bims-lifras 2019-12-22 papers

bims-lifras

Biomed News

on Li-Fraumeni Syndrome

Issue of 2019‒12‒22
eighteen papers selected by
Joanna Zawacka-Pankau

AML through the prism of molecular genetics.
ATM-Mutated Pancreatic Cancer: Clinical and Molecular Response to Gemcitabine/Nab-Paclitaxel After Genome-Based Therapy Resistance.
MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer.
Extent of Pedigree Required to Screen for and Diagnose Hereditary Nonpolyposis Colorectal Cancer: Comparison of Simplified and Extended Pedigrees.
Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma.
CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management.
CDH1 on multigene panel testing: Look before you leap.
Colorectal cancer in Lynch syndrome associated with PMS2 and MSH6 mutations.
Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes.
Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.
Multiple Cutaneous Leiomyomas with Uterus Myomatosus (MCUL) - Two Case Reports and One New Mutation of FH Gene.
De novo pathogenic germline variant in PALB2 in a patient with pancreatic cancer.
Immune gene expression profiling reveals heterogeneity in luminal breast tumors.
Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.
Acromegaly in the setting of Tatton-Brown-Rahman Syndrome.
Germline Polymorphisms in the Nuclear Receptors PXR and VDR as Novel Prognostic Markers in Metastatic Colorectal Cancer Patients Treated With FOLFIRI.
Germline variants and response to systemic therapy in advanced prostate cancer.
PMS2 germline mutation c.1577delA (p.Asp526Alafs*69)-induced Lynch syndrome-associated endometrial cancer: A case report.

Br J Haematol. 2020 Jan;188(1): 49-62

AML through the prism of molecular genetics.

Charrot S, Armes H, Rio-Machin A, Fitzgibbon J.

  Modern management of acute myeloid leukaemia (AML) relies on the integration of phenotypic and genetic data to assign classification, establish prognosis, enhance monitoring and guide treatment. The prism through which we can now disperse a patient's leukaemia, interpret and apply our understanding has fundamentally changed since the completion of the first whole-genome sequencing (WGS) of an AML patient in 2008 and where possible, many clinicians would now prefer to delay treatment decisions until the karyotype and genetic status of a new patient is known. The success of global sequencing initiatives such as The Cancer Genome Atlas (TCGA) have brought us significantly closer to cataloguing the full spectrum of coding mutations involved in human malignancy. Indeed, genetic capability has raced ahead of our capacity to apply much of this knowledge into clinical practice and we are in the peculiar position of having routine access to genetic information on an individual patient's leukaemia that cannot be reliably interpreted or utilised. This is a measure of how rapid the progress has been, and this rate of change is likely to continue into the foreseeable future as research intensifies on the non-coding genome and the epigenome, as we scrutinise disease at a single cell level, and as initiatives like Beat AML and the Harmony Alliance progress. In this review, we will examine how interrogation of the coding genome is revolutionising our understanding of AML and improving our ability to underscore differences between paediatric and adult onset, sporadic and inherited forms of disease. We will look at how this knowledge is informing improvements in outcome prediction and the development of novel treatments, bringing us a step closer to personalised therapy for myeloid malignancy.

Keywords:  acute myeloid leukaemia; germline predisposition; molecular genetics; next generation sequencing

DOI:  https://doi.org/10.1111/bjh.16356
Pancreas. 2020 Jan;49(1): 143-147

ATM-Mutated Pancreatic Cancer: Clinical and Molecular Response to Gemcitabine/Nab-Paclitaxel After Genome-Based Therapy Resistance.

Martino C, Pandya D, Lee R, Levy G, Lo T, Lobo S, Frank RC.

Metastatic pancreatic cancer (PC) is an aggressive malignancy, with most patients deriving benefit only from first-line chemotherapy. Increasingly, the recommended treatment for those with a germline mutation in a gene involved in homologous recombination repair is with a platinum drug followed by a poly (ADP-ribose) polymerase (poly adenosine phosphate-ribose polymerase [PARP]) inhibitor. Yet, this is based largely on studies of BRCA1/2 or PALB2 mutated PC. We present the case of a 44-year-old woman with ATM-mutated PC who achieved stable disease as the best response to first-line fluorouracil, leucovorin, irinotecan, and oxaliplatin, followed by progression on a PARP inhibitor. In the setting of jaundice, painful hepatomegaly, and a declining performance status, she experienced rapid disease regression with the nonplatinum regimen, gemcitabine plus nab-paclitaxel. Both physical stigmata and abnormal laboratory values resolved, imaging studies showed a reduction in metastases and her performance status returned to normal. Measurement of circulating tumor DNA for KRAS G12R by digital droplet polymerase chain reaction confirmed a deep molecular response. This case highlights that first-line treatment with a platinum-containing regimen followed by PARP inhibition may not be the best choice for individuals with ATM-mutated pancreatic cancer. Additional predictors of treatment response are needed in this setting.

DOI: https://doi.org/10.1097/MPA.0000000000001461
Eur J Gastroenterol Hepatol. 2019 Dec 16.

MSH6 gene pathogenic variant identified in familial pancreatic cancer in the absence of colon cancer.

Mannucci A, Zuppardo RA, Crippa S, Carrera P, Patricelli MG, Russo Raucci A, Calabrese F, Lazarevic D, Giannese F, Tonon G, Ferrari M, Testoni PA, Cavestro GM.

OBJECTIVES: Lynch syndrome is characterized by pathogenetic variants in the mismatch repair genes and autosomal dominant inheritance with incomplete penetrance. Lynch syndrome is characterized by colorectal and, with lesser and variable extent, extracolonic cancers. We describe a family with MSH6-dependent Lynch syndrome and familial pancreatic cancer and other tumours (gastric and endometrial), in the absence of colorectal neoplasia.METHODS: Patients were analysed by sequencing, Next Generation or Sanger, to identify germinal pathogenic variants in hereditary cancer genes.
RESULTS: We identified the MSH6 gene pathogenic variant c.2194C>T, p.(Arg732Ter) in a family with hereditary pancreatic cancer without diagnosed cases of colorectal adenocarcinoma. Seven family members were affected by the MSH6 pathogenic variant. Three had pancreatic adenocarcinoma at 65, 57 and 44 years; one had endometrial cancer at 36 years. None of the remaining three subjects (75, 45 and 17 years old) had developed any cancer yet.
CONCLUSIONS: Lynch syndrome should be suspected in families with familial pancreatic cancer, even in the absence of colon cancers. Specifically, our observation supports the association between the MSH6 c.2194C>T pathogenic variant and extracolonic tumours and it suggests that MSH6 pathogenic variants are associated with familial pancreatic cancer more frequently than assumed.

DOI: https://doi.org/10.1097/MEG.0000000000001617
Dis Colon Rectum. 2019 Dec 13.

Extent of Pedigree Required to Screen for and Diagnose Hereditary Nonpolyposis Colorectal Cancer: Comparison of Simplified and Extended Pedigrees.

Heo Y, Kim MH, Kim DW, Lee SA, Bang S, Kim MJ, Oh HK, Kang SB, Kang SI, Park JW, Ryoo SB, Jeong SY, Park KJ.

BACKGROUND: Obtaining an accurate pedigree is the first step in recognizing a patient with hereditary nonpolyposis colorectal cancer, or Lynch syndrome. However, lack of standardization of the degree of relationship included in the pedigrees generally limits obtaining a complete and/or accurate pedigree.DESIGN: This study analyzed the extent of pedigree required to screen for colorectal cancer and to diagnose Lynch syndrome.
SETTINGS: The study was conducted at 2 tertiary care centers.
PATIENTS: A detailed family history was obtained from patients undergoing surgery for colorectal cancer from 2003 to 2016. A simplified pedigree that included only first-degree relatives was obtained and compared with the extended pedigree.
MAIN OUTCOME MEASURES: The eligibility of the 2 pedigrees was assessed for each proband. The proportion of patients who would be missed using a simplified rather than an extended pedigree was calculated based on the American Cancer Society guidelines for recommending screening for colorectal cancer, on the revised Bethesda guidelines and the revised suspected hereditary nonpolyposis colorectal cancer criteria for screening for hereditary colorectal cancer, and on the Amsterdam II criteria for diagnosis of Lynch syndrome.
RESULTS: The study examined 2015 families, including 41,826 individuals. Use of simplified and extended pedigrees was comparable in screening for colorectal cancer, with ratios of 183 of 185 (98.9%) for American Cancer Society guidelines, 295 of 295 (100%) for revised Bethesda guidelines, and 60 of 60 (100%) for revised suspected hereditary nonpolyposis colorectal cancer criteria. However, the use of simplified pedigrees missed a definitive diagnosis of Lynch syndrome in 6 of 10 patients fulfilling Amsterdam II criteria based on extended pedigrees. The mean ages at diagnosis of the 4 probands included and the 6 missed using simplified pedigrees differed significantly (60.8 vs 38.2 y).
LIMITATIONS: The study was limited by its recall bias, cross-sectional nature, lack of germline testing, and potential inapplicability to the general population.
CONCLUSIONS: A simplified pedigree is acceptable for selecting candidates to screen for hereditary colorectal cancer, whereas an extended pedigree is still required for a more precise diagnosis of Lynch syndrome, especially in younger patients. See Video Abstract at http://links.lww.com/DCR/B97.

DOI: https://doi.org/10.1097/DCR.0000000000001550
Genet Med. 2019 Dec 17.

Prevalence of pathogenic germline cancer risk variants in high-risk urothelial carcinoma.

Nassar AH, Abou Alaiwi S, AlDubayan SH, Moore N, Mouw KW, Kwiatkowski DJ, Choueiri TK, Curran C, Berchuck JE, Harshman LC, Nuzzo PV, Chanza NM, Van Allen E, Esplin ED, Yang S, Callis T, Garber JE, Rana HQ, Sonpavde G.

  PURPOSE: To date, there has not been a large, systematic evaluation of the prevalence of germline risk variants in urothelial carcinoma (UC).METHODS: We evaluated the frequency of germline pathogenic and likely pathogenic variants in 1038 patients with high-risk UC who underwent targeted clinical germline testing. Case-control enrichment analysis was performed to screen for pathogenic variant enrichment in 17 DNA repair genes in 1038 UC patients relative to cancer-free individuals.
RESULTS: Among 1038 patients with UC, the cumulative frequency of patients with pathogenic variants was 24%; 18.6% of patients harbored ≥1 actionable germline variant with preventive or therapeutic utility. MSH2 (34/969, 3.5%) and BRCA1/2 (38/867, 4.4%) germline variants had the highest frequency. Germline variants in DNA damage repair genes accounted for 78% of pathogenic germline variants. Compared to the cancer-free cohort, UC patients had significant variant enrichment in MSH2 (odds ratio [OR]: 15.4, 95% confidence interval [CI]: 7.1-32.7, p < 0.0001), MLH1 (OR: 15.9, 95% CI: 4.4-67.7, p < 0.0001), BRCA2 (OR: 5.7, 95% CI: 3.2-9.6, p < 0.0001), and ATM (OR: 3.8, 95% CI: 1.8-8.3, p = 0.02).
CONCLUSION: In this study, 24% of UC patients harbored pathogenic germline variants and 18.6% had clinically actionable variants. MLH1 and MSH2 were validated as UC risk genes while ATM and BRCA2 were highlighted as potential UC predisposition genes. This work emphasizes the utility of germline testing in selected high-risk UC cohorts.

Keywords:  DNA damage repair; bladder cancer; clinical genetics; germline; urothelial carcinoma

DOI:  https://doi.org/10.1038/s41436-019-0720-x
Cancer Manag Res. 2019 ;11 10477-10486

CDH1 (E-Cadherin) Mutation and Gastric Cancer: Genetics, Molecular Mechanisms and Guidelines for Management.

Shenoy S.

  Introduction: Germline mutation in CDH1 (E-cadherin) tumor suppressor gene is associated with hereditary diffuse gastric cancer (HDGC) and lobular breast cancers (LBC). E-Cadherin protein is necessary for physiological signaling pathways, such as cell proliferation, maintenance of cell adhesion, cell polarity and epithelial-mesenchymal transition. Dysregulation leads to tumor proliferation, invasion, migration and metastases. We review current perspectives in CDH1 genetics with molecular mechanisms and also discuss management strategies for this aggressive form of gastric cancer.Methods: Relevant articles from PubMed/Medline and Embase (1994-2019) were searched and collected using the phrases "Hereditary diffuse gastric cancer, Familial gastric cancer, CDH1 mutation, E-Cadherin, Lobular breast cancer, Prophylactic total gastrectomy".
Results: Current guidelines suggest maintaining a high degree of suspicion of hereditary etiology and recommend testing for CDH1 mutations in patients with familial clustering of HDGC and LBC, especially onset at an early age (before 40 years). In families lacking CDH1 mutations but with high suspicion for hereditary predisposition, testing of CTNNA1 and other closely related HDGC susceptibility genes could be considered. Prophylactic total gastrectomy is recommended for individuals with identified pathogenic germline variants. Endoscopic surveillance with biopsies is recommended for those choosing to delay prophylactic gastrectomy.
Conclusion: Mutation or transcriptional silencing of the CDH1 gene is associated with familial diffuse gastric cancer. Further studies on the expression and the alteration in the proteins in the E-cadherin pathways may serve as biomarkers for early detection; stratify risk and selection of appropriate therapy in these families. Until then prophylactic total gastrectomy is recommended for individuals with CDH1 mutations and family history of diffuse gastric cancer. Endoscopic surveillance and biopsies by experienced gastroenterologists is recommended for those choosing not to have prophylactic gastrectomy and in individuals with CDH1 variants.

Keywords:  CDH1 gene; E-cadherin functions; diffuse gastric cancer; lobular breast carcinoma

DOI:  https://doi.org/10.2147/CMAR.S208818
J Natl Cancer Inst. 2019 Dec 16. pii: djz229. [Epub ahead of print]

CDH1 on multigene panel testing: Look before you leap.

Katona BW, Clark DF, Domchek SM.

  Multigene panel testing (MGPT) has become a critical component of cancer risk assessment in clinical practice. As technology and access improves, and costs decrease, more individuals than ever are undergoing MGPT for genetic evaluation. One gene that deserves special consideration when included on MGPT is CDH1, which codes for the cell-cell adhesion protein E-cadherin. Pathogenic germline variants in CDH1 have been associated with hereditary diffuse gastric cancer syndrome, and in highly penetrant families, testing for these variants is critical for proper risk management. However, recent data demonstrated that gastric cancer penetrance in unselected CDH1 carriers may be lower than expected. Further complicating matters are the lack of effective screening strategies for gastric cancer and recommendation for risk-reducing total gastrectomy in CDH1 carriers. Therefore, the discovery of an unexpected pathogenic CDH1 variant on multigene panel testing, when testing for CDH1 would not normally be considered based on personal or family history alone, creates dilemmas for both patients and providers. In this commentary, we highlight the potential for unexpected CDH1 variants on MGPT, outline the uncertainties associated with these variants, and emphasize the importance of pre-test counseling regarding the potential for an unexpected CDH1 variant. While CDH1 testing is often important for clinical decision making, individuals and providers need to be aware of the potential for an unexpected CDH1 variant when CDH1 is included on MGPT for cancer risk assessment.

Keywords:   CDH1 ; diffuse gastric cancer; multigene panel testing

DOI:  https://doi.org/10.1093/jnci/djz229
Int J Colorectal Dis. 2019 Dec 16.

Colorectal cancer in Lynch syndrome associated with PMS2 and MSH6 mutations.

Yılmaz A, Mirili C, Bilici M, Tekin SB.

  BACKGROUND: It is known that colorectal cancers (CRC) are frequently seen and constitute an important part of cancer-related deaths. Lynch syndrome (LS) is responsible for 3-5% of CRCs and develops due to mutations in DNA mismatch repair (MMR) genes. The most important MMR genes are MutL homolog1 (MLH1), mutS homolog 2 (MSH2), mutS homolog 6 (MSH6) and postmeiotic segregation increased 2 (PMS2). PMS2 and MSH6 mutations are very rarely seen in LS.CASE PRESENTATION: We present a case that developed metastatic CRC, which we diagnosed as LS in association with a very rarely seen PMS2 and MSH6 germline mutation. Genetic counseling was recommended for the family, and screening programs were initiated for the family of the patient whose chemotherapy was continued after the diagnosis.
CONCLUSION: With the increase in daily use of next-generation sequencing (NGS) technology, it is thought that detection rate of both combined mutations and rare mutations will be increased.

Keywords:  Colorectal cancer; Lynch syndrome; MSH6; PMS2

DOI:  https://doi.org/10.1007/s00384-019-03454-4
Mod Pathol. 2019 Dec 19.

Retained mismatch repair protein expression occurs in approximately 6% of microsatellite instability-high cancers and is associated with missense mutations in mismatch repair genes.

Hechtman JF, Rana S, Middha S, Stadler ZK, Latham A, Benayed R, Soslow R, Ladanyi M, Yaeger R, Zehir A, Shia J.

Immunohistochemistry for mismatch repair protein expression is widely used as a surrogate for microsatellite instability status-an important signature for immunotherapy and germline testing. There are no systematic analyses examining the sensitivity of immunohistochemistry for microsatellite instability-high status. Mismatch repair immunohistochemistry and microsatellite instability testing were performed routinely as clinically validated assays. We classified germline/somatic mutation types as truncating (nonsense, frameshift, and in/del) versus missense and predicted pathogenicity of the latter. Discordant cases were compared with concordant groups: microsatellite instability-high/mismatch repair-deficient for mutation comparison and microsatellite stable/mismatch repair-proficient for immunohistochemical comparison. 32 of 443 (7%) microsatellite instability-high cases had immunohistochemistry. Four additional microsatellite instability-high research cases had discordant immunohistochemistry. Of 36 microsatellite instability-high cases with discordant immunohistochemistry, 30 were mismatch repair-proficient, while six (five MLH1 and one MSH2) retained expression of the defective mismatch repair protein and lost its partner. In microsatellite instability-high tumors with discordant immunohistochemistry, we observed an enrichment in deleterious missense mutations over truncating mutations, with 69% (25/36) of cases having pathogenic germline or somatic missense mutations, as opposed to only 19% (7/36) in a matched microsatellite instability-high group with concordant immunohistochemistry (p = 0.0007). In microsatellite instability-high cases with discordant immunohistochemistry and MLH1 or PMS2 abnormalities, less cells showed expression (p = 0.015 and p = 0.00095, respectively) compared with microsatellite stable/mismatch repair-proficient cases. Tumor mutation burden, MSIsensor score, and truncating mismatch repair gene mutations were similar between microsatellite instability-high cases with concordant versus discordant immunohistochemical expression. Approximately 6% of microsatellite instability-high cases have retained mismatch repair protein expression and would be missed by immunohistochemistry-based testing, hindering patient access to immunotherapy. Another 1% of microsatellite instability-high cases show isolated loss of the defective gene's dimerization partner, which may lead to germline testing of the wrong gene. These cases are enriched for pathogenic mismatch repair missense mutations.

DOI: https://doi.org/10.1038/s41379-019-0414-6
OMICS. 2019 Dec 17.

Next-Generation Sequencing Identifies BRCA1 and/or BRCA2 Mutations in Women at High Hereditary Risk for Breast Cancer with Shorter Telomere Length.

Peker Eyüboğlu İ, Yenmiş G, Bingöl EN, Yüksel Ş, Tokat F, Özbek P, Güllü Amuran G, Yakıcıer C, Akkiprik M.

  Telomeres, and telomere length in particular, have broad significance for genome biology and thus are prime research targets for complex diseases such as cancers. In this context, BRCA1 and BRCA2 gene mutations have been implicated in relationship to telomere length, and breast cancer susceptibility. Yet, the linkages among human genetic variation and telomere length in persons with high hereditary cancer risk are inadequately mapped. We report here original findings in 113 unrelated women at high hereditary risk for breast cancer, who were characterized for the BRCA1 and BRCA2 mutations using next-generation sequencing. Thirty-one BRCA2 and 21 BRCA1 mutations were identified in 47 subjects (41.6%). The women with a mutation in BRCA1 and/or BRCA2 genes had, on average, 12% shorter telomere compared to women with no BRCA1 or BRCA2 mutation (p = 0.0139). Moreover, the association between telomere length and BRCA mutation status held up upon stratified analysis in those with or without a breast cancer diagnosis. We also indentified two rare mutations, c.536_537insT and c.10078A>G, and a novel mutation c.8680C>G in BRCA2 that was studied further by homology modeling of the DNA binding tower domain of BRCA2 and the structure of the protein. These data collectively lend evidence to the idea that BRCA1 and BRCA2 mutations play a role in telomere length in women at high hereditary risk for breast cancer. Further clinical and diagnostics discovery research on BRCA1 and BRCA2 variation, telomere length, and breast cancer mechanistic linkages are called for in larger study samples.

Keywords:  BRCA1; BRCA2; breast cancer; family history; next-generation sequencing; telomere length

DOI:  https://doi.org/10.1089/omi.2019.0103
Open Access Maced J Med Sci. 2019 Sep 30. 7(18): 3026-3029

Multiple Cutaneous Leiomyomas with Uterus Myomatosus (MCUL) - Two Case Reports and One New Mutation of FH Gene.

Koch A, Schönlebe J, Vojvodic A, Lotti T, Wollina U.

  BACKGROUND: Reed syndrome or multiple cutaneous leiomyomas with uterine leiomyomas are part of the spectrum of heterozygous hereditary disorders with cutaneous, genital and renal manifestations.CASE REPORTS: We report two female cases of multiple cutaneous leiomyomas with uterine leiomyomas (MCUL) without renal disease, in particular without cysts or papillary renal carcinoma, aged 52 and 55 years, respectively. The diagnosis of pilar leiomyomas was confirmed by histology and immunostaining for smooth muscle actin and desmin. Both females had a hysterectomy in the past because of uterus myomatosus. In one patient, a new mutation of the FH gene was detected, i.e. a heterozygote c1300_1301del (p.Cys434Argfs17) mutation in the exon 9 of the FH gene.
CONCLUSION: Since MCUL shares features with the genetic cancer syndrome hereditary leiomyomatosis and renal cell carcinoma (HLRCC), these patients need a regular follow-up to prevent the late diagnosis of renal cancer.

Keywords:  Fumarate dehydrogenase; Leiomyomatosis; Reed syndrome

DOI:  https://doi.org/10.3889/oamjms.2019.625
Fam Cancer. 2019 Dec 19.

De novo pathogenic germline variant in PALB2 in a patient with pancreatic cancer.

Bernstein Molho R, Zalmanoviz S, Laitman Y, Friedman E.

  De novo mutations in the major breast/ovarian cancer susceptibility genes BRCA1 and BRCA2 are rare. De novo mutations in the PALB2 gene have never been reported. Here we report a de novo PALB2 germ line mutation (c.3455delC (p.Pro1152Hisfs*11) in a patient with pancreatic cancer, where non-paternity and somatic parental mosaicism have to the extent possible been excluded as a mechanism for detecting the de novo mutation. The lack of previous reports on de novo PALB2 mutations maybe the limited number of PALB2germline mutations reported overall.

Keywords:  Inherited predisposition to cancer; Mosaicism; PALB2 gene; de novo mutation

DOI:  https://doi.org/10.1007/s10689-019-00157-1
Breast Cancer Res. 2019 Dec 19. 21(1): 147

Immune gene expression profiling reveals heterogeneity in luminal breast tumors.

Zhu B, Tse LA, Wang D, Koka H, Zhang T, Abubakar M, Lee P, Wang F, Wu C, Tsang KH, Chan WC, Law SH, Li M, Li W, Wu S, Liu Z, Huang B, Zhang H, Tang E, Kan Z, Lee S, Park YH, Nam SJ, Wang M, Sun X, Jones K, Zhu B, Hutchinson A, Hicks B, Prokunina-Olsson L, Shi J, Garcia-Closas M, Chanock S, Yang XR.

  BACKGROUND: Heterogeneity of immune gene expression patterns of luminal breast cancer (BC), which is clinically heterogeneous and overall considered as low immunogenic, has not been well studied especially in non-European populations. Here, we aimed at characterizing the immune gene expression profile of luminal BC in an Asian population and associating it with patient characteristics and tumor genomic features.METHODS: We performed immune gene expression profiling of tumor and adjacent normal tissue in 92 luminal BC patients from Hong Kong using RNA-sequencing data and used unsupervised consensus clustering to stratify tumors. We then used luminal patients from The Cancer Genome Atlas (TCGA, N = 564) and a Korean breast cancer study (KBC, N = 112) as replication datasets.
RESULTS: Based on the expression of 130 immune-related genes, luminal tumors were stratified into three distinct immune subtypes. Tumors in one subtype showed higher level of tumor-infiltrating lymphocytes (TILs), characterized by T cell gene activation, higher expression of immune checkpoint genes, higher nonsynonymous mutation burden, and higher APOBEC-signature mutations, compared with other luminal tumors. The high-TIL subtype was also associated with lower ESR1/ESR2 expression ratio and increasing body mass index. The comparison of the immune profile in tumor and matched normal tissue suggested a tumor-derived activation of specific immune responses, which was only seen in high-TIL patients. Tumors in a second subtype were characterized by increased expression of interferon-stimulated genes and enrichment for TP53 somatic mutations. The presence of three immune subtypes within luminal BC was replicated in TCGA and KBC, although the pattern was more similar in Asian populations. The germline APOBEC3B deletion polymorphism, which is prevalent in East Asian populations and was previously linked to immune activation, was not associated with immune subtypes in our study. This result does not support the hypothesis that the germline APOBEC3B deletion polymorphism is the driving force for immune activation in breast tumors in Asian populations.
CONCLUSION: Our findings suggest that immune gene expression and associated genomic features could be useful to further stratify luminal BC beyond the current luminal A/B classification and a subset of luminal BC patients may benefit from checkpoint immunotherapy, at least in Asian populations.

Keywords:  APOBEC3B germline deletion; Asian; Immune subtypes; Luminal breast cancer; Somatic mutations; Tumor-infiltrating lymphocytes

DOI:  https://doi.org/10.1186/s13058-019-1218-9
Genet Med. 2019 Dec 19.

Classification of variants of uncertain significance in BRCA1 and BRCA2 using personal and family history of cancer from individuals in a large hereditary cancer multigene panel testing cohort.

Li H, LaDuca H, Pesaran T, Chao EC, Dolinsky JS, Parsons M, Spurdle AB, Polley EC, Shimelis H, Hart SN, Hu C, Couch FJ, Goldgar DE.

  PURPOSE: Genetic testing of individuals often results in identification of genomic variants of unknown significance (VUS). Multiple lines of evidence are used to help determine the clinical significance of these variants.METHODS: We analyzed ~138,000 individuals tested by multigene panel testing (MGPT). We used logistic regression to predict carrier status based on personal and family history of cancer. This was applied to 4644 tested individuals carrying 2383 BRCA1/2 variants to calculate likelihood ratios informing pathogenicity for each. Heterogeneity tests were performed for specific classes of variants defined by in silico predictions.
RESULTS: Twenty-two variants labeled as VUS had odds of >10:1 in favor of pathogenicity. The heterogeneity analysis found that among variants in functional domains that were predicted to be benign by in silico tools, a significantly higher proportion of variants were estimated to be pathogenic than previously indicated; that missense variants outside of functional domains should be considered benign; and that variants predicted to create de novo donor sites were also largely benign.
CONCLUSION: The evidence presented here supports the use of personal and family history from MGPT in the classification of VUS and will be integrated into ongoing efforts to provide large-scale multifactorial classification.

Keywords:  BRCA1; BRCA2; VUS; clinical history; likelihood ratio

DOI:  https://doi.org/10.1038/s41436-019-0729-1
Pituitary. 2019 Dec 19.

Acromegaly in the setting of Tatton-Brown-Rahman Syndrome.

Hage C, Sabini E, Alsharhan H, Fahrner JA, Beckers A, Daly A, Salvatori R.

  PURPOSE: Tatton-Brown-Rahman syndrome (TBRS) is a newly defined genetic entity characterized by overgrowth and intellectual disability, resulting from germline mutations in the gene encoding DNA methyltransferase 3 alpha (DNMT3A). Affected individuals with benign and malignant tumors have been reported; to our knowledge pituitary adenomas (and other tumors identified in our patient) have not yet been described in this syndrome.CASE: We report the case of a 34-year-old woman with TBRS who developed a GH-secreting pituitary macroadenoma and other benign tumors and cystic lesions involving diverse organ systems. Whole-exome sequencing revealed a heterozygous, likely pathogenic variant (c.700_709 del10, p. Gly234ArgfsX79) in exon7 of DNMT3A, and a heterozygous variant of uncertain significance (c.25 C>T, p.Arg9Trp) in exon 1 of the gene encoding aryl hydrocarbon receptor-interacting protein (AIP). The patient failed somatostatin analog treatment, and underwent surgery. The tumor retained AIP expression, and analysis of tumor DNA indicated the presence of both AIP alleles, consistent with no loss of heterozygosity. These findings suggest that the AIP variant was not the primary driver of pituitary adenoma development.
CONCLUSION: Our case suggests that TBRS might be associated with pituitary adenoma and a broader spectrum of tumors than previously thought, making long-term follow up of these patients crucial to identify tumors early, and to elucidate the clinical spectrum of the disorder for optimization of management.

Keywords:  Aryl hydrocarbon receptor interacting protein (AIP); DNA methyltransferase 3 alpha (DNMT3A); Growth hormone (GH); Overgrowth; Pituitary adenoma; Tatton-Brown-Rahman syndrome (TBRS)

DOI:  https://doi.org/10.1007/s11102-019-01019-w
Front Oncol. 2019 ;9 1312

Germline Polymorphisms in the Nuclear Receptors PXR and VDR as Novel Prognostic Markers in Metastatic Colorectal Cancer Patients Treated With FOLFIRI.

De Mattia E, Polesel J, Roncato R, Labriet A, Bignucolo A, Dreussi E, Romanato L, Guardascione M, Buonadonna A, D'Andrea M, Lévesque E, Jonker D, Couture F, Guillemette C, Cecchin E, Toffoli G.

  Nuclear receptors act as mediators of cancer-related inflammation and gene expression. They have a regulatory effect on genes encoding proteins related to drug adsorption, distribution, metabolism, and excretion. The aim of the present study was to highlight novel prognostic markers among polymorphisms in genes encoding for nuclear receptor proteins and inflammation-related cytokines in patients treated with a FOLFIRI regimen. This study included two independent cohorts comprising a total of 337 mCRC patients homogeneously treated with first-line FOLFIRI. Genotyping of 246 haplotype-tagging polymorphisms in 22 genes was performed using bead array technology. The NR1I2 (PXR)-rs1054190 and VDR-rs7299460 polymorphisms were significantly associated with patient overall survival (OS). A detrimental effect of the NR1I2 rs1054190-TT genotype on OS was observed in both the discovery and replication cohorts (HR = 6.84, P = 0.0021, q-value = 0.1278 and HR = 3.56, P = 0.0414, respectively). Patients harboring the NR1I2 rs1054190-TT genotype had a median OS of 9 months vs. 21 months in patients with C-allele (P < 0.0001 log-rank test). VDR rs7299460-T was consistently associated with a longer OS in both cohorts (discovery: HR = 0.61, P = 0.0075, q-value = 0.1535; replication: HR = 0.57, P = 0.0477). Patients with the VDR rs7299460-T allele had a median OS of 23 months compared to 18 months in those with the CC genotype (P = 0.0489, log-rank test). The NR1I2-rs1054190 polymorphism also had an effect on the duration of progression-free survival, consistent with the effect observed on OS. Two novel prognostic markers for mCRC treated with FOLFIRI were described and, if validated by prospective trials, have a potential application in the management of these patients.

Keywords:  FOLFIRI; PXR; VDR; colorectal cancer; pharmacogenetics; survival

DOI:  https://doi.org/10.3389/fonc.2019.01312
Pharmacogenomics. 2020 Jan;21(1): 75-81

Germline variants and response to systemic therapy in advanced prostate cancer.

Johnson E, Nussenzveig R, Agarwal N, Swami U.

  Our current understanding of prostate cancer pharmacogenomics is growing at a rapid pace. Apart from evaluating relevant biomarkers and genomic alterations in tumor tissues, an increasing focus is being placed on decoding the impact of germline alterations on prostate cancer and its treatment. Herein we summarize various germline variants that have shown to associate with response to systemic therapy in men with advanced prostate cancer. Covered biomarkers include HSD3B1, SLCO2B1, SULT1E1, TRMT11, CYP17A1, CYP1B1, genes involved in homologous recombination and DNA mismatch repair.

Keywords:  CYP17A1; HSD3B1; PARP; SLCO2B1; germline variants; prostate cancer pharmacogenomics

DOI:  https://doi.org/10.2217/pgs-2019-0125
Medicine (Baltimore). 2019 Dec;98(51): e18279

PMS2 germline mutation c.1577delA (p.Asp526Alafs*69)-induced Lynch syndrome-associated endometrial cancer: A case report.

Cui MH, Zhang XW, Yu T, Huang DW, Jia Y.

RATIONALE: Lynch syndrome (LS) is an autosomal dominant cancer predisposition condition caused by germline heterozygous mutations in mismatch repair (MMR) genes. However, as one of the MMR genes, PMS2 mutation-induced LS-associated endometrial cancer (LSAEC) was rarely reported.PATIENT CONCERNS: A 26-year-old female patient suffered from prolonged menstrual period and increased menstrual flow for 2 months.
DIAGNOSES: The patient was diagnosed with cervix CIN III, endometrial cancer (EC), anemia, and LS.
INTERVENTIONS: Total hysterectomy, bilateral salpingectomy, pelvic lymphadenectomy were performed for treating EC, while ovariectomy was refused by the patient. The patient underwent postoperative chemotherapy with paclitaxel combined with carboplatin for 6 courses of treatment. Laparoscopic partial enterectomy was applied for treating colon cancer 5 years later after the surgery treatment for EC. Besides, Sanger sequencing and high-throughput genome sequencing were employed to detect the genetic status of the family that included two generations with four members. Immunohistochemistry (IHC) staining was used to identify the function of PMS2 mutation.
OUTCOMES: The 26-year-old Chinese patient suffered from LSAEC and recovered well after surgery. A PMS2 germline heterozygous mutation (c.1577delA) was confirmed by gene sequencing 5 years later. In addition, PMS2 mutation was verified by IHC. The patient was followed up for 7 years.
LESSONS: Carrying PMS2 germline mutation (c.1577delA) confers an extremely high susceptibility of suffering from LS-associated cancers. Thus, close clinical monitoring and prophylactic surgery are highly recommended to reduce the morbidity and mortality of LS-associated cancers.

DOI: https://doi.org/10.1097/MD.0000000000018279