Cancer Risks for PMS2-Associated Lynch Syndrome Ten Broeke, Sanne W; van der Klift, Heleen M; Tops, Carli M J ...
Journal of clinical oncology,
10/2018, Letnik:
36, Številka:
29
Journal Article
Recenzirano
Odprti dostop
Lynch syndrome due to pathogenic variants in the DNA mismatch repair genes MLH1, MSH2, and MSH6 is predominantly associated with colorectal and endometrial cancer, although extracolonic cancers have ...been described within the Lynch tumor spectrum. However, the age-specific cumulative risk (penetrance) of these cancers is still poorly defined for PMS2-associated Lynch syndrome. Using a large data set from a worldwide collaboration, our aim was to determine accurate penetrance measures of cancers for carriers of heterozygous pathogenic PMS2 variants.
A modified segregation analysis was conducted that incorporated both genotyped and nongenotyped relatives, with conditioning for ascertainment to estimates corrected for bias. Hazard ratios (HRs) and corresponding 95% CIs were estimated for each cancer site for mutation carriers compared with the general population, followed by estimation of penetrance.
In total, 284 families consisting of 4,878 first- and second-degree family members were included in the analysis. PMS2 mutation carriers were at increased risk for colorectal cancer (cumulative risk to age 80 years of 13% 95% CI, 7.9% to 22% for males and 12% 95% CI, 6.7% to 21% for females) and endometrial cancer (13% 95% CI, 7.0%-24%), compared with the general population (6.6%, 4.7%, and 2.4%, respectively). There was no clear evidence of an increased risk of ovarian, gastric, hepatobiliary, bladder, renal, brain, breast, prostate, or small bowel cancer.
Heterozygous PMS2 mutation carriers were at small increased risk for colorectal and endometrial cancer but not for any other Lynch syndrome-associated cancer. This finding justifies that PMS2-specific screening protocols could be restricted to colonoscopies. The role of risk-reducing hysterectomy and bilateral salpingo-oophorectomy for PMS2 mutation carriers needs further discussion.
Providers and patients encounter challenges related to the management of Variants of Unknown Significance (VUS). A VUS introduces new counseling dilemmas for the understanding and psychosocial impact ...of uncertain genetic test results. This descriptive study uses Mishel’s theory of uncertainty in illness to explore the experience of individuals who have received a VUS as part of the genetic testing process. Semi-structured interviews were conducted with 27 adult individuals who received a VUS for Lynch syndrome mismatch repair genes between 2002 and 2013. The interviews were transcribed and analyzed. Most individuals recalled their result and perceived various types of uncertainty associated with their VUS. Half of the participants appraised their variant as a danger and implemented coping strategies to reduce the threat of developing cancer. Mobilizing strategies to reduce their risk included vigilant cancer surveillance, information seeking and notifying relatives. The majority of participants were unaware of the possibility of a VUS before receiving their result and expected reclassification over time. These results provide insight into the ways healthcare providers can support patients who receive VUS for Lynch syndrome. Findings also provide direction for future work that can further explicate the impact of receiving a VUS.
DNA-Based population screening in the United States has the promise to improve the health of all people in all communities. We highlight recent DNA-based population screening examples at the state, ...local, and individual level. Key public health principles and concepts with a focus on equity appear to be lacking in current efforts. We request 'A Call to Action' that involves all partners in DNA-based population screening. Potential actions to consider include: a) identification and elimination of systemic barriers that result in health inequities in DNA-based population screening and follow-up; b) creation of a national multidisciplinary advisory committee with representation from underserved communities; c) revisiting well-described public health screening principles and frameworks to guide new screening decisions and initiatives; d) inclusion of the updated Ten Essential Public Health Services with equity at the core in efforts at the local, state and national level.
"Mainstreaming" is a proposed strategy to integrate genomic testing into oncology. The aim of this paper is to develop a mainstreaming oncogenomics model by identifying health system interventions ...and implementation strategies for mainstreaming Lynch syndrome genomic testing.
A rigorous theoretical approach inclusive of conducting a systematic review and qualitative and quantitative studies was undertaken using the Consolidated Framework for Implementation Research. Theory-informed implementation data were mapped to the Genomic Medicine Integrative Research framework to generate potential strategies.
The systematic review identified a lack of theory-guided health system interventions and evaluation for Lynch syndrome and other mainstreaming programs. The qualitative study phase included 22 participants from 12 health organizations. The quantitative Lynch syndrome survey included 198 responses: 26% and 66% from genetic and oncology health professionals, respectively. Studies identified the relative advantage and clinical utility of mainstreaming to improve genetic test access and to streamline care, and adaptation of current processes was recognized for results delivery and follow-up. Barriers identified included funding, infrastructure and resources, and the need for process and role delineation. The interventions to overcome barriers were as follows: embedded mainstream genetic counselors, electronic medical record genetic test ordering, results tracking, and mainstreaming education resources. Implementation evidence was connected through the Genomic Medicine Integrative Research framework resulting in a mainstreaming oncogenomics model.
The proposed mainstreaming oncogenomics model acts as a complex intervention. It features an adaptable suite of implementation strategies to inform Lynch syndrome and other hereditary cancer service delivery. Implementation and evaluation of the model are required in future research.
Mutations in the DNA polymerase delta 1 (POLD1) exonuclease domain cause DNA proofreading defects, hypermutation, hereditary colorectal and endometrial cancer, and are predictive of immunotherapy ...response. Exonuclease activity is carried out by two magnesium cations, bound to four highly conserved, negatively charged amino acids (AA) consisting of aspartic acid at amino acid position 316 (p.D316), glutamic acid at position 318 (p.E318), p.D402, and p.D515 (termed DEDD motif). Germline polymorphisms resulting in charge-discordant AA substitutions in the DEDD motif are classified as variants of uncertain significance (VUSs) by laboratories and thus would be considered clinically inactionable. We hypothesize this mutation class is clinically pathogenic.
A review of clinical presentation was performed in our index patient with a POLD1(p.D402N) heterozygous proband with endometrial cancer. Implications of this mutation class were evaluated by a Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA)-guided systematic review, in silico analysis with orthogonal biochemical confirmation, and whole-exome and RNA sequencing analysis of the patient's tumor and engineered cell lines.
Our systematic review favored a Mendelian disease mutation class associated with endometrial and colorectal cancers. In silico analysis predicted defective protein function, confirmed by biochemical assay demonstrating loss of nuclease activity. A
-specific mutational signature was found in both the patient's tumor and
(p.D402N) overexpressing cell. Furthermore, paired whole-exome/transcriptome analysis of endometrial tumor demonstrated hypermutation and T cell-inflamed gene expression profile (GEP), which are joint predictive biomarkers for pembrolizumab. Our patient showed a deep, durable response to immune checkpoint inhibitor (ICI).
Charge-discordant AA substitution in the DEDD motif of
is detrimental to DNA proofreading and should be reclassified as likely pathogenic and possibly predictive of ICI sensitivity.
The role of the human gut microbiome in colorectal cancer (CRC) is unclear as most studies on the topic are unable to discern correlation from causation. We apply two-sample Mendelian randomization ...(MR) to estimate the causal relationship between the gut microbiome and CRC. We used summary-level data from independent genome-wide association studies to estimate the causal effect of 14 microbial traits (n = 3890 individuals) on overall CRC (55,168 cases, 65,160 controls) and site-specific CRC risk, conducting several sensitivity analyses to understand the nature of results. Initial MR analysis suggested that a higher abundance of Bifidobacterium and presence of an unclassified group of bacteria within the Bacteroidales order in the gut increased overall and site-specific CRC risk. However, sensitivity analyses suggested that instruments used to estimate relationships were likely complex and involved in many potential horizontal pleiotropic pathways, demonstrating that caution is needed when interpreting MR analyses with gut microbiome exposures. In assessing reverse causality, we did not find strong evidence that CRC causally affected these microbial traits. Whilst our study initially identified potential causal roles for two microbial traits in CRC, importantly, further exploration of these relationships highlighted that these were unlikely to reflect causality.
Abstract Introduction: Implementation of universal tumor screening for Lynch syndrome has been adopted more slowly for endometrial cancer patients than colorectal cancer patients yet the data is very ...similar. Recent guidelines have suggested doing both universal tumor screening and considering multi-gene panel testing for all colorectal cancer patients and so the data in endometrial cancer patients was reviewed to determine if the same recommendation could be made for endometrial cancer. Methods: Review of the literature found 4 large studies of universal tumor screening for Lynch syndrome among and 6 large studies of universal multi-gene panel testing among large cohorts of endometrial cancer patients. Results were reviewed and a meta-analysis performed. Results: Four large studies have looked at universal tumor screening among all endometrial cancer patients. They found that 23-26.7% of endometrial cancers are MSI-high or dMMR. The majority of these dMMR endometrial cancers are caused by MLH1 promoter hypermethylation which is present in 14-20.2% of all EC cases (60.3-75.8% of dMMR cases). Lynch syndrome was ultimately diagnosed in 2.5-3.3% of all endometrial cancer patients. The mutation distribution among Lynch syndrome patient diagnosed through universal tumor screening was 53.1% MSH6, 24.5% MSH2, 12.2% MLH1, and 10.2% PMS2. IHC was better at identifying Lynch syndrome cases than MSI among endometrial cancers (mainly due to MSH6 tumors not always being MSI-high). Multi-gene panel testing (MGPT) for all endometrial cancer patients has been reported in 6 studies of endometrial cancer patients (3 high risk and 3 unselected). MGPT studies found that 10 – 14% of unselected and 9 - 15% of selected endometrial cancer patients have a pathogenic variant in a cancer susceptibility gene. Patients diagnosed under age 50 were not significantly more likely to test positive. In the three selected cohorts, the prevalence of Lynch syndrome was 8.1% (575/7095). In the three unselected cohorts, the prevalence of Lynch syndrome was 2.7% (73/2742). Conclusions: Tumor screening with MSI or MMR IHC for all endometrial cancers will only identify Lynch syndrome (as intended). It will miss patiesporadicny other hereditary cancer syndrome and some patients with Lynch syndrome who have a sporadic endometrial cancer. However, it is now necessary for treatment purposes (Immune Checkpoint Blockade therapy). Universal germline MGPT testing for all endometrial cancers will identify some Lynch syndrome cases who have normal tumor screening and will identify many non-Lynch syndrome cases that would be completely missed by tumor screening. Citation Format: Heather Hampel. Universal tumor screening for Lynch syndrome versus germline multi-gene panel testing for all endometrial cancer patients abstract. In: Proceedings of the AACR Special Conference on Endometrial Cancer: Transforming Care through Science; 2023 Nov 16-18; Boston, Massachusetts. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(5_Suppl):Abstract nr IA004.
Universal screening for mismatch repair deficiency (dMMR) in cancer is increasingly being implemented to detect Lynch syndrome and aid in treatment decisions. The mismatch repair (MMR) ...immunohistochemistry (IHC) concordance rate between primary colorectal cancer (CRC) and metastasis is unknown. At times, only metastatic tumor is available for screening (lymph node, liver, lung etc.) rather than the primary tumor. Therefore, it is important to confirm that tissue from metastases can be used for screening for dMMR. We tested dMMR primary and metastatic tumor to assess concordance between the two. We identified dMMR CRC resected at Ohio State University from 1999 to 2013 and stained a corresponding metastasis for all four MMR proteins (MLH1, MSH2, MSH6, PMS2) with IHC. A total of 50 primary CRC with dMMR and available regional lymph nodes (LN; 26 cases) or other metastatic tissue (24 cases) were identified. Thirteen cases were explained by
MLH1
hypermethylation and 10 cases had Lynch syndrome. Two cases had somatic MMR mutations and the etiology for dMMR was unknown in 25 cases. All cases showed concordance in IHC staining between the primary tumor and corresponding metastatic tissue. In 36 cases, metastatic LN/other site was resected at the same time as the primary tumor. In 14 cases, time lapsed median 16.5 months; quartile (Q)1 8.0; Q3 25; range 3–69 from the primary resection until metastatic resection. Metastatic tissue can be used to screen for Lynch syndrome and dMMR.
Lynch syndrome has not traditionally been considered to have a high colorectal adenoma burden. However, with increasing adenoma detection rates in the general population, the incidence of adenoma ...detection in Lynch syndrome may also be increasing and leading to higher cumulative adenoma counts.
To clarify the prevalence and clinical impact of multiple colorectal adenomas (MCRA) in Lynch syndrome.
A retrospective review of patients with Lynch syndrome at our institution was performed to assess for MCRA (defined as ≥10 cumulative adenomas).
There were 222 patients with Lynch syndrome among whom 14 (6.3%) met MCRA criteria. These patients had increased incidence of advanced neoplasia (OR 10, 95% CI: 2.7-66.7).
MCRA is not unusual in Lynch syndrome and is associated with a significantly increased likelihood of advanced colon neoplasia. Consideration should be given to differentiating colonoscopy intervals based on the presence of polyposis in Lynch syndrome.
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