The U.S. Food and Drug Administration (FDA) recently approved pembrolizumab, an anti- programmed cell death protein 1 cancer immunotherapeutic, for use in advanced solid tumors in patients with the ...microsatellite-high/DNA mismatch repair-deficient biomarker. This is the first example of a tissue-agnostic FDA approval of a treatment based on a patient's tumor biomarker status, rather than on tumor histology. Here we discuss key issues and implications arising from the biomarker-based disease classification implied by this historic approval.
Lynch syndrome is a hereditary cancer predisposition syndrome caused by germline alterations in the mismatch repair genes and is the most common etiology of hereditary colorectal cancer. While Lynch ...syndrome was initially defined by the clinical Amsterdam criteria, these criteria lack the sensitivity needed for clinical utility. This review covers the evolution of screening for Lynch syndrome from the use of tumor microsatellite instability and or somatic alterations in mismatch repair protein expression by immunohistochemistry to the newest methods using next-generation sequencing. Additionally, it discusses the clinical implications of the diagnosis of Lynch syndrome as it affects cancer therapeutics and the role of screening in noncolorectal Lynch-associated cancers. As molecular oncology continues to evolve, it is crucial to remain current on the increasing complexity of Lynch syndrome diagnostics and treatment options.
MSH2 Loss in Primary Prostate Cancer Guedes, Liana B; Antonarakis, Emmanuel S; Schweizer, Michael T ...
Clinical cancer research,
11/2017, Volume:
23, Issue:
22
Journal Article
Peer reviewed
Open access
Inactivation of mismatch repair (MMR) genes may predict sensitivity to immunotherapy in metastatic prostate cancers. We studied primary prostate tumors with MMR defects.
A total of 1,133 primary ...prostatic adenocarcinomas and 43 prostatic small cell carcinomas (NEPC) were screened by MSH2 immunohistochemistry with confirmation by next-generation sequencing (NGS). Microsatellite instability (MSI) was assessed by PCR and NGS (mSINGS).
Of primary adenocarcinomas and NEPC, 1.2% (14/1,176) had MSH2 loss. Overall, 8% (7/91) of adenocarcinomas with primary Gleason pattern 5 (Gleason score 9-10) had MSH2 loss compared with 0.4% (5/1,042) of tumors with any other scores (
< 0.05). Five percent (2/43) of NEPC had MSH2 loss. MSH2 was generally homogenously lost, suggesting it was an early/clonal event. NGS confirmed
loss-of-function alterations in all (12/12) samples, with biallelic inactivation in 83% (10/12) and hypermutation in 83% (10/12). Overall, 61% (8/13) and 58% (7/12) of patients had definite MSI by PCR and mSINGS, respectively. Three patients (25%) had germline mutations in
Tumors with MSH2 loss had a higher density of infiltrating CD8
lymphocytes compared with grade-matched controls without MSH2 loss (390 vs. 76 cells/mm
;
= 0.008), and CD8
density was correlated with mutation burden among cases with MSH2 loss (
= 0.72,
= 0.005). T-cell receptor sequencing on a subset revealed a trend toward higher clonality in cases versus controls.
Loss of MSH2 protein is correlated with
inactivation, hypermutation, and higher tumor-infiltrating lymphocyte density, and appears most common among very high-grade primary tumors, for which routine screening may be warranted if validated in additional cohorts.
.
Universal screening for Lynch syndrome in colorectal cancer is recommended, and immunohistochemistry for the mismatch repair proteins is commonly used. To reduce cost, some screen using only MSH6 and ...PMS2, with reflex to the partner stain if either are absent (two-stain method). An expression pattern revealing absent MSH2 and intact MSH6 is not expected, but could result in failed Lynch syndrome detection. We analyzed tumors with absent MSH2 but any degree of MSH6 expression to determine if the two-stain method could miss MSH2 mutations. One-thousand seven-hundred thirty colorectal cancer patients from the Ohio Colorectal Cancer Prevention Initiative underwent tumor screening using microsatellite instability and immunohistochemistry. The two-stain method was used for 1235 cases; staining for all four proteins was completed for 495 cases. The proportion of positive cells and staining intensity were reviewed for MSH6, as well as MSH2 when available. Patients with mismatch repair deficiency underwent next-generation sequencing of germline DNA for mismatch repair genes. If negative, tumor next-generation sequencing was performed to assess for somatic mutations. Overall, thirty-three (1.9%, 33/1730) MSH2-absent cases were identified. Of those, fourteen had no MSH6 expression but eight (0.5%, 8/1730) had ambiguous and eleven (0.6%, 11/1730) had convincing MSH6 expression that could have been interpreted as intact. Germline next-generation sequencing identified MSH2 mutations in 11/14 cases with absence of both stains, 7/8 cases with ambiguous MSH6 expression, and 9/11 cases with convincing MSH6 expression. All remaining cases, except one, had double somatic mutations. The two-stain method fails to detect some patients with Lynch syndrome: (1) significant staining weaker than the control may be incorrectly interpreted as intact MSH6, or (2) Weak or focal/patchy MSH6 can be retained with the absence of MSH2. Accordingly, we recommend the four-stain method be used for optimal Lynch syndrome screening detection.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Germline mutations in DNA damage repair (DDR) genes are identified in a significant proportion of patients with metastatic prostate cancer, but the clinical implications of these genes remain ...unclear. This prospective multicenter cohort study evaluated the prevalence and effect of germline DDR (gDDR) mutations on metastatic castration-resistance prostate cancer (mCRPC) outcomes.
Unselected patients were enrolled at diagnosis of mCRPC and were screened for gDDR mutations in 107 genes. The primary aim was to assess the impact of ATM/BRCA1/BRCA2/ PALB2 germline mutations on cause-specific survival (CSS) from diagnosis of mCRPC. Secondary aims included the association of gDDR subgroups with response outcomes for mCRPC treatments. Combined progression-free survival from the first systemic therapy (PFS) until progression on the second systemic therapy (PFS2) was also explored.
We identified 68 carriers (16.2%) of 419 eligible patients, including 14 with BRCA2, eight with ATM, four with BRCA1, and none with PALB2 mutations. The study did not reach its primary end point, because the difference in CSS between ATM/BRCA1/BRCA2/PALB2 carriers and noncarriers was not statistically significant (23.3 v 33.2 months; P = .264). CSS was halved in germline BRCA2 (g BRCA2) carriers (17.4 v 33.2 months; P = .027), and g BRCA2 mutations were identified as an independent prognostic factor for CCS (hazard ratio HR, 2.11; P = .033). Significant interactions between g BRCA2 status and treatment type (androgen signaling inhibitor v taxane therapy) were observed (CSS adjusted P = .014; PFS2 adjusted P = .005). CSS (24.0 v 17.0 months) and PFS2 (18.9 v 8.6 months) were greater in g BRCA2 carriers treated in first line with abiraterone or enzalutamide compared with taxanes. Clinical outcomes did not differ by treatment type in noncarriers.
g BRCA2 mutations have a deleterious impact on mCRPC outcomes that may be affected by the first line of treatment used. Determination of g BRCA2 status may be of assistance for the selection of the initial treatment in mCRPC. Nonetheless, confirmatory studies are required before these results can support a change in clinical practice.
Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine ...(NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determine the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1-deficient tumors are classified as AR-active adenocarcinomas, indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss is associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 are highly resistant to all single-agent therapeutics tested, the combination of PARP and ATR inhibition is found to produce significant responses, reflecting a clinically exploitable vulnerability resulting from replication stress.
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•Prostate cancers (PCs) with TP53 and RB1 loss exhibit very poor clinical outcomes•PCs with TP53/RB1 loss exhibit stem cell-like features and loss of AR activity•Loss of TP53/RB1 does not uniformly promote neuroendocrine transdifferentiation•TP53/RB1-null PCs exhibit replication stress and respond to PARP and ATR inhibition
Nyquist et al. demonstrate that TP53 and RB1 loss in prostate carcinoma (PC) attenuates AR signaling and enhances cell proliferation but does not uniformly induce neuroendocrine phenotypes. PCs with TP53/RB1 loss resist a wide range of cancer therapeutics but respond to PARP and ATR inhibition, likely reflecting enhanced replication stress.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The incorporation of genomics into medicine is stimulating interest on the return of incidental findings (IFs) from exome and genome sequencing. However, no large-scale study has yet estimated the ...number of expected actionable findings per individual; therefore, we classified actionable pathogenic single-nucleotide variants in 500 European- and 500 African-descent participants randomly selected from the National Heart, Lung, and Blood Institute Exome Sequencing Project. The 1,000 individuals were screened for variants in 114 genes selected by an expert panel for their association with medically actionable genetic conditions possibly undiagnosed in adults. Among the 1,000 participants, 585 instances of 239 unique variants were identified as disease causing in the Human Gene Mutation Database (HGMD). The primary literature supporting the variants’ pathogenicity was reviewed. Of the identified IFs, only 16 unique autosomal-dominant variants in 17 individuals were assessed to be pathogenic or likely pathogenic, and one participant had two pathogenic variants for an autosomal-recessive disease. Furthermore, one pathogenic and four likely pathogenic variants not listed as disease causing in HGMD were identified. These data can provide an estimate of the frequency (∼3.4% for European descent and ∼1.2% for African descent) of the high-penetrance actionable pathogenic or likely pathogenic variants in adults. The 23 participants with pathogenic or likely pathogenic variants were disproportionately of European (17) versus African (6) descent. The process of classifying these variants underscores the need for a more comprehensive and diverse centralized resource to provide curated information on pathogenicity for clinical use to minimize health disparities in genomic medicine.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The promise of precision medicine is now a clinical reality. Advances in our understanding of the molecular genetics of colorectal cancer (CRC) are leading to the development of a variety of ...biomarkers that are being used as early detection markers, prognostic markers, and markers for predicting treatment responses. This is no more evident than in the recent advances in testing CRCs for specific molecular alterations in order to guide treatment with the monoclonal antibody therapies cetuximab and panitumumab, which target the epidermal growth factor receptor. In this review, we update a prior review published in 2010 and describe our current understanding of the molecular pathogenesis of CRC and how these alterations relate to emerging biomarkers for early detection and risk stratification (diagnostic markers), prognosis (prognostic markers), and the prediction of treatment responses (predictive markers).
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
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