Identification of a Mosaic BMPR1A Pathogenic Variant in Juvenile Polyposis Syndrome: A Case Study and Its Impact on Cancer Screening

Hereditary and Familial Colon Cancer

Inherited Polyposis Syndromes: Molecular Mechanisms, Clinicopathology, and Genetic Testing

Introduction: Juvenile polyposis syndrome (JPS) is an autosomal dominant gastrointestinal (GI) polyposis syndrome that affects 1 in 100,000 to 160,000 people. The germline pathogenic variants (PV) in the SMAD4 and BMPR1A genes cause JPS in 60% cases. The syndrome predisposes to hamartomatous GI polyps especially in the colon. It also increases the risk of colonic and gastric cancer. But, due to its rarity, and likely ascertainment bias in published studies, the true rate of gastric cancer in JPS is unknown. Accurate information regarding the risk of gastric cancer may help individualize surveillance endoscopy intervals in these patients. Hence, we conducted a systematic review and meta-analysis to assess the occurrence of gastric cancer in patients with JPS. Methods: We searched Medline, Embase and Scopus databases for keywords ‘Juvenile polyposis syndrome, juvenile polyps, stomach cancer, and hereditary cancers.’ All published studies from January 1974 to May 2021 were screened. The diagnosis of JPS was based on phenotype: >3 colonic juvenile polyps (JP), or multiple JP in other parts of the GI tract or family history of JPS and any number of JP. Studies reporting upper GI manifestations in JPS patients were considered eligible for inclusion. The primary and secondary outcomes were to assess the occurrence of gastric cancer in all patients with JPS and per the underlying PV, respectively. A random-effects model was used. Inter-study heterogeneity was estimated using I2 statistic. Results: Nine studies including 553 patients met our criteria (Table 1). 254 (45.9%) patients had a SMAD4 PV, 154 (27.8%) had BMPR1A PV, 93 (16.8%) had no identifiable PVs and 52 (9.4%) patients were untested. The pooled occurrence of gastric cancer was 4.5% (95% CI: 1.9, 7.1; I2: 35.2%) (Figure 1a). The median age of gastric cancer detection was 42.5 years (range: 29-57.6 years). In studies with no prior genetic testing, gastric cancer occurred in 7.8 % (95% CI: 0,16.3; I2 = 0) patients. In patients with known PVs, gastric cancer was seen only in patients with SMAD4 (11.5%, 95% CI: 3.5, 19.6; I2: 67.1%) (Figure 1b). No gastric cancer was reported in patients with BMPR1A PV those without detectable PV. There was an overall moderate risk of bias in the studies. Conclusion: The risk of gastric cancer is increased in patients with JPS especially in patients with SMAD4 PV. The patients without prior PV testing in the present literature may harbor BMPR1A PV, these patients need to be studied in further large-scale studies.Figure 1.: CONSORT diagram Figure 2. Performance of Model.Table 1.: Characteristics of the included studies Footnotes: *Multicenter studies, †Age at any cancer diagnosis, not specific to gastric cancer, ‡Included patients from the same family, §13 patients were not tested for pathogenic variants, none of these patients developed gastric cancer. **The risk of bias of individual studies was assessed using the validated criteria by Hoy et al. Abbreviations: JPS: Juvenile Polyposis syndrome, PV: Pathogenic variants, NR: Not reported.

INTRODUCTION: Juvenile Polyposis Syndrome (JPS) is characterized by the development of numerous hamartomatous polyps in the GI tract, increasing individuals’ risk of colorectal and gastric cancer by as much as 68% by age 60. These odds are further compounded by the syndrome’s autosomal dominant (AD) mode of inheritance, placing children at a 50% risk of transmission from an affected parent. Bone Morphogenic Protein Receptor type-1A (BMPR1A) genes located on chromosome 10q22-23 are strongly associated with JPS, with nearly 60% of cases testing positive for the mutation. Effects of this anomaly cascade down the transforming growth factor-beta (TGF-beta) pathway, resulting in patients developing tens to hundreds of polyps within their lifetime, often by the first decade. Mutations in SMAD4 proteins can also lead to JPS and Hereditary Hemorrhagic Telangiectasia (HHT) as they are also vital in TGF-beta signaling. JPS is clinically diagnosed by the absence of other hamartomatous polyposis syndromes (eg, Peutz-Jeghers or Cowden) and the presence of either >5 juvenile polyps in the colorectum, multiple juvenile polyps elsewhere in GI tract, or any polyps with a family history of juvenile polyps. CASE DESCRIPTION/METHODS: A 41-year-old female with intermittent IBS symptoms presented for colon cancer screening. Two years earlier, the patient’s mother had been diagnosed at age 64 with multiple juvenile colon polyps and colon cancer testing positive for BMPR1A gene mutation. Patient’s initial colonoscopy revealed multiple 3–4 cm irregularly shaped pedunculated polyps, many less than 1cm and an irregularly shaped mass in the mid-ascending colon. The mass was circumferential, broad-based at 4–5 cm and nearly completely obstructing. Polyps removed revealed tubular adenomas and tubular villous adenomas. Though none of these were documented as juvenile polyps, the patient did test positive for BMPR1A mutation suggestive of JPS. The patient was referred to general surgery for resection of the mass and upper endoscopy. DISCUSSION: JPS is a rare polyposis syndrome with AD inheritance. In at-risk patients, it is imperative that genetic testing be performed to determine appropriate cancer screening. Testing should include both SMAD4 and BMPR1A gene mutations, with positive SMAD4 mutations undergoing evaluation for HHT. Current guidelines recommend screening the stomach and colon early, as the length of time to diagnosis remains the single most influenceable and impacting factor in the outcomes of patients and their families.

Genetic Testing for Inherited Colon Cancer

Challenges With Colorectal Cancer Family History Assessment—Motivation to Translate Polygenic Risk Scores Into Practice

The contribution of MALAT1 gene rs3200401 and MEG3 gene rs7158663 to the risk of lung, colorectal, gastric and liver cancer.

When Should Patients Undergo Genetic Testing for Hereditary Colon Cancer Syndromes?

We evaluated the associations between gastric cancer (GC) family history (FH) and colorectal cancer (CRC) risk and between CRC FH and GC/gastric adenoma risk. We used data of participants who underwent national cancer screening between 2013 and 2014. Participants with GC or CRC FH in first-degree relatives (n=1 172 750) and those without cancer FH (n=3 518 250) were matched 1:3 by age and gender. Of the 1 172 750 participants with a FH, 871 104, 264 040, and 37 606 had FHs of only GC, only CRC, and both GC and CRC, respectively. The median follow-up time was 4.8years. GC and CRC FHs were associated with increased GC and CRC risks, respectively. GC FH was associated with CRC risk (adjusted hazard ratio 1.05; 95% confidence interval [CI] 1.01-1.10), whereas CRC FH was not associated with the risk of GC or gastric adenoma. However, gastric adenoma risk increased 1.62-fold (95% CI 1.40-1.87) in participants with FHs of both GC and CRC, demonstrating a significant difference with the 1.39-fold (95% CI 1.34-1.44) increase in participants with only GC FH. Furthermore, GC risk increased by 5.32 times (95% CI 1.74-16.24) in participants with FHs of both GC and CRC in both parents and siblings. GC FH was significantly associated with a 5% increase in CRC risk. Although CRC FH did not increase GC risk, FH of both GC and CRC further increased the risk of gastric adenoma. FHs of GC and CRC may affect each other's neoplastic lesion risk.

Previous haplotype Genome Wide Association Studies (GWASs) have suggested several rare loci with a shared increased risk of colorectal, gastric, and prostate cancer. This study aimed to find out more about markers specifically addressing the shared risk of colorectal and gastric cancer, as well as the shared risk of colorectal and prostate cancer. One analysis used 426 colorectal cancer cases with gastric cancer, with no prostate cancer cases in their families, and another analysis used 324 colorectal cancer cases with prostate cancer but no gastric cancer among relatives. The computational program PLINK v1.07 was used for the analysis and for the calculation of corresponding ORs, standard errors, and 95% confidence intervals (CI). The study found support for the loci from previous studies and many new loci with a shared risk of colorectal cancer and gastric cancer. There were no significant loci from the second analysis for a shared risk of colorectal and prostate cancer. Altogether, more than 100 new loci with a shared risk of colorectal cancer and gastric cancer were suggested. A shared risk of colorectal and prostate cancer at some loci could not be ruled out. Haplotype GWAS has again demonstrated its ability to find rare risk loci mostly associated with coding genes.

Development of Colorectal Tumors in Colonoscopic Surveillance in Lynch Syndrome

Clinical management and genetics of gastrointestinal polyps in children.

Introduction: Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Adenoma removal has been shown to reduce deaths from CRC. Although smoking has been associated with an increased risk of CRC, smoking status is not included in algorithms that guide colonoscopy for CRC screening and surveillance. This study evaluated the impact of smoking on adenoma detection in patients who are at elevated risk for CRC. Methods: Reports of consecutive colonoscopies performed at an urban university hospital during a 6-month period were reviewed and their indications and results noted. Colonoscopies performed for screening of elevated risk patients and/or surveillance indications were included. Elevated risk was defined as personal or family history of CRC or polyp, inflammatory bowel disease (IBD), or “high risk for CRC” as the stated indication. Patients’ demographics, family history, and smoking history were collected. Maintaining patient confidentiality, a database was created using Microsoft Excel. Statistical analysis was performed using Fisher’s exact test with significance set at p<0.05. The study was approved by the university IRB. Results: There were 589 screening or surveillance colonoscopies for elevated-risk patients. Among them, 373 never smoked and 216 had. Adenoma were detected in 123 elevated-risk patients who had smoked (56.9%) and 166 (44.5%) of the never smokers (p=0.0037). Family history was the sole risk factor for 79 patients deemed high risk (20 male, 59 female), and adenomas were discovered in 25 (31.6%). Colonoscopies were performed in 421 patients with history of polyp; 243 (57.7%) had adenomas. There were 56 IBD patients and 3 (5.4%) had adenomas. Among elevated CRC risk patients, smoking was associated with a higher adenoma detection rate than was IBD (p<0.001), and family history of CRC (p=0.001), but not personal history of colon polyp (p=0.8659). Conclusion: Adenoma detection and removal decreases CRC deaths. Personal and family history of CRC or adenoma and IBD are recognized risk factors and influence the recommended age of onset and interval of screening colonoscopy. In this study, there was a significantly higher adenoma detection rate in smokers at increased risk of CRC. The rate of adenoma detection was significantly higher in smokers than in those with a family history of CRC or IBD. The patient’s smoking status should be considered when individualizing recommendations for CRC screening and surveillance, particularly in patients who are at high risk.

When I was first introduced to the concept of carcinogenesis as a medical student in 1969, the problem was conceptually a “black box”. Certain stimuli were carcinogenic, something happened to a cell, and cancer resulted. It had been noted in the beginning of the 20th Century that cancer cells had abnormal chromosomes (Boveri); it had been noted that chicken sarcomas could be transmitted by a “filterable agent” (Rous sarcoma virus); a variety of compounds could cause cancers on the skin of mice (chemical carcinogenesis), as well other physical agents (UV light, Xrays). There were other empirical observations, but there were no unifying concepts of what was inside the black box of any cancer, let alone the hereditary forms. The mechanisms of inheritance were known to be related to the nucleus, but it was not until 1953 that the structure of DNA was deduced, and actually a few years later that the number of human chromosomes was accurately determined to be 46. Concepts of inheritance were entirely descriptive. Progress was excruciatingly slow. It had been a century since the initial appreciation of dominant and recessive inheritance. However, only a few diseases with very distinctive phenotypes were clearly identified as familial, and only a few of these had any biochemical explanation. There was no obvious place to begin the search for the genetic basis of familial diseases. Worse, for the more common diseases such as cancer, diabetes and hypertension, it was thought that environmental influences were much more important than genetic ones. The discovery process accelerated through technical advances that permitted deeper dives into the genetic processes underlying these diseases. Chromosomal banding was only useful when there were grossly detectable defects in a chromosome. DNA sequencing was a slow, laborious process. However, in the 1970s, the pace of discovery heated up (automated sequencing, oncogenes), and this increased ever faster over the next 3-4 decades. The 1980s represented the “inflection point” of discovery into the causes of cancer. By the end of the 1980s, the concept of multistep carcinogenesis driven by “alterations” in the genome was advanced by Vogelstein's lab at Johns Hopkins. Alfred Knudson in 1971, based upon studies of familial and sporadic retinoblastoma (RB) that two copies of a gene related to this disease had to be disabled in the evolution of RB, and that individuals with the familial form of RB had a germline mutation in that gene, which accounted for the increased risk and early onset. This set the stage for the appearance of techniques to prove the concept. In the 1970s, familial adenomatous polyposis (FAP), Peutz-Jeghers Syndrome (PJS) and juvenile polyposis syndrome (JPS) were recognized as distinctive clinical phenotypes, and occurred on a familial basis. Actually, this first required the standardized pathological interpretation of colonic and intestinal polyps. Then, in 1986 Lemuel Herrera, a surgeon at Roswell Park in Buffalo, identified a patient with multiple congenital abnormalities and “Gardner's Syndrome” (FAP), which his family did not have. He asked his colleague Avery Sandberg to do chromosomal analysis, which led to the discovery of a microscopically visible interstitial deletion on 5q. They accurately proposed that this represented the loss of multiple genes on 5q, leading to a complex (and unique) phenotype, and that one of those genes deleted was connected to FAP. In 1987, Walter Bodmer's lab in London used restriction fragment length polymorphism (RFLP) analysis and linked families with FAP to the 5q locus. Moreover, they showed losses on 5q in 20% of sporadic colorectal cancers (CRCs). This resonated with the Knudson hypothesis and suggested that a gene responsible for FAP would be on chr 5q21-22, but it took four years and the collaboration of several labs to finally clone the APC gene in 1991. The function of the gene was a complete surprise, as it played a central role in the WNT growth-regulatory pathway. The APC gene was also the 5q event that Vogelstein placed at the beginning of the multistep carcinogenesis model of 1990. These early days were largely driven by techniques that could identify genetic losses in tumor DNA. The discovery of microsatellite instability (MSI) and its link to Lynch Syndrome (LS) came as lightning strike in 1993. Many labs were looking for the losses of tumor suppressor genes (TSGs) in cancers using RFLPs, and then extended the analyses by using variable number tandem repeats (VNTRs) and microsatellites (simple VNTRs with cassettes of 1-4 nucleotides), both of which are widespread throughout the human genome and valuable for genomic mapping. In 1992, Perucho (in San Diego) used “arbitrarily-primed PCR” to generate a large number of PCR products from DNA, separated them on PAGE gels, and compared results from CRCs with the patient's normal DNA to look for allelic losses (or gains), which would then lead to TSGs (or oncogenes) involved in carcinogenesis. However, his careful eye noted that some of the differences between the AP-PCR products from cancers and normal DNA represented band shifts, due to a small change in the length of the PCR product in cancer. He sequenced the altered bands, and discovered deletions (or insertions) in microsatellite sequences that were very widespread in a subset of the cancers, but not present in most other CRCs. He proposed that this was a unique “pathway” to carcinogenesis for ~15% of CRCs, but had a hard time convincing reviewers of this novel concept. While he was trying to get his findings published, Steve Thibodeau discovered the same thing at the Mayo Clinic. At the same time, Lauri Aaltonen (Finland; part of the Vogelstein-de la Chapelle collaboration) used a microsatellite marker (D2S123) located on chr 2p and found significant linkage between this locus and Lynch Syndrome (LS). Microsatellites markers were then used to look for TSG losses on 2p21 and elsewhere. Instead, MSI was recognized, and suddenly there were 3 groups with the same discovery published in May and June of 1993. The three groups who found MSI published their odd-looking autoradiographs in Science and Nature, but none of the human geneticists immediately recognized the implications. However, those who had been working in basic yeast genetics for years (Richard Kolodner, Rick Fishel, Paul Modrich, Thomas Petes, Michael Liskay and others) recognized that this probably represented loss of the DNA mismatch repair (MMR) system in the tumors, which would represent a totally unique mechanistic basis for this subset of about 15% of CRCs. In May, 1993, by coincidence, Kolodner's group at Dana Farber in Boston had just cloned the hMSH2 gene based upon its similarity to the yeast MSH2 gene, but they had to identify pedigrees with LS and find a germline mutation to make their point. The human geneticists had the families and familiarity with the human genome (organized differently than in yeast), and soon suspected DNA MMR genes themselves. The race was on, and by December 1993, both groups linked LS to germline mutations in hMSH2, and reported this in Cell; Kolodner won the race by 2 weeks, although he mistook a simple SNP for the mutation The Vogelstein-de la Chapelle collaboration cloned the hMSH2 gene, found mutations in families, and found a cell line with MSI (which happened not to have an MSH2 mutation; rather it was mutated at the hMLH1 locus, reported in a few months). What is notable is how quickly this story went from the empirical observation of MSI to the cloning of the familial CRC genes. The pace of discovery continued to be astonishing, and both Kolodner's and the Vogelstein-de la Chapelle groups found germline mutations in the hMLH1 gene in other LS families—published on consecutive days in Nature and Science on March 17 and 18, 1994. Kolodner used hybridization techniques to find hMLH1 based upon the yeast MLH sequence, but Vogelstein's group also used bioinformatics approaches to find not only hMLH1, but 2 more yeast MLH homologs, hPMS1 and hPMS2. hPMS2 turned out to be a legitimate LS gene; hPMS1 did not. The LS story had a long tail after this initial cluster of reports; hMSH6 was initially cloned by Vogelstein and Jiricny in June 1995, but not linked to LS families until Miyaki did so in November 1997. EPCAM was linked to some MSH2-like LS families in 2006. It would be an understatement to say that this led to a subsequent series of insights into how the DNA MMR system works, and what happens when this system is disabled. The 21st Century has provided ongoing broad insight into gut development and carcinogenesis in the context of both WNT signaling and DNA MMR. Most colorectal neoplasms begin by disabling the WNT pathway that regulates epithelial proliferation. It is now appreciated that about 15-20% of CRCs are hypermutated though the inactivation of both MMR genes and (less often) DNA polymerase proofreading subunits, and develop through a unique pathway of “target” genes, that they grow and evolve differently, have different clinical behaviors, and respond differently to oncological treatment. Tumors with MSI do not respond to classical cytotoxic chemotherapy (unlike non-MSI CRCs), but do respond to immune checkpoint therapies—to which non-MSI tumors are non-responsive. Moreover, we now have panel that test for multiple genes for any of the hereditary cancer syndromes. Finally the genes for PJS, JPS, Cowden's Disease (CD) and Bannayan-Riley Ruvalcaba Syndrome (BRRS) were all discovered by variations on positional cloning, but with less noto

A counseling framework for moderate-penetrance colorectal cancer susceptibility genes