer; genetics; ulcerative colitis

DOI:  https://doi.org/10.1093/ibd/izab195
J Clin Pathol. 2021 Aug 05. pii: jclinpath-2021-207830. [Epub ahead of print]

Gene of the month: FH.

Roman E Zyla, Anjelica Hodgson.

  Fumarate hydratase (FH), encoded by the FH gene, is an enzyme which catalyses the conversion of fumarate to L-malate as part of the tricarboxylic acid cycle. Biallelic germline mutations in FH result in fumaric aciduria, a metabolic disorder resulting in severe neurological and developmental abnormalities. Heterozygous germline mutations in FH result in hereditary leiomyomatosis and renal cell carcinoma, a cancer predisposition syndrome. FH deficiency has multiple oncogenic mechanisms including through promotion of aerobic glycolysis, induction of pseudohypoxia, post-translational protein modification and impairment of DNA damage repair by homologous recombination. FH-deficient neoplasms can present with characteristic morphological features that raise suspicion for FH alterations and also frequently demonstrate loss of FH immunoreactivity and intracellular accumulation of 2-succinocysteine, also detected by immunohistochemistry.

Keywords:  genetics; hereditary; neoplastic syndromes; oncogenes

DOI:  https://doi.org/10.1136/jclinpath-2021-207830
Int J Cancer. 2021 Jul 31.

Early detection of duodenal cancer by upper GI-endoscopy in Lynch syndrome.

German Consortium for Familial Intestinal Cancer

  Small bowel cancer (SBC) is the malignancy with the highest standardized incidence ratio in Lynch syndrome (LS) patients. Of all SBCs, about 50% are duodenal cancers (DC), therefore being accessible by esophago-gastro-duodenoscopy (EGD) for surveillance. We asked whether early detection of DC is possible for LS patients undergoing surveillance by EGD and if surveillance should be limited to specific subgroups. Data for LS patients with DC were retrieved from the registry of the German Consortium for Familial Intestinal Cancer. Patients undergoing active surveillance by EGDs (surveillance-group) were compared to those who did not (non-surveillance-group) regarding tumor stage at diagnosis. UICC stages I-IIA were defined as early stage disease and IIB-IV as advanced stage disease. Statistical analysis was performed using Fisher's exact test. Among 2015 patients with pathogenic variants in any mismatch-repair-gene, 47 patients with 49 DCs were identified. In 10% of cases, patients were under 35 years at diagnosis; family and personal tumor history did not correlate with DC diagnosis. Pathogenic germline variants in MSH6, PMS2 or EPCAM were present in 10% of patients. Statistical analysis could be performed on 13 DC patients in the surveillance-group and 14 in the non-surveillance-group. Early detection was possible for 71% of patients in the surveillance-group and 29% of patients in the non-surveillance-group (P = 0.021). Early detection of DC by EGD in LS patients is feasible regardless of family history, mutational status and should start no later than 25 years of age.

Keywords:  HNPCC; Lynch syndrome; Small bowel cancer; duodenal cancer; surveillance

DOI:  https://doi.org/10.1002/ijc.33753
Int J Mol Sci. 2021 Jul 26. pii: 7962. [Epub ahead of print]22(15):

Germline Whole-Gene Deletion of FH Diagnosed from Tumor Profiling.

Arisa Ueki, Kokichi Sugano, Kumiko Misu, Eriko Aimono, Kohei Nakamura, Shigeki Tanishima, Nobuyuki Tanaka, Shuji Mikami, Akira Hirasawa, Miho Ando, Teruhiko Yoshida, Mototsugu Oya, Hiroshi Nishihara, Kenjiro Kosaki.

  Hereditary leiomyomatosis and renal cell carcinoma (HL (RCC)) entails cutaneous and uterine leiomyomatosis with aggressive type 2 papillary RCC-like histology. HLRCC is caused by pathogenic variants in the FH gene, which encodes fumarate hydratase (FH). Here, we describe an episode of young-onset RCC caused by a genomic FH deletion that was diagnosed via clinical sequencing. A 35-year-old woman was diagnosed with RCC and multiple metastases: histopathological analyses supported a diagnosis of FH-deficient RCC. Although the patient had neither skin tumors nor a family history of HLRCC, an aggressive clinical course at her age and pathological diagnosis of FH-deficient RCC suggested a germline FH variant. After counseling, the patient provided written informed consent for germline genetic testing. She was simultaneously subjected to paired tumor profiling tests targeting the exome to identify a therapeutic target. Although conventional germline sequencing did not detect FH variants, exome sequencing revealed a heterozygous germline FH deletion. As such, paired tumor profiling, not conventional sequencing, was required to identify this genetic deletion. RCC caused by a germline FH deletion has hitherto not been described in Japan, and the FH deletion detected in this patient was presumed to be of maternal European origin. Although the genotype-phenotype correlation in HLRCC-related tumors is unclear, the patient's family was advised to undergo genetic counseling to consider additional RCC screening.

Keywords:  exome sequencing; fumarate hydratase; germline genetic testing; hereditary leiomyomatosis and renal cell carcinoma; tumor profiling

DOI:  https://doi.org/10.3390/ijms22157962
Front Oncol. 2021 ;11 710156

The Distinct Performances of Ultrasound, Mammograms, and MRI in Detecting Breast Cancer in Patients With Germline Pathogenic Variants in Cancer Predisposition Genes.

Jiaqi Liu, Xin Wang, Lin Dong, Xin Huang, Hengqiang Zhao, Jiaxin Li, Shengkai Huang, Pei Yuan, Wenyan Wang, Jie Wang, Zeyu Xing, Ziqi Jia, Yue Ming, Xiao Li, Ling Qin, Gang Liu, Jiang Wu, Yiqun Li, Menglu Zhang, Kexin Feng, Jianming Ying, Xiang Wang.

  A proportion of up to 10% of breast cancer resulted from hereditary germline pathogenic variants (GPVs) in cancer predisposition genes (CPGs), which been demonstrated distinct clinical features and imaging manifestations. However, the performance of imaging modalities for breast cancer surveillance in CPG mutation-carriers is still unclear, especially in Asian women. A population of 3002 breast cancer patients who received germline genetic testing of CPGs was enrolled from three hospitals in China. In total, 343 (11.6%) patients were found to harbor GPVs in CPGs, including 137 (4.6%) in BRCA1 and 135 (4.6%) in BRCA2. We compared the performances of ultrasound, mammograms, MRI, and the combining strategies in CPG mutation carriers and non-carriers. As a result, the ultrasound showed a higher detection rate compared with mammograms regardless of the mutation status. However, its detection rate was lower in CPG mutation carriers than in non-carriers (93.2% vs 98.0%, P=2.1×10-4), especially in the BRCA1 mutation carriers (90.9% vs 98.0%, P=2.0×10-4). MRI presented the highest sensitivity (98.5%) and the lowest underestimation rate (14.5%) in CPG mutation carriers among ultrasound, mammograms, and their combination. Supplemental ultrasound or mammograms would add no significant value to MRI for detecting breast cancer (P>0.05). In multivariate logistic regression analysis, the family or personal cancer history could not replace the mutation status as the impact factor for the false-negative result and underestimation. In summary, clinicians and radiologists should be aware of the atypical imaging presentation of breast cancer in patients with GPVs in CPGs.

Keywords:  BRCA1/2; hereditary breast cancer; magnetic resonance imaging; mammography; ultrasonography

DOI:  https://doi.org/10.3389/fonc.2021.710156
Ther Adv Hematol. 2021 ;12 20406207211032433

Clinical features of DDX41 mutation-related diseases: a systematic review with individual patient data.

Ziqi Wan, Bing Han.

   Background: DDX41 serves as a DNA sensor in innate immunity and mutated DDX41 is pathogenic, mainly for myeloid neoplasms.
Methods: In this study, "DDX41" was searched in PubMed and Web of Science between 1 January 2015 and 29 April 2021 with individual-patient data seeking. A meta-analysis was not valid here due to the absence of a large dataset. Thirty articles were finally included in the qualitative analysis and 277 patients from 20 studies without overlap were involved in the quantitative summary.
Results: Pooled incidence was 3.3% (95% confidence interval 2.4-4.2%) of unselected myeloid neoplasms. Patients with hematologic disorders harboring mutated DDX41 were featured as 80% males, median 66 (20-88) years old at diagnosis, 75% acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS), 64% with normal karyotype. Eighty-five percent of patients had germline variants which were nationally diverse and more of frameshift type, whereas 64% of patients had somatic DDX41 variants where p.R525H and missense dominated. ASXL1 and TP53 were the top frequent concomitant somatic mutations. Therapeutically, 70% overall response rate was obtained of hypomethylating agents in MDS, 96% complete remission of chemotherapy in AML, and 8% of relapse in hematopoietic stem cell transplant. Neither overall survival nor progression-free survival could be summed.
Conclusions: Several significant clinical differences were observed in different diagnosis groups, familial and sporadic cases, and p.R525H compared with other somatic variants. In conclusion, myeloid neoplasms carrying DDX41 mutations were mainly older, male, MDS, and AML patients who had promising responses to treatment. Both germline and somatic DDX41 variants possessed unique characteristics and groups of interest presented certain differences worth further research. (CRD42021228886).

Keywords:  DDX41 mutation; germline; hematologic; somatic

DOI:  https://doi.org/10.1177/20406207211032433
Cancer Prev Res (Phila). 2021 Aug 02. pii: canprevres.0161.2021. [Epub ahead of print]

EUS-based pancreatic cancer surveillance in BRCA1/BRCA2/PALB2/ATM carriers without a family history of pancreatic cancer.

Bryson W Katona, Jessica M Long, Nuzhat A Ahmad, Sara Attalla, Angela R Bradbury, Erica L Carpenter, Dana Farengo Clark, Gillain Constantino, Koushik K Das, Susan M Domchek, Christina Dudzik, Jessica Ebrahimzadeh, Gregory G Ginsberg, Jordan Heiman, Michael L Kochman, Kara N Maxwell, Danielle B McKenna, Jacquelyn Powers, Payal D Shah, Kirk J Wangensteen, Anil K Rustgi.

Carriers of a pathogenic/likely pathogenic (P/LP) BRCA1/BRCA2/ATM/PALB2 variant are at increased risk of pancreatic ductal adenocarcinoma (PDAC), yet current guidelines recommend surveillance only for those with a family history of PDAC. We aimed to investigate outcomes of endoscopic ultrasound (EUS)-based PDAC surveillance in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC. We performed a retrospective analysis of all P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent endoscopic ultrasound (EUS) at a tertiary care center. Of 194 P/LP BRCA1/BRCA2/ATM/PALB2 carriers who underwent EUS, 64 (33%) had no family history of PDAC and had at least one EUS for PDAC surveillance. These individuals underwent 143 total EUSs, were predominantly female (72%) and BRCA2 carriers (73%), with the majority having a personal history of cancer other than PDAC (67%). The median age at time of first EUS was 62 years (IQR 53-67 years) and a median of 2 EUSs (IQR 1-3) were performed per patient, with a median of 3 years (IQR 2-4.5 years) between the first and last EUS for those with more than 1 EUS. Pancreatic abnormalities were detected in 44%, including cysts in 27%, and incidental luminal abnormalities in 41%. Eight percent developed a new pancreatic mass or cyst during surveillance, two individuals developed PDAC, and no serious complications resulted from surveillance. After discussion of the risks, limitations, and potential benefits, PDAC surveillance can be considered in BRCA1/BRCA2/ATM/PALB2 carriers without a family history of PDAC, however the effectiveness of PDAC surveillance in this population requires further study.

DOI: https://doi.org/10.1158/1940-6207.CAPR-21-0161
J Pers Med. 2021 Jul 05. pii: 634. [Epub ahead of print]11(7):

Somatic Tumor Profile Analysis in a Patient with Germline PMS2 Mutation and Synchronous Ovarian and Uterine Carcinomas.

Karen M Huelsman, Jack B Basil, Rebecca Sisson, Lindsay R Lipe, Brett Mahon, David J Draper.

  Lynch syndrome patients with synchronous endometrial and ovarian cancer (SEOC) are rare. When these cases occur, they are most often endometrioid histology and early grade. Early-grade tumors are not often sent for somatic tumor profiling. We present a 39 year old SEOC patient with germline PMS2 Lynch syndrome and clinical tumor analysis leading to insight regarding the origin and cause of these tumors, with potential therapy options. PMS2-related SEOC is less common due to lower risks for these cancers associated with germline PMS2 mutation compared to other Lynch genes. While synchronous cancers are not common, they are more likely to occur with Lynch syndrome. Tumor profiling with next-generation sequencing of 648 genes identified sixteen shared somatic actionable and biologically relevant mutations. This case is a rare example of a patient with PMS2 germline Lynch syndrome with shared somatic variants that demonstrate clonality of the two tumors arising from one common site.

Keywords:  HRD; Lynch syndrome; PMS2 germline mutation; cancer genomics; synchronous endometrial ovarian tumor; tumor profiling

DOI:  https://doi.org/10.3390/jpm11070634
Aust J Gen Pract. 2021 08;50(8): 538-544

Benefits and burdens of risk management for young people with inherited cancer: A focus on Li-Fraumeni syndrome.

Rowan Forbes Shepherd, Louise A Keogh, Allison Werner-Lin, Martin B Delatycki, Laura E Forrest.

BACKGROUND AND OBJECTIVES: Discussing population-based cancer risk and screening is common in general practice. Patients with an inherited cancer syndrome, however, may need more nuanced discussions. Li-Fraumeni syndrome (LFS) is a rare, inherited cancer syndrome that affects many organ systems from birth and requires intensive, whole-body cancer risk management. The aim of this study was to explore the risk management experiences of young people (aged 15-39 years) with, or at risk of, LFS.
METHOD: Using an interpretive description design, semi-structured interviews were conducted with young people diagnosed with, or at risk of, LFS from across Australia. Interview transcripts were analysed with team-based, codebook thematic analysis.
RESULTS: Thirty young people (mean age 25.5 years) participated. Participants described intensive screening and risk-reducing mastectomy (for women) as their 'best shot' to control their cancer risks with LFS. Engaging in these options as a young person came with a slew of psychosocial implications.
DISCUSSION: General practitioners may help to improve care for young people with inherited cancer syndromes by acknowledging the benefits and complex burdens of their risk management.

DOI: https://doi.org/10.31128/AJGP-04-21-5954
Genes Chromosomes Cancer. 2021 Aug 02.

The novel KIT exon 11 germline mutation K558N is associated with gastrointestinal stromal tumor, mastocytosis and seminoma development.

Michael Meir, Katja Maurus, Jochen Kuper, Mohammed Hankir, Eva Wardelmann, Andreas Rosenwald, Christoph-Thomas Germer, Armin Wiegering.

  Familial gastrointestinal stromal tumors (GIST) are dominant genetic disorders that are caused by germline mutations of the type III receptor tyrosine kinase KIT. While sporadic mutations are frequently found in mastocytosis and GISTs, germline mutations of KIT have only been described in 39 families until now. We detected a novel germline mutation of KIT in exon 11 (p.Lys-558-Asn; K558N) in a patient from a kindred with several GISTs harboring different secondary somatic KIT mutations. Structural analysis suggests that the primary germline mutation alone is not sufficient to release the autoinhibitory region of KIT located in the transmembrane domain. Instead, the KIT kinase module becomes constitutively activated when K558N combines with different secondary somatic mutations. The identical germline mutation in combination with an additional somatic KIT mutation was detected in a second patient of the kindred with seminoma while a third patient within the family had a cutaneous mastocytosis. These findings suggest that the K558N mutation interferes with the juxtamembranous part of KIT, since seminoma and mastocystosis are usually not associated with Exon 11 mutations. This article is protected by copyright. All rights reserved.

Keywords:  GIST; KIT; germline mutation; mastocytosis; seminoma

DOI:  https://doi.org/10.1002/gcc.22988