bims-lifras 2021-04-18 papers

bims-lifras

Biomed News

on Li-Fraumeni syndrome

Issue of 2021‒04‒18
eleven papers selected by
Joanna Zawacka-Pankau
Karolinska Institutet

Germline and tumor BRCA1/2 mutations in Chinese high grade serous ovarian cancer patients.
Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2.
Case Report: Coinheritance of Germline Mutations in APC and BRCA1 in Colorectal Cancer.
Management of BRCA Mutation Carriers With Pancreatic Adenocarcinoma.
Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer.
Gardner-associated fibroma of the neck: role of a multidisciplinary evaluation for familial adenomatous polyposis diagnosis.
Germline cancer susceptibility gene testing in unselected patients with colorectal adenocarcinoma: A multi-center prospective study.
Diagnosing MonoMAC Syndrome in GATA2 Germline Mutated Myelodysplastic Syndrome via Next-Generation Sequencing in a Patient with Refractory and Complex Infection: Case Report and Literature Review.
Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.
Genomic profiling of multiple tissues in two patients with multiple endocrine neoplasia type 1.
Germline mutations and age at onset of lung adenocarcinoma.

Ann Transl Med. 2021 Mar;9(6): 453

Germline and tumor BRCA1/2 mutations in Chinese high grade serous ovarian cancer patients.

Ji G, Yao Q, Bao L, Zhang J, Bai Q, Zhu X, Tu X, Bi R, Zhou X.

  Background: Studies on the prevalence of BRCA1/2 mutations in ovarian cancer mainly focused on germline single-nucleotide variant (SNV)/insertion/deletion (indel). The status of large genomic rearrangement (LRG) and somatic mutation were poorly investigated.Methods: Paired blood and tumor DNA from an unselected cohort of 115 Chinese high grade serous ovarian cancer (HGSOC) patients were collected and analyzed for BRCA1/2 SNV and indel by NGS. BRCA1/2 LRG was detected by MLPA. Clinicopathological characteristics including age at diagnosis, FIGO stage, family history and follow-up data were collected for further analysis.
Results: A total of 115 HGSOC patients were screened. Among them, 30 (26.1%) had germline BRCA1/2 mutations, including 19 (16.5%) SNV/indels, 5 (4.3%) LGRs in BRCA1, and 6 (5.2%) SNV/indels in BRCA2. Ten (8.7%) had somatic BRCA1/2 mutations, including 5 (4.3%) in BRCA1 and 5 (4.3%) in BRCA2. The entire tumor BRCA1/2 mutation frequency was 34.8%. No patients were found with two or more deleterious BRCA1/2 mutations. The proportion of germline (66.7%) and tumor (75%) mutation carriers was significantly increased for patients with family history when compared with those without (P<0.05). Patients with germline BRCA1/2 mutation appeared to be younger than non-carriers (mean age, 50.9 vs. 54.4 years, P=0.004) and somatic mutation carriers (mean age, 50.9 vs. 58.7 years, P=0.009). No significant association was found between BRCA1/2 status and clinicopathological characteristics including stage and family history of other cancer than breast and ovarian cancer. In univariate and Cox regression analysis, patients with tumor BRCA1/2 mutations had significant improvements than non-carriers in overall survival in the first two years after surgery (P<0.05). No significant impacts were found between various mutation status in PFS.
Conclusions: There is a high germline and tumor BRCA1/2 mutation incidences in Chinese HGSOC patients. Germline mutations were associated with family history and age at diagnosis, whereas somatic mutations were not. In our study, tumor BRCA1/2 mutations showed a time-depended improved survival outcome. A larger cohort should be examined to clarify the relation between BRCA1/2 mutation and survival outcomes.

Keywords:  BRCA1/2, somatic mutation; High grade serous ovarian cancer (HGSOC); large genomic rearrangement (LRG)

DOI:  https://doi.org/10.21037/atm-20-6827
Eur J Hum Genet. 2021 Apr 15.

Familial wild-type gastrointestinal stromal tumour in association with germline truncating variants in both SDHA and PALB2.

Whitworth J, Casey RT, Smith PS, Giger O, Martin JE, Clark G, Cook J, Fernando MS, Taniere P, , Maher ER.

Gastrointestinal stromal tumour (GIST) is a mesenchymal neoplasm arising in the gastrointestinal tract. A rare subset of GISTs are classified as wild-type GIST (wtGIST) and these are frequently associated with germline variants that affect the function of cancer predisposition genes such as the succinate dehydrogenase subunit genes (SDHA, SDHB, SDHC, SDHD) or NF1. However, despite this high heritability, familial clustering of wtGIST is extremely rare. Here, we report a mother-son diad who developed wtGIST at age 66 and 34 years, respectively. Comprehensive genetic testing revealed germline truncating variants in both SDHA (c.1534C>T (p.Arg512*)) and PALB2 (c.3113G>A (p.Trp1038*)) in both affected individuals. The mother also developed breast ductal carcinoma in-situ at age 70 years. Immunohistochemistry and molecular analysis of the wtGISTs revealed loss of SDHB expression and loss of the wild-type SDHA allele in tumour material. No allele loss was detected at PALB2 suggesting that wtGIST tumourigenesis was principally driven by succinate dehydrogenase deficiency. However, we speculate that the presence of multilocus inherited neoplasia alleles syndrome (MINAS) in this family might have contributed to the highly unusual occurrence of familial wtGIST. Systematic reporting of tumour risks and phenotypes in individuals with MINAS will facilitate the clinical interpretation of the significance of this diagnosis, which is becoming more frequent as strategies for genetic testing for hereditary cancer becomes more comprehensive.

DOI: https://doi.org/10.1038/s41431-021-00862-5
Front Oncol. 2021 ;11 658389

Case Report: Coinheritance of Germline Mutations in APC and BRCA1 in Colorectal Cancer.

Huang W, Bian J, Qian X, Shao L, Li H, Zhang L, Wang L.

  Deleterious mutations in APC gene cause the autosomal dominant familial adenomatous polyposis (FAP) which is typically characterized by the occurrence of hundreds to thousands of colorectal adenomas that eventually lead to colorectal cancers (CRCs). BRCA1/2 are the two major susceptibility genes for breast and ovarian cancers. Here, we reported a coinheritance of mutations in APC and BRCA1 genes in a 20-year-old CRC patient with typical clinical features for FAP. Multiple relatives in the family of the patient were affected by colorectal and other cancers. Next-generation sequencing analysis using a panel consisting of 53 hereditary cancer related genes revealed a maternally inherited APC (exon15cn_del) mutation and a paternally inherited BRAC1 (p.lle1824AspfsX3) mutation. This is the first coexistence of APC and BRCA1 mutations in a CRC patient with the mutation inheritance pattern comprehensively characterized in the family. The patient underwent a colonoscopy and a subtotal colectomy and was subsequently diagnosed with colonic adenocarcinomas accompanied with hundreds of tubulovillous adenomas. The case reveals the scenario where two disease-causing mutations of different hereditary tumor syndromes coexist, and illustrates the importance of evaluating detailed family history and performing a multiple-gene panel test in patients with hereditary cancer.

Keywords:  adenomatous polyposis coli (APC) gene; breast cancer susceptibility (BRCA) gene; double germline mutations; familial adenomatous polyposis (FAP); next generation sequencing (NGS)

DOI:  https://doi.org/10.3389/fonc.2021.658389
J Natl Compr Canc Netw. 2021 Apr;pii: jnccn20544. [Epub ahead of print]19(4): 469-473

Management of BRCA Mutation Carriers With Pancreatic Adenocarcinoma.

Golan T, Hammel P.

Pancreatic ductal adenocarcinoma (PDAC) has a dismal prognosis, with a 5-year survival rate of ≤7% across all stages. Most patients are diagnosed with advanced disease and median overall survival is limited. The limited success of conventional therapies for PDAC is at least partially attributable to its genetic heterogeneity. Extensive genomic efforts have been made to subtype PDAC. The DNA damage repair (DDR) deficiency subtype, also known as unstable genome/DSBR (DNA double-strand break repair) subtype, is one of the most clinically relevant biologic abnormalities in PDAC. Increased PDAC risk was found to be associated with inherited syndromes, which are present in approximately 10% of patients with PDAC. Recent updates to the ASCO and NCCN guidelines recommend risk assessment for all individuals with PDAC, irrespective of personal or family history or ethnicity. Germline BRCA mutations associated with DNA repair dysfunction is one of the best illustrations of actionable biologic subtypes in PDAC. This genetic alteration can indeed be targeted by PARP inhibitors (PARPi). Treatment implications for germline BRCA carriers with PDAC include the use of platinum-based therapy and the validation of PARPi administration as a maintenance strategy in platinum-sensitive patients. In the era of precision medicine, this is the first convincing example of targeting identified germline hereditary mutations in PDAC.

DOI: https://doi.org/10.6004/jnccn.2021.7031
Leukemia. 2021 Apr 13.

Targeted gene panels identify a high frequency of pathogenic germline variants in patients diagnosed with a hematological malignancy and at least one other independent cancer.

Singhal D, Hahn CN, Feurstein S, Wee LYA, Moma L, Kutyna MM, Chhetri R, Eshraghi L, Schreiber AW, Feng J, Wang PP, Babic M, Parker WT, Gao S, Moore S, Das S, Thomas D, Pattnaik S, Brown AL, D'Andrea RJ, Poplawski NK, Thomas D, Scott HS, Godley LA, Hiwase DK.

The majority of studies assessing the contribution of pathogenic germline variants (PGVs) to cancer predisposition have focused on patients with single cancers. We analyzed 45 known cancer predisposition genes (CPGs) in germline samples of 202 patients with hematological malignancies (HMs) plus one or more other independent cancer managed at major tertiary medical centers on two different continents. This included 120 patients with therapy-related myeloid neoplasms (t-MNs), where the HM occurred after cytotoxic treatment for a first malignancy, and 82 patients with multiple cancers in which the HM was not preceded by cytotoxic therapy (MC-HM). Using American College of Medical Genetics/Association for Molecular Pathology variant classification guidelines, 13% of patients had PGVs, most frequently identified in CHEK2 (17% of PGVs), BRCA1 (13%), DDX41 (13%), and TP53 (7%). The frequency of PGVs in MC-HM was higher than in t-MN, although not statistically significant (18 vs. 9%; p = 0.085). The frequency of PGVs in lymphoid and myeloid HM patients was similar (19 vs. 17.5%; p > 0.9). Critically, patients with PGVs in BRCA1, BRCA2 or TP53 did not satisfy current clinical phenotypic criteria for germline testing. Our data suggest that a personal history of multiple cancers, one being a HM, should trigger screening for PGVs.

DOI: https://doi.org/10.1038/s41375-021-01246-w
Tumori. 2021 Apr 13. 3008916211009316

Gardner-associated fibroma of the neck: role of a multidisciplinary evaluation for familial adenomatous polyposis diagnosis.

Signoroni S, Piozzi GN, Collini P, Cocco IMF, Biasoni D, Chiaravalli S, Ricci MT, Vitellaro M.

  INTRODUCTION: Familial adenomatous polyposis (FAP) is a hereditary autosomal dominant disorder characterized by the development of multiple adenomas in the colon and rectum with a lifetime risk of 80%-100% to develop colorectal cancer if undetected or untreated. Gardner-associated fibroma (GAF) is a rare, benign soft tissue lesion with uncertain pathogenesis. GAF is generally associated with FAP in its clinical variant, called Gardner syndrome (GS).CASE DESCRIPTION: A 16-year-old boy with no comorbidities and no significant medical history was referred to the Unit of Hereditary Digestive Tract Tumours, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy, for genetic counselling after surgical removal of a right anterior cervical paramedian fibroma. The histopathology on the specimen led to the diagnosis of GAF. He had no family history for colorectal cancer or gastrointestinal polyposis and denied any gastrointestinal symptoms. Physical examination showed a small frontal osteoma and colonoscopy showed the presence of multiple small sessile polyps (>100 polyps, diameter <5 mm) diffusely present on the large bowel. Genetic testing revealed a pathogenic germline variant in the APC gene. The predictive genetic test on the patient's parents and sister was negative for the identified APC mutation; therefore, the patient carried an apparent de novo germline mutation.
CONCLUSIONS: GAF may represent a sentinel sign of FAP, preceding gastrointestinal symptoms and endoscopic findings. A careful multidisciplinary approach is determinant for correct and early diagnosis of FAP.

Keywords:  APC gene; Familial adenomatous polyposis; Gardner-associated fibroma

DOI:  https://doi.org/10.1177/03008916211009316
Clin Gastroenterol Hepatol. 2021 Apr 12. pii: S1542-3565(21)00447-X. [Epub ahead of print]

Germline cancer susceptibility gene testing in unselected patients with colorectal adenocarcinoma: A multi-center prospective study.

Uson Junior PLS, Riegert-Johnson D, Boardman L, Kisiel J, Mountjoy L, Patel N, Lizaola-Mayo B, Borad MJ, Ahn D, Sonbol MB, Jones J, Leighton JA, Gurudu S, Singh H, Klint M, Kunze KL, Golafshar MA, Esplin ED, Nussbaum RL, Stewart AK, Bekaii-Saab T, Samadder NJ.

  BACKGROUND & AIM: Hereditary factors play a role in the development of colorectal cancer (CRC). Identification of germline predisposition can have implications on treatment and cancer prevention. To determine prevalence of pathogenic germline variants (PGV) in CRC patients using an universal testing approach, association with clinical outcomes and the uptake of family variant testing.DESIGN: We undertook a prospective multi-site study of germline sequencing using an >80 gene NGS platform among CRC patients (not selected for age or family history) receiving care at Mayo Clinic Cancer Centers between April 1, 2018 and March 31, 2020.
RESULTS: Of 361 patients, the median age was 57 years (SD 12.4), 43.5% were female, 82% were white and 38.2% had stage IV disease. PGV were found in 15.5% (n=56) of patients, including 44 in moderate and high penetrance cancer susceptibility genes. Thirty-four (9.4%) patients had incremental clinically actionable findings that would not have been detected by practice guideline criteria or a CRC specific gene panel. Only younger age at diagnosis was associated with presence of PGV (OR 1.99, 95% CI:1.12-3.56). After a median follow-up of 20.7 months, no differences in overall survival was seen between those with or without a PGV (P=0.2). 11% of patients had modifications in their treatment based on genetic findings. Family cascade testing was low (16%).
CONCLUSIONS: Universal multi-gene panel testing in CRC was associated with a modest, but significant detection of heritable mutations over guideline-based testing. One in ten patients had changes in their management based on test results. Uptake of cascade family testing was low, a concerning observation which warrants further study.

Keywords:  colorectal cancer; germline testing; homologous recombination deficiency; lynch syndrome

DOI:  https://doi.org/10.1016/j.cgh.2021.04.013
Infect Drug Resist. 2021 ;14 1311-1317

Diagnosing MonoMAC Syndrome in GATA2 Germline Mutated Myelodysplastic Syndrome via Next-Generation Sequencing in a Patient with Refractory and Complex Infection: Case Report and Literature Review.

Shen Y, Li Y, Li H, Liu Q, Dong H, Wang B, Ye B, Lin S, Shen Y, Wu D.

  Monocytopenia and mycobacterial infection (MonoMAC) syndrome is a rare disease. Herein, we reported a 65-year-old Asian woman, previously diagnosed with myelodysplastic syndrome (MDS), suffering from recurrent pneumonia, intermittent fever, fatigue, and chest tightness lasting for five months. She was ultimately diagnosed with MonoMAC syndrome with Mycobacterium kansasii (M. kansasii) infection and GATA2 mutation through metagenomic generation sequencing (mNGS) of peripheral blood specimen, for which she was given anti-NTM therapy. Her situation significantly improved within 2 weeks of therapy. We discussed the clinical features, genetic characteristic, and prognosis of this disorder, aiming to further elucidate this rare syndrome. For MDS/AML patient with recurrent mixed infection and pancytopenia (especially with monocyte absence), MonoMAC syndrome should be highly suspected, and germline mutation and pathogen sequencing should be performed.

Keywords:  GATA-2 germline mutation; M. kansasii; MonoMAC; monocytopenia and mycobacterial infection syndrome; next-generation sequencing; nontuberculous mycobacteria

DOI:  https://doi.org/10.2147/IDR.S305825
Int J Gynecol Cancer. 2021 Apr 15. pii: ijgc-2020-002299. [Epub ahead of print]

Lynch syndrome associated endometrial carcinomas in Western Australia: an analysis of universal screening by mismatch repair protein immunohistochemistry.

Gupta S, Nichols CB, Phillips J, O'Sullivan S, Ayres C, Mohan GR, Leung Y, Stewart CJR, Tan A, Schofield L, Salfinger SG, Kiraly-Borri C, Pachter N, Cohen PA.

  BACKGROUND: In 2016 universal screening with mismatch repair protein immunohistochemistry in all newly diagnosed endometrial carcinomas was introduced in Western Australia.OBJECTIVE: To compare the prevalence of Lynch syndrome associated endometrial carcinomas between 2016 and 2019 with a historical control (2015). Additionally, to compare the number of cases appropriately referred for genetic assessment.
METHODS: A cross-sectional study of cases presented at the Western Australia gynecologic oncology tumor board was carried out. The primary outcome was the prevalence of Lynch syndrome associated endometrial carcinomas. A secondary outcome was the number of cases appropriately referred for genetic assessment. The following variables were extracted: date of birth; age at diagnosis; vital status; tumor mismatch repair protein expression status (retained or lost) and if lost, the specific mismatch repair protein deficiency; patients who were referred to a genetic clinic; and family history, if recorded. Data were collected from the clinical databases of the Familial Cancer Program at Genetic Services of Western Australia and WOMEN Center, to determine whether patients were appropriately referred for genetic evaluation and to ascertain the results of genetic testing.
RESULTS: Between 2016 and 2019, there were 1040 new endometrial carcinomas. Tumors of 883 (85%) patients underwent mismatch repair protein immunohistochemistry compared with 117 of 199 patients (59%) in 2015 (χ2 73.14, p<0.001). Of 883 tumors tested, 242 (27%) showed loss of mismatch repair protein expression. In 2015, 30 (26%) tumors of 117 tested showed loss of mismatch repair protein expression. During the 4 years of universal screening, 13 (1.5%) of 883 patients screened were diagnosed with Lynch syndrome compared with 2 (1.7%) of 117 in 2015 (Fisher's exact test 0.04, p=0.69). In 2015, 11 (37%) of 30 patients with loss of mismatch repair protein expression were not referred for genetic assessment compared with 36 (17%) of 209 patients in the universal screening group (χ2 6.28, p=0.02). No cases of Lynch syndrome were diagnosed in patients aged over 70 years.
CONCLUSIONS: Universal immunohistochemical screening did not increase the proportion of Lynch syndrome associated endometrial carcinomas identified, although the study was underpowered to detect small differences. There was an improvement in appropriate referrals for genetic assessment.

Keywords:  endometrial neoplasms; lynch syndrome II

DOI:  https://doi.org/10.1136/ijgc-2020-002299
Biomed Res. 2021 ;42(2): 89-94

Genomic profiling of multiple tissues in two patients with multiple endocrine neoplasia type 1.

Naruoka A, Ohnami S, Nagashima T, Serizawa M, Hatakeyama K, Ohshima K, Ohnami S, Urakami K, Horiuchi Y, Kiyozumi Y, Matsubayashi H, Abe M, Ohishi T, Kameya T, Sugino T, Onitsuka T, Isaka M, Ohde Y, Sugiura T, Ito T, Uesaka K, Akiyama Y, Kusuhara M, Yamaguchi K.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant tumor syndrome. This hereditary cancer is caused by germline variants in MEN1. Two patients with MEN1 were identified via whole exome sequencing and gene expression profile analysis, conducted for 5,063 patients with various types of cancers. We obtained multiple tumors from each patient; tumors derived from these two MEN1 patients had a loss of the normal MEN1 allele and frequently chromosomal copy number changes. Thus, we investigated whether structural variants were present in the MEN1 patient genomes. Whole-genome sequencing revealed no catastrophic rearrangements, and the tumor samples had very low somatic variants. The two patients had germline variants in MEN1 and some chromosomal copy number changes including on chromosome 11. The only pathogenic variant detected was the MEN1 germline variant, and chromosomal rearrangements led to tumorigenesis in somatic cells. Furthermore, the MEN1 tumor samples displayed a specific signature characterized by T:A>C:G transition. Studies of multiple tumors obtained from single patients are rare in hereditary cancer syndromes, and our results provide insights that the second hit of the tumor suppressor gene MEN1 may be caused by a gross genome rearrangement, not a small insertion and deletion, nor a change in epigenetic regulation.

DOI: https://doi.org/10.2220/biomedres.42.89
Cancer. 2021 Apr 15.

Germline mutations and age at onset of lung adenocarcinoma.

Reckamp KL, Behrendt CE, Slavin TP, Gray SW, Castillo DK, Koczywas M, Cristea MC, Babski KM, Stearns D, Marcum CA, Rodriguez YP, Hass AJ, Vecchio MM, Mora P, Cervantes AE, Sand SR, Mejia RM, Tsou TC, Salgia R, Weitzel JN.

  BACKGROUND: To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset.METHODS: The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model.
RESULTS: Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking.
CONCLUSIONS: Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

Keywords:  BRCA2; EGFR; TP53; adenocarcinoma; germline pathogenic variants; hereditary lung cancer

DOI:  https://doi.org/10.1002/cncr.33573