Oncology

Predictability: A new distinguishing feature of cancer?

Cancer is a consequence of stochastic (mutations, genetic, and epigenetic instabilities) and deterministic (evolutionary bottlenecks) events. Stochastic events are less amenable to prediction, whereas deterministic events yield more predictable results. The relative contribution of these opposing fo...
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Cancer is a consequence of stochastic (mutations, genetic, and epigenetic instabilities) and deterministic (evolutionary bottlenecks) events. Stochastic events are less amenable to prediction, whereas deterministic events yield more predictable results. The relative contribution of these opposing forces determines cancer predictability, which affects the accuracy of our prognostic predictions and is critical for treatment planning. In this study, we attempted to quantify predictability. The predictability index (PI) was defined as the median overall-survival at any time point divided by the standard error at that time. Using data obtained from the SEER program, we found striking differences in the PI of different tumors. Highly predictable tumors were malignancies of the breast, thyroid, prostate, and testis (5-year PI of 3516, 1920, 1919, and 1805, respectively). Less predictable tumors were colorectal, melanoma, and bladder (5-year PI of 1264, 1197, and 760, respectively). Least predictable were pancreatic cancer and chronic myelogenous leukemia (5-year PI of 129, and 42). PI decreased during follow-up in all examined tumors and showed sex differences in some cases. Thyroid cancer was significantly more predictable in women (5-year PI of 2579 vs. 748, p = 0.00017) and bladder cancer more predictable in men (5-year PI of 723 vs. 385, p = 0.012), Predictability is a potentially new distinguishing feature of malignancy. This study sheds light on prognostic accuracy and provides insight into the relative roles of stochastic and deterministic forces during carcinogenesis.
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Evaluation and comparison of hereditary Cancer guidelines in the population

Background Family health history (FHx) is an effective tool for identifying patients at risk of hereditary cancer. Hereditary cancer clinical practice guidelines (CPG) contain criteria used to evaluate FHx and to make recommendations for genetic consultation. Comparing different CPGs used to evalua...
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Background Family health history (FHx) is an effective tool for identifying patients at risk of hereditary cancer. Hereditary cancer clinical practice guidelines (CPG) contain criteria used to evaluate FHx and to make recommendations for genetic consultation. Comparing different CPGs used to evaluate a common set of FHx provides insight into how well the CPGs perform, the extent of agreement across guidelines, and how well they identify patients who should consider a cancer genetic consultation. Methods We compare the American College of Medical Genetics and Genomics (ACMG) and the National Comprehensive Cancer Networks (NCCN) (2019) CPG criteria for FHx collected by a chatbot and evaluated by ontologies and web services in a previous study. Collected FHx met criteria from seven groups: Gene Mutation, Breast and Ovarian, Li-Fraumeni syndrome (LFS), Colorectal and Endometrial, Relative Meets Criteria, ACMG Only Criteria, and NCCN Testing. CPG Criteria were coded and matched across 12 ACMG sub-guidelines and 6 NCCN sub-guidelines for comparison purposes. Results The dataset contains 4915 records, of which 2221 met either ACMG or NCCN criteria and 2694 did not. There was significant overlap—1179 probands met both ACMG and NCCN criteria. The greatest similarities were for Gene Mutation and Breast and Ovarian criteria and the greatest disparity existed among Colorectal and Endometrial criteria. Only 156 positive gene mutations were reported and of the 2694 probands who did not meet criteria, 90.6% of them reported at least one cancer in their personal or family cancer history. Conclusion Hereditary cancer CPGs are useful for identifying patients at risk of developing cancer based on FHx. This comparison shows that with the aid of chatbots, ontologies, and web services, CPGs can be more efficiently applied to identify patients at risk of hereditary cancer. Additionally this comparison examines similarities and differences between ACMG and NCCN and shows the importance of using both guidelines when evaluating hereditary cancer risk.
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The knowledge of hereditary breast cancer, and attitude and intention towards genetic testing of the patients with high-risk hereditary breast cancer

Purpose: This study aimed to explore the knowledge of hereditary breast cancer (HBC) and attitudes and intention towards genetic testing of the patients with high-risk HBC, and to describe their differences according to the intention of genetic test. Methods: High-risk HBC patients (n = 138) who did...
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Purpose: This study aimed to explore the knowledge of hereditary breast cancer (HBC) and attitudes and intention towards genetic testing of the patients with high-risk HBC, and to describe their differences according to the intention of genetic test. Methods: High-risk HBC patients (n = 138) who did not take genetic test or relevant counseling were recruited in D city, Korea. Participants completed questionnaires including demographic characteristics, knowledge of HBC, and attitudes and intention of genetic test. Results: The average score of knowledge on HBC was 9.59±2.32, and the average positive and negative attitude scores were 31.36±4.12 and 24.13±4.78, respectively. The benefit of genetic test rated as most important was “to help my daughters or sisters decide whether to undergo genetic testing” and “to motivate me to perform breast self-examination more frequently”. The most important perceived limitation was “if I were found to carry the gene, my concerns about my female offspring developing breast cancer would increase.” Of the participants, 40.6% indicated willingness to test their genes and 48.6% considered it. Participants with a partner (p=.043) and higher educational level (p=.005) showed significantly lower willingness to test. Conclusion: These results suggest that high-risk HBC patients understand important facts regarding the inheritance of breast cancer and genetic test and their interest in genetic testing is substantial. Considering previous reports that perceptions of the benefits of genetic testing were important predictors of genetic test utilization, the developments of educational and counseling programs to deliver proper knowledge are necessary.
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A sheep in wolf's clothing; a case of renal leiomyoma masquerading as hereditary leiomyomatosis and renal cell carcinoma

Introduction: Active surveillance has become a standard of care for the management of small renal masses. Decision to transition from surveillance to intervention relies on several factors including growth kinetics, histologic grade on biopsy and patient comorbidities. Management of renal masses in ...
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Introduction: Active surveillance has become a standard of care for the management of small renal masses. Decision to transition from surveillance to intervention relies on several factors including growth kinetics, histologic grade on biopsy and patient comorbidities. Management of renal masses in pregnancy presents a unique change when clinical triggers must be weighed with risk to fetus. We present the case of a third trimester patient with an enlarging and enhancing renal mass managed with robotic assisted laparoscopic partial nephrectomy. Histologic analysis was consistent with renal leiomyoma. Renal leiomyomas are a rare benign mesenchymal tumor influenced by changes in progesterone-estrogen axis.
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Hereditary Cancer Syndromes: Identifying and Managing High-Risk Patients

Hereditary Cancer Syndromes: Identifying and Managing High-Risk Patients

Current status of inherited pancreatic cancer

Background It is estimated that about 10% of pancreatic cancer cases have a genetic background. People with a familial predisposition to pancreatic cancer can be divided into 2 groups. The first is termed hereditary pancreatic cancer, which occurs in individuals with a known hereditary cancer syndr...
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Background It is estimated that about 10% of pancreatic cancer cases have a genetic background. People with a familial predisposition to pancreatic cancer can be divided into 2 groups. The first is termed hereditary pancreatic cancer, which occurs in individuals with a known hereditary cancer syndrome caused by germline single gene mutations (e.g.,BRCA1/2,CDKN2A). The second is considered as familial pancreatic cancer, which is associated with several genetic factors responsible for the more common development of pancreatic cancer in certain families, but the precise single gene mutation has not been found. Aim This review summarizes the current state of knowledge regarding the risk of pancreatic cancer development in hereditary pancreatic cancer and familial pancreatic cancer patients. Furthermore, it gathers the latest recommendations from the three major organizations dealing with the prevention of pancreatic cancer in high-risk groups and explores recent guidelines of scientific societies on screening for pancreatic cancers in individuals at risk for hereditary or familial pancreatic cancer. Conclusions In order to improve patients’ outcomes, authors of current guidelines recommend early and intensive screening in patients with pancreatic cancer resulting from genetic background. The screening should be performed in excellence centers. The scope, extent and cost-effectiveness of such interventions requires further studies.
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Advanced adenomas may be a red flag for hereditary cancer syndromes

Background: 16–25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced p...
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Background: 16–25% of colorectal cancers (CRCs) diagnosed under age 50 are associated with hereditary cancer syndromes. Advanced adenomas are considered precursors to CRC. Although polyp removal prevents cancer, polypectomy does not change underlying genetic risk. Patients with isolated advanced polyps do not currently qualify for genetic testing unless they have a personal or family history of cancer. Aim: Describe the prevalence of hereditary cancer syndromes among patients with advanced colorectal polyps. Methods: We performed a single center retrospective review from 2015 to 2019 of patients who underwent germline genetic testing with indication for testing listed as colorectal polyp. We excluded patients with a personal history of CRC and those with ≥10 cumulative polyps. We collected patient demographics, polyp characteristics, family history data and genetic testing results from the medical record. Discrete variables were reported as frequency and percentages and continuous variables reported as mean with range. Results: A total of 42 patients underwent genetic testing due to a personal history of advanced adenoma. 17% of patients met current genetic testing criteria. All patients underwent multi-gene panel testing. Two patients (4.8%) had a germline pathogenic mutation (one in MLH1 and one in CHEK2). The patient with an MLH1 mutation met current criteria for genetic testing (PREMM5 score 5.8), however the patient with the CHEK2 mutation did not. Both mutation carriers had a personal history of synchronous or metachronous advanced adenomas. 38% had a variant of uncertain significance. Conclusions: 5% of patients with advanced adenomas in our retrospective series had a pathogenic germline mutation in a cancer predisposition gene. Though the patient with a pathogenic mutation in MLH1 met current clinical criteria for genetic testing, this was not recognized prior to referral; he was referred based on a personal history of advanced adenoma. Advanced polyps may be a red flag to identify patients who are at risk for hereditary cancer syndromes. Keywords: Colorectal cancer, Colorectal polyps, Adenomas, Genetic testing, Lynch syndrome
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Hereditary leiomyomatosis and renal cell cancer syndrome

Introduction: Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a rare autosomal dominantly inherited cancer predisposing syndrome giving rise to cutaneous and uterine leiomyomatosis, leiomyosarcoma and renal cell cancer. Patients with this syndrome harbours germline pathogenic var...
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Introduction: Hereditary leiomyomatosis and renal cell cancer syndrome (HLRCC) is a rare autosomal dominantly inherited cancer predisposing syndrome giving rise to cutaneous and uterine leiomyomatosis, leiomyosarcoma and renal cell cancer. Patients with this syndrome harbours germline pathogenic variants in the fumarate hydratase (FH) gene.Case presentation: A 28-year-old Sri Lankan female, a product of a consanguineous marriage with strong family history of young onset fibroids presented with progressive dysmenorrhea, menorrhagia and irregular menstrual cycles for 2 years duration. There was recent onset lower abdominal colicky pain lasting for 3-5 min occurring during the post coital and intermenstrual period over 2 months. Examination did not reveal abnormal skin lesions or abdominal masses.Ultrasound examination revealed enlarged uterus with 2 large fibroids in the posterior wall and fundus of the uterus. She underwent laparoscopic myomectomy without perioperative complications. Histology revealed a leiomyoma with morphological features supporting the variant “fumarate hydratase deficient leiomyoma”.Whole exome sequencing of the patient revealed her to be harbouring a pathogenic variant c.878T>G| p:Val293Gly in the FH gene for which she was heterozygous confirming that she had inherited the cancer predisposing syndrome of hereditary leiomyomatosis and renal cell cancer(HLRCC). Postoperatively her symptoms resolved, and she was able to sustain an uncomplicated pregnancy one year after. Currently she is closely followed up for future development of tumors including renal cell cancer bothclinically and via imaging.Conclusion: HLRCC is a rare autosomal dominantly inherited cancer syndrome predisposing to skin, uterine and renal tumors warranting surveillance at a younger age.
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Various Histological Types of Renal Cell Carcinoma Associated With Hereditary Papillary Renal Cell Carcinoma (HPRCC): a Case Report

Background: Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, dis...
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Background: Hereditary papillary renal cell carcinoma (HPRCC) is a rare autosomal dominant disease characterized by the development of multiple and bilateral papillary type I renal cell carcinomas (RCC) and papillary adenomas caused by activating mutations in the MET proto-oncogene. Classically, distinctive histological features of RCC are described according to the familial renal cell carcinoma syndrome. To date, no clear cell RCC has been reported in HPRCC syndrome. Case presentation: We describe the case of a 51-year-old man with a germline MET mutation, who developed numerous papillary tumors but also unexpectedly clear cell renal cell carcinomas. During the follow-up, an adrenal metastasis was observed seven years after the initial diagnosis corresponding to a clear cell RCC metastasis. Using FISH, the metastatic tumor presented a trisomy of chromosomes 7 and 17. These genomic alterations are usually detected in papillary RCC, highlighting the potential link between both histological subtypes of tumors and the HPRCC syndrome. Conclusions: The pathologist must be aware that the presence of a non-papillary RCC associated with numerous papillary tumors should not exclude the diagnostic suspicion of HPRCC and thus to perform a thorough genomic study.
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Sequential therapy for hereditary leiomyomatosis and renal cell cancer-associated renal cell carcinoma: a case report and report of a new family pedigree

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal-dominant disorder caused by a heterozygous germline mutation in the fumarate hydratase (FH) gene. HLRCC is clinically characterized by the development of three tumors: uterine leiomyomata, cutaneous leiomyomata, and renal ce...
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Hereditary leiomyomatosis and renal cell cancer (HLRCC) is a rare autosomal-dominant disorder caused by a heterozygous germline mutation in the fumarate hydratase (FH) gene. HLRCC is clinically characterized by the development of three tumors: uterine leiomyomata, cutaneous leiomyomata, and renal cell carcinoma (RCC). HLRCC-associated RCC is aggressive and diagnosed at a much earlier age than sporadic RCC. It is essential for carriers of HLRCC to undergo annual renal screening by magnetic resonance imaging to detect early stage RCCs. Metastatic HLRCC-associated RCC must be treated by systemic therapy; however, it is unclear which medicines are most effective in treating this cancer owing to its low incidence rate. Immune checkpoint inhibitor (ICI) combinations or ICIs plus tyrosine kinase inhibitors are administered as systemic therapy for clear cell RCC. Here, we report a patient with HLRCC-associated RCC treated with sequential therapy, including ipilimumab plus nivolumab combination and cabozantinib, after diagnosis of HLRCC-associated RCC using FoundationOne Liquid CDx and single-site analysis. We also investigated familial FH mutations and describe a new family pedigree for HLRCC.
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