Extracolonic Cancers Research Articles

Differences in MSI phenotype between cancer types using a new PCR-based pan-cancer biomarker panel.

e13145 Background: A multiplexed biomarker panel was developed for detection of MSI that is more sensitive than currently available systems. Preliminary data showed an increased MSI sensitivity for colon polyps, endometrial (EC) and skin cancers. This study expands that finding to 14 different types of cancer. Methods: Selection of the best microsatellite markers was done using a cohort of 160 patients ≤55 years with ≥1 colon polyp and 100 EC patients ≤ 50 years. To validate the new panel, a cohort of 100 Lynch syndrome CRC, 100 sporadic MSI-High CRC, 100 sporadic MSI stable CRC and 219 extra-colonic cancers from the Colon Cancer Family Registry were tested for MSI. Samples were screened using a new 8-marker panel and Promega’s MSI Analysis System. Mismatch repair (MMR) gene mutation status and expression were determined. To compare the relative sensitivity of the 8-marker panel across all cancer types we developed a quantitative “MSI-score” for each cancer type. Results: Considerable differences in MSI phenotypes were observed between cancer types and a new approach to scoring MSI in extra-colonic cancers is proposed. Relative intensity of the MSI phenotype was characterized by MSI-Scores ranging from high of 66 (small intestine) to 6 (brain). The mutations in MSI samples were significantly more common and allele size shifts larger with the new biomarkers, making MSI classification more accurate and robost. MSI, IHC and MMR gene mutation status were highly correlated. Conclusions: The MSI sensitivity of the new biomarker panel for most cancer types was significantly higher than currently available PCR-based MSI systems. Development of the new pan-cancer PCR-based MSI system allows laboratories to leverage established equipment and known analysis techniques to keep turnaround time and costs, quick and affordable compared with emerging NGS-based technologies.

SAT-314 Malignant Pheochromocytoma: A Rare Neoplasm Easily Confounded with Metastasis and Associated with Lynch Syndrome

Introduction: Pheochromocytomas are a rare neoplasm of chromaffin cells of the adrenal medulla with an annual incidence in the United States between 500 to 1600 cases, of which about 10% are malignant. Due to this rarity, adrenal masses, especially in the context of other concurrent primary tumors, can be easily confounded with metastasis. Case Report: A 56-year-old male with diabetes mellitus and hypertension presents with left flank pain associated with hematochezia, constipation, and an 8.2kg weight loss over 2.5 months. Physical examination was unremarkable. Abdominal CT scan showed a 4x5cm left adrenal gland mass with infiltration of peri-adrenal tissues and hemorrhage. Dexamethasone suppression test was normal. Plasma metanephrines and aldosterone were not elevated. Repeat CT a month later showed marked increase of the mass to 6.2x5.8cm and an ascending colon mass. Colonoscopy with biopsy revealed a moderately differentiated adenocarcinoma with immunohistochemistry (IHC) staining negative for MSH2 and MSH6 mismatch repair proteins, typical of Lynch syndrome. The patient had a strong family history of malignancy, positive for endometrial cancer (mother) and colon cancer (mother/brothers). A right segmental hemicolectomy and left adrenalectomy-nephrectomy was performed with a presumption that the adrenal mass was a metastatic site. On pathology, the colon specimen confirmed a 5x4x2cm adenocarcinoma. Surprisingly, the adrenal specimen revealed a 7x6x6cm malignant pheochromocytoma with a Pheochromocytoma of the Adrenal Gland Scaled Score (PASS) of 18 with IHC also negative for MSH2 and MSH6. Repeat CT 4 months post-resection showed new lymphadenopathy followed by PET/CT revealing a 2.7x3.4cm FDG avid left para-aortic lymph node consistent with metastasis and a 2.5cm non-FDG avid cystic mass in the pancreatic tail. Discussion: There is a high prevalence of germline mutations associated with pheochromocytomas, commonly including succinate dehydrogenase (SDH) subunit genes, SDHAF2, TMEM127, MAX-gene, and three main associated syndromes including von Hippel Lindau, multiple endocrine neoplasia type 2, and neurofibromatosis type 1. Lynch Syndrome is diagnosed by a mutation in at least one of these mismatch repair genes: MLH1, MSH2, MSH6, and PMS2. It is often associated with extra-colonic cancers including the endometrium, gastric, biliary, urinary tract, pancreas, small intestine, brain, and skin. There is a growing number of cases reporting neuroendocrine tumors in the setting of Lynch Syndrome. To date, there are only two cases reporting an association between pheochromocytoma and Lynch Syndrome, neither of which were described as malignant pheochromocytomas. We present a case of MSH2 and MSH6 mismatch repair protein deficiency in both colon and adrenal masses, suggesting that Lynch Syndrome may be an additional rare risk factor for malignant pheochromocytoma.

Immunomodulatory Therapy Does Not Increase the Risk of Cancer in Persons With Inflammatory Bowel Disease and a History of Extracolonic Cancers.

Immunosuppressant therapies (IMTs; thiopurines, anti-tumor necrosis factor agents) may influence the immunologic control of cancer and might facilitate the spread and recurrence of cancer. This study assesses the impact of the use of IMTs on the development of incident cancers (recurrent or new) in patients with inflammatory bowel disease (IBD) and a history of malignancy. Patients with IBD included in the ENEIDA registry with a history of cancer without being exposed to IMTs were identified and retrospectively reviewed and compared regarding further treatment with IMTs or not by means of a log-rank test. Overall, 520 patients with previous extracolonic cancer naive to IMTs before the diagnosis of cancer were identified. Of these, 146 were subsequently treated with IMTs (exposed), whereas 374 were not (nonexposed). The proportion of patients with incident cancers was similar in both exposed (16%) and nonexposed (18%) patients (P = 0.53); however, there was more than a 10-year difference in the age at index cancer between these 2 groups. Cancer-free survival was 99%, 98%, and 97% at 1, 2, and 5 years in exposed patients, and 97%, 96%, and 92% at 1, 2, and 5 years in non-exposed patients, respectively (P = 0.03). No differences in incident cancer rates were observed between exposed and nonexposed patients when including only those who were exposed within the first 5 years after cancer diagnosis. In patients with IBD and a history of cancer not related to immunosuppression, the use of IMTs is not associated with an increased risk of new or recurrent cancers even when IMTs are started early after cancer diagnosis.

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-tumor Phenotype

Biallelic germline mutations affecting NTHL1 predispose carriers to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown. We describe 29 individuals carrying biallelic germline NTHL1 mutations from 17 families, of which 26 developed one (n= 10) or multiple (n= 16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in female carriers (60%). Mutational signature analysis of 14 tumors from 7 organs revealed that NTHL1 deficiency underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

Targeted Next-Generation Sequencing of MLH1, MSH2, and MSH6 Genes in Patients with Endometrial Carcinoma under 50 Years of Age

Background:Lynch syndrome is an inherited cancer disorder that causes an increased lifetime risk of various types of cancers. Endometrial cancer is the most common extracolonic cancer in Lynch syndrome. Guidelines recommend that patients with endometrial cancer younger than 50 years of age should be evaluated for Lynch syndrome. Molecular analysis of the mismatch repair genes and EPCAM gene is required for a definitive diagnosis of Lynch syndrome.Aims:To report the mutation analysis of mismatch repair genes using targeted next-generation sequencing in endometrial cancer diagnosed patients <50 years of age.Study Design:Retrospective cross-sectional study.Methods:Seventy-nine endometrial cancer diagnosed patients <50 years of age underwent genetic counseling. They were selected among 1094 consecutive endometrial cancer patients between 2006 and 2017. Molecular analysis of MLH1, MSH2, and MSH6 genes was performed in 79 patients by using next-generation sequencing. Deletion/duplication analysis of mismatch repair genes and EPCAM gene was also performed in 79 patients by using the multiplex ligation-dependent probe amplification method.Results:Germline testing of mismatch repair genes was performed in 79 endometrial cancer patients. Lynch syndrome was confirmed in 4 patients (5%; 4/79). A total of 14 variants (6 in MSH2, 5 in MLH1, 3 in MSH6 genes) were found in 14 patients. Four variants were assessed as pathogenic/likely pathogenic, and 10 variants were assessed as variants of uncertain significance.Conclusion:Lynch syndrome should be investigated in patients diagnosed with endometrial cancer that are less than 50 years of age due to the increased lifetime risk of developing cancer.

Cancer risk in microscopic colitis: a retrospective cohort study

BackgroundThe long-term natural history of microscopic colitis (MC) (collagenous colitis (CC), lymphocytic colitis (LC)), traditionally considered relapsing but non-progressive diseases, is poorly defined. Whether persistent histologic inflammation in such diseases is associated with an increased risk of colorectal neoplasia (CRN) or extracolonic cancers has not been robustly established.MethodsThis retrospective cohort included diagnosed with MC at a referral center. Rates of CRN and extracolonic cancer were compared to patients undergoing screening colonoscopy (n = 306) and to the United States population using data from the Surveillance, Epidemiology, and End-Results (SEER) program. Standardized incidence ratios (SIR) and 95% confidence intervals were calculated and multivariable regression models used to identify the effect of MC diagnosis and severity on cancer risk.ResultsOur study included 221 patients with microscopic colitis (112 CC, 109 LC) among whom 77% were women. Compared to the colonoscopy control population, MC was associated with similar odds of tubular adenoma (Odds ratio (OR) 1.07, 95% CI 0.69–1.66) or villous adenoma (OR 1.26, 95% CI 0.17–9.42). Compared to patients with a single episode of MC, those with 2 or more episodes had similar risk of colon cancer (OR 0.83, 95% CI 0.20–3.39) or tubular adenoma (OR 1.49 95% CI 0.83–2.67). We also identified no statistical increase in the rates of cancer in the MC population compared to US-SEER data.ConclusionMicroscopic colitis was not associated with increased risk of CRN and extracolonic cancers when compared to controls undergoing colonoscopy or the US SEER population.

Multi-gene panel testing confirms phenotypic variability in MUTYH-Associated Polyposis.

Biallelic pathogenic variants (PVs) in MUTYH cause MUTYH-Associated Polyposis (MAP), which displays phenotypic overlap with other hereditary colorectal cancer (CRC) syndromes including Familial Adenomatous Polyposis (FAP) and Lynch syndrome. We report the phenotypic spectrum of MAP in the context of multi-gene hereditary cancer panel testing. Genetic testing results and clinical histories were reviewed for individuals with biallelic MUTYH PVs detected by panel testing at a single commercial molecular diagnostic laboratory. Biallelic MUTYH PVs were identified in 82 individuals (representing 0.2% of tested individuals) with most (75/82; 91.5%) reporting a personal history of CRC and/or polyps. Ten percent (6/61) of individuals reporting polyp number reported fewer than 10 polyps and therefore did not meet current MAP testing criteria. Extracolonic cancers (21/82; 25.6%), multiple primaries (19/82; 23.2%), Lynch-like (17/82; 20.7%) and FAP-like phenotypes (16/82; 19.5%) were observed, including individuals with mismatch repair-deficient tumors (3/82; 3.7%), sebaceous neoplasms (2/82; 2.4%), or congenital hypertrophy of the retinal pigment epithelium (CHRPE) (2/82; 2.4%). We report what is to our knowledge the first cohort of individuals with MAP identified by panel testing. The phenotypic spectrum of MAP observed in this cohort aligns with the published literature. In addition to standard indications for MUTYH testing, our data provide evidence to support consideration of MAP in the differential diagnosis for some individuals with fewer than 10 polyps, depending on other personal and/or family history, as well as for individuals suspected to have Lynch syndrome or FAP.

Increased serological, cancer-associated protein biomarker levels at diagnosis of large bowel adenoma: Risk of subsequent primary malignancy?

Background: Blood-based, cancer-associated biomarkers may detect subjects at risk of having neoplastic diseases. The aim of the present study was to evaluate whether elevated serological protein biomarker levels may identify adenoma patients, who are at increased risk of being diagnosed with subsequent primary malignancy.Methods: Levels of CEA, CA19-9, TIMP-1 and YKL-40 were determined in blood samples collected prior to diagnostic bowel endoscopy due to symptoms of colorectal neoplasia. Follow-up time was ten years, and identified adenoma patients, who were diagnosed with subsequent primary intra- or extra-colonic malignant diseases. The biomarker levels were also determined in 400 subjects, who underwent diagnostic colonoscopy, had clean colorectum and were without apparent co-morbidity; these levels were used as reference levels. In the present study, biomarkers were interpreted as elevated when levels were above the reference intervals adjusting for age and gender. The 1-year and 5-years cumulative incidences were calculated.Results: Primary malignancies were identified in 175 (19%) of the 923 subjects diagnosed with adenomas at the primary bowel endoscopy. In detail, 20 of the 175 subjects were diagnosed with colorectal cancer (CRC) and 155 subjects with extra-colonic cancers. Thirty patients were diagnosed with malignancy within the first year. Three groups were established: 0: no elevated biomarkers; 1: 1 of the 4 biomarkers elevated; and 2: ≥2 biomarkers elevated. The cumulative 5-years incidence of malignancy was: 0: 6.9%; 1: 11.8%; and 2: 17.5% (p = .0009).Conclusion: Elevated blood-based, cancer-associated protein biomarker levels in subjects diagnosed with adenomas at large bowel endoscopy identifies subjects at increased risk of being diagnosed with subsequent primary malignancy.

Cancer Risks for PMS2-Associated Lynch Syndrome.

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.

CT colonography screening in extracolonic cancer survivors: impact on rates of colorectal and extracolonic findings by cancer type.

To compare the rates of colorectal and extracolonic findings at CT colonography (CTC) screening between patients with and without a personal prior history of other. Over a 160-month interval, 349 adults (mean age, 60.3 years; 67% female) with a positive history of extracolonic cancer [Ca(+)], excluding 271 patients with isolated non-melanoma skin cancers, underwent CTC screening. This study cohort was compared against 8859 controls (mean age, 57.0 years; 53% female) without a prior cancer history [Ca(-)]. Primary outcome measures included the rates of relevant colorectal (C-RADS C2-C4) and extracolonic (C-RADS E3-E4) findings at CTC. Wilcoxon rank sum test was used to test for statistical significance with post-hoc analysis by relative rate (RR). Both colorectal (C2-C4) and extracolonic (E3-E4) findings were significantly increased in the Ca(+) group versus Ca(-) control group (p = 0.0283 and 0.0236, respectively). Positive colorectal findings were most notably increased among survivors of non-small cell lung cancer (RR 3.1), head/neck cancers (RR, 3.4), and bladder cancers (RR 2.2). The proportion of C2-C4 patients undergoing intervention in the Ca(+) cohort was not significantly different than the Ca(-). Potentially relevant extracolonic findings (E3) were increased in survivors of hematogenous malignancies (RR 2.0), while likely important extracolonic findings (E4) were increased in survivors of female gynecological malignancies (RR 3.4). Relevant colorectal and extracolonic findings at CTC screening are increased in patients with a previous extracolonic cancer history, particularly among certain cancer subsets. These results may have important implications for choice of colorectal test in these patients.

Mutational Signature Analysis Reveals NTHL1 Deficiency to Cause a Multi-Tumor Phenotype Including a Predisposition to Colon and Breast Cancer

Biallelic germline mutations affecting NTHL1 predispose to adenomatous polyposis and colorectal cancer, but the complete phenotype is unknown, which hampers patient recognition. We describe 29 individuals from 17 families, of which 26 developed one (n=10) or multiple (n=16) malignancies in 14 different tissues. An unexpected high breast cancer incidence was observed in women with biallelic NTHL1 mutations (60%). Mutational signature analysis of 14 tumors from seven organs revealed that deficient NTHL1 repair underlies the main mutational process in all but one of the tumors (93%). These results reveal NTHL1 as a multi-tumor predisposition gene with a high lifetime risk for extracolonic cancers, and a typical mutational signature observed across tumor types, which can assist in the recognition of this syndrome.

Comprehensive clinical genetics care for patients with inherited colorectal cancer associated with Lynch syndrome: Western and Asian perspectives.

Lynch syndrome (LS) arises from germline mutations that lead to defective functioning of the DNA mismatch repair (MMR) system. It is the most common cause of inherited colorectal cancer (CRC), and predisposes individuals to significantly elevated risks for extracolonic cancers. A sensitive and accurate diagnostic approach will enable proactive management of the proband and at-risk relatives in order to minimize their cancer burden. Comprehensive clinical genetics care should include personalized and tailored multidisciplinary oncologic care, with consideration for the extent of surgical resection, the choice of systemic agents, and the use of radiation. Preventive strategies including lifelong multi-organ surveillance, testing of family members, prophylactic-intent surgery and chemoprevention should be considered. In this review, we aim to provide an update on the diagnostic approach to LS, and to summarize key components of comprehensive clinical genetics care, through an examination of existing data and guidelines from Asian and from Western perspectives.

Incidence of Colorectal Cancer and Extracolonic Cancers in Veteran Patients With Inflammatory Bowel Disease.

The risk for colorectal cancer (CRC) and certain extracolonic cancers is thought to be increased in inflammatory bowel disease (IBD), but few recent US studies have evaluated this issue. We aimed to estimate the incidence of CRC and extracolonic cancers in IBD patients. In this case-control study, cases were all IBD patients treated in our Department of Veterans Affairs (VA) hospital who developed CRC or extracolonic cancers between 1996 and 2015. Controls were patients in the general VA population who developed these cancers during the same time. We compared cancer incidence rates (IRs) in cases and controls. There was no significant difference between cases and controls in the 20-year IR for CRC (148/100 000 in IBD patients, 97/100 000 in controls; relative risk [RR], 1.53; 95% confidence interval [CI], 0.86-2.69). In contrast, IBD cases had a significantly higher 20-year IR for all extracolonic cancers than controls (2839/100 000 in IBD patients, 1960/100 000 in controls; RR, 1.45; 95% CI, 1.27-1.65). Site-specific analyses revealed that IBD patients had significantly elevated risks for nonmelanoma skin cancers (RR, 2.38; 95% CI, 1.99-2.85), melanoma skin cancers (RR, 2.85; 95% CI, 1.63-4.88), renal tumors (RR, 2.90; 95% CI, 1.46-5.84), prostate cancer (RR, 1.70; 95% CI, 1.28-2.27), and pancreatic cancer (RR, 4.23; 95% CI, 1.35-13.29). The incidence of CRC was not significantly higher in our veteran patients with IBD than in control patients in the general VA population. In contrast, our IBD patients had a significantly higher risk for extracolonic cancers than controls, including cancers of the skin, kidneys, prostate, and pancreas. 10.1093/ibd/izx046_video1Video 1.izx046_Mosher_Video5734484616001.

Serrated Polyposis Syndrome in a Single-Center 10-Year Experience.

Aims:Serrated polyposis syndrome is a disease that is often missed in the clinical setting and is associated with colorectal cancer. We investigated the prevalence of SPS and the association between colorectal or other cancers in a 10-year, retrospective data analysis.Methods:We reviewed complete colonoscopy data obtained from January 2005 through January 2015 at a health-screening centre. Serrated polyposis syndrome was defined on the basis of the criteria established by the 2010 World Health Organization.Results:Of a total of 53.842 consecutive subjects who underwent complete colonoscopy, 12 (0.022%) patients had serrated polyposis syndrome. All of these cases were under-recognized by the endoscopist or referring physician. The mean patient age was 58.6 years; 67% of the patients were men and 33% were women. No serrated polyposis syndrome patients had a first-degree relative with serrated polyposis syndrome, and no serrated polyposis syndrome patients had colorectal cancer. Two cases (17%) had extra-colonic cancers (prostate cancer and thyroid cancer). Eight cases (67%) had a family history of cancer (stomach, breast, lung, pancreas, prostate and colorectal cancer).Conclusion:Serrated polyposis syndrome was a rare condition in a 10-year database, and it was diagnosed late in all cases. Serrated polyposis syndrome may be associated with an increased risk of extra-colonic cancer.

Clean Colorectum at Diagnostic Colonoscopy: Subsequent Detection of Extracolonic Malignancies by Plasma Protein Biomarkers?

Introduction:Most of the subjects undergoing diagnostic colonoscopy do not have neoplastic bowel lesions. Potentially, some of the symptoms may therefore be caused by extracolonic malignancy, and subjects with persisting symptoms may need subsequent examinations. Blood-based, cancer-associated biomarkers may aid in directing the examinations for other specific malignant diseases.Methods:EDTA plasma samples available from a previous prospective study of subjects undergoing diagnostic colonoscopy were used for analysis of 18 protein biomarkers. The study population of 3732 subjects included 400 patients with colorectal cancer (CRC) and 177 patients with extracolonic malignancies. Univariable analysis of the association of specific biomarkers and extracolonic cancers included those with 10 or more cases. Subsequently, reduced models of 4 or 6 biomarkers, respectively, were established by choosing those with the highest likelihood; age and sex were included as well.Results:Univariable analyses showed that CyFra21-1 had an area under curve (AUC) of 0.87 for lung cancers (n = 33), CA19-9 had an AUC of 0.85 for pancreatic cancer (n = 22), CA125 had an AUC of 0.95 for ovary cancer (n = 16), B2M had an AUC of 0.81 for non-Hodgkin lymphoma (n = 12), and total prostate-specific antigen had an AUC of 0.99 for prostate cancer (n = 10). The multivariable analysis of 4 or 6 biomarkers plus age and sex as explanatory variables showed AUCs of 0.82 to 0.85 both for extracolonic cancers and CRC. The 4 biomarkers included in the model for detection of extracolonic cancers were CA125, hsCRP, CA19-9, and CyFra21-1; the 2 additional for the 6 biomarkers model were CEA and Galectin-3. Similarly, the 4 biomarkers included in the model for detection of CRC were CEA, CyFra21-1, Ferritin, and HE4; the two additional for the 6 biomarkers model were hsCRP and Pepsinogen 2.Conclusions:Results of this study indicate that it may be possible to detect subjects that have an increased risk of extracolonic cancer following a colonoscopy without findings of neoplastic lesions. Combinations of various protein biomarkers may direct subsequent examination after colonoscopy with clean colorectum. The results, although preliminary, may form the basis for additional research directed both for primary examinations of subjects with symptoms of malignancy and subsequent examinations after colonoscopy.

Same MSH2 Gene Mutation But Variable Phenotypes in 2 Families With Lynch Syndrome: Two Case Reports and Review of Genotype-Phenotype Correlation.

Lynch syndrome is an autosomal dominant syndrome that can be subdivided into Lynch syndrome I, or site-specific colonic cancer, and Lynch syndrome II, or extracolonic cancers, particularly carcinomas of the stomach, endometrium, biliary and pancreatic systems, and urinary tract. Lynch syndrome is associated with point mutations and large rearrangements in DNA MisMatch Repair (MMR) genes. This syndrome shows a variable phenotypic expression in people who carry pathogenetic mutations. So far, a correlation in genotype-phenotype has not been definitely established. In this study, we describe 2 Lynch syndrome cases presenting with the same genotype but different phenotypes and discuss possible reasons for this.

Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries.

Approximately one-third of individuals diagnosed with colorectal cancer have a family history of cancer, suggesting that CRCs may result from a heritable component. Despite the availability of current gene-identification techniques, only 5% of all CRCs emerge from well-identifiable inherited causes for predisposition, including polyposis and nonpolyposis syndromes. Hereditary nonpolyposis colorectal cancer represents a large proportion of cases, and robustly affected patients are at increased risk for early onset, synchronous, and metachronous colorectal malignancies and extracolonic malignancies. HNPCC encompasses several cancer syndromes, such as Lynch syndrome, Lynch-like syndrome, and familial colorectal cancer type X, which have remarkable clinical presentations and overlapping genetic profiles that make clinical diagnosis a challenging task. Therefore, distinguishing between the HNPCC disorders is crucial for physicians as an approach to tailor different recommendations for patients and their at-risk family members according to the risks for colonic and extracolonic cancer associated with each syndrome. Identification of these potential patients through epidemiological characteristics and new genetic testing can estimate the individual risk, which informs appropriate cancer screening, surveillance, and/or treatment strategies. In the past three years, many appealing and important advances have been made in our understanding of the relationship between HNPCC and CRC-associated syndromes. The knowledge from the genetic profile of cancer syndromes and unique genotype-phenotype profiles in the different syndromes has changed our cognition. Therefore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation.

Phenotypic and genotypic heterogeneity of Lynch syndrome: a complex diagnostic challenge

Lynch syndrome is the hereditary disorder that most frequently predisposes to colorectal cancer as well as predisposing to a number of extracolonic cancers, most prominently endometrial cancer. It is caused by germline mutations in the mismatch repair genes. Both its phenotype and genotype show marked heterogeneity. This review gives a historical overview of the syndrome, its heterogeneity, its genomic landscape, and its implications for complex diagnosis, genetic counseling and putative implications for immunotherapy.

Abstract 1411: Differential mismatch repair-dependent damage responses in subpopulations of cells from human intestinal organoids

Abstract Hereditary mutations in DNA mismatch repair (MMR) genes cause the cancer predisposition syndrome called Lynch syndrome. Patients predominantly develop colorectal cancer and some extracolonic cancers at a young age. The MMR pathway repairs mismatches created during DNA replication, but also can induce apoptosis and cell cycle arrest in response to certain DNA damaging agents as a protective mechanism to eliminate cells at risk of accumulating mutations. Our understanding of this MMR-directed DNA damage response has come primarily from studies in human cancer cell lines. We wished to examine the role of the MMR-dependent damage response in a model that may be more relevant to the human intestine. Therefore, we have created human intestinal organoids (HIOs) in vitro either by directing the differentiation of human embryonic stem cells (hESCs) or through culturing of adult intestinal tissue samples. We have used these HIOs to specifically study the MMR dependent damage response to DNA alkylation damage. We have found that whereas hESCs undergo rapid apoptosis in response to alkylation damage, the differentiated HIOs or those created from adult tissues undergo not only apoptosis, but also senescence and accelerated differentiation following damage. Using CRISPR-Cas9 gene editing in hESCs, we also created MMR-deficient HIOs that failed to respond to the drug indicating that these responses are MMR-dependent. We then determined that the cells undergoing apoptosis following DNA damage are most likely the intestinal stem cells suggesting that different cell types in the intestine have different MMR-dependent responses to damage. Together these results suggest that loss of MMR function in the intestinal crypts may provide a selective advantage particularly in an environment conducive with DNA damage that promotes tumorigenesis. Note: This abstract was not presented at the meeting. Citation Format: Bo Lin, Qingfen Yang, Abhijit Rath, Christopher D. Heinen. Differential mismatch repair-dependent damage responses in subpopulations of cells from human intestinal organoids [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1411. doi:10.1158/1538-7445.AM2017-1411

Adenomatous Polyposis Syndromes: Familial Adenomatous Polyposis and MutYH-Associated Polyposis

The purpose of this review is to provide an overview of the etiology, diagnosis, and clinical management of the two most common polyposis; change adenomatous to polyposis hereditary colorectal cancer syndromes, familial adenomatous polyposis (FAP) and MUTYH-associated polyposis (MAP). The syndromes are caused by inherited genetic variants in the APC and MutYH genes, respectively. Both syndromes carry significant increased risk of colorectal and extracolonic cancers. Intense surveillance is required to reduce this risk, and colectomy or proctocolectomy is frequently the ultimate form of colorectal cancer risk reduction. The colorectal phenotype and extracolonic manifestations continue to evolve as more is learned about the natural history of the diseases, particularly MAP.