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Hindawi Journal of Oncology Volume 2018, Article ID 3979135, 11 pages https://doi.org/10.1155/2018/3979135 Review Article Hereditary Nonpolyposis Colorectal Cancer and Cancer Syndromes: Recent Basic and Clinical Discoveries Erbao Chen, Xiaojing Xu, and Tianshu Liu Department of Medical Oncology, Zhongshan Hospital, Fudan University, Shanghai, China Correspondence should be addressed to Tianshu Liu; liu email@example.com Received 19 December 2017; Revised 12 March 2018; Accepted 20 March 2018; Published 23 April 2018 Academic Editor: Akira Hara Copyright © 2018 Erbao Chen et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 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 c linical 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. er Th efore, this review presents and discusses HNPCC and several common nonpolyposis syndromes with respect to molecular phenotype, histopathologic features, and clinical presentation. 1. Introduction The hereditary CRCs syndromes are broadly divided into nonpolyposis and polyposis syndromes. In 1966, Lynch first Colorectal cancers (CRCs) are one of the most common defined familial CRC type I for families with CRC only and malignancies and represent the third most common cancer type II for families with both CRC and gynecological cancer in men and the second in women worldwide. It is estimated . Later, the term hereditary nonpolyposis colorectal cancer that one-third of individuals diagnosed with colorectal cancer (HNPCC) was recommended to emphasize the absence of have a family history of cancer . However, approximately a polyposis phenotype. Currently, HNPCC defines a patient 5% to 10% of all CRCs, called hereditary CRCs, are related who meets Amsterdam criteria I or II [7–9], and HNPCC to mutations and defects in certain genes . In addition, patents are prone to develop synchronous and metachronous approximately 20–30% of familial CRC patients have at least cancers at relative young ages. Generally, the “nonpolyposis” one relative aect ff ed by neoplasms that act as nonsyndromic label of HNPCC can be misleading and confusing to physi- familial CRCs and are likely driven by shared genes and/or cians, because adenomas typically present a villous growth environmental factors [3, 4]. In individuals, high-risk hered- characteristic and have different degrees of cell dysplasia . itary predisposition syndromes have been associated with Therefore, identification of these individuals is critical for a 70–100% lifetime risk for earlier development of CRCs early intervention and treatment of associated malignancies or metachronous cancers, and many syndromes carry an to reduce HNPCC-associated morbidity and mortality. Most increased risk for extra-intestinal manifestations . of the cancer syndromes involve inherited mutations in genes 2 Journal of Oncology Lynch syndrome: Germline mutation+ Extracolonic cancers MMR-deﬁcient Lynch-like syndrome: Germline mutation− Rare extracolonic cancers HNPCC: clinically determined Relatively younger age FCCX: Unknown genetic causes, MMR-proﬁcient No extracolonic cancers Figure 1: The category of hereditary nonpolyposis colorectal cancer. that modulate growth processes in colonic stem cells and/or improved the diagnostic sensitivity and included associated protect the fidelity of the genome passed into progeny cells. cancers (e.g., endometrial, small bowel). Later, Bethesda Given the substantial risk of synchronous and metachronous criteria were created and revised in 2004 to identify CRC cancer, these mutation carriers are recommended to abide patients who should undergo pathologic examination (MSI by standard surveillance and comprehensive management and/or immunohistochemistry (IHC) assessment for the protocols when compared with the general population with MMR protein deficiency in the tumor) for HNPCC/Lynch an average CRC risk profile. eTh role of genetic counseling syndrome  (Box 1). becomes crucial in treating these patients. Regardless, the Amsterdam criteria fail to identify As such, understanding and distinguishing the vari- approximately 50% of cases, and Bethesda guidelines fail to ous syndromes are useful and clinically meaningful as the identify at least 30% of cases , which has led to increased approach to diagnosing and surveilling patients and their at- support for the universal application of the polymerase risk family members. Previously, testing of patient tumors chain reaction (for detection of MSI-high tumors) and/or for microsatellite instability (MSI) and mutation of DNA IHC testing to all CRC specimens . Currently, many MMR genes is an eeff ctive strategy to discriminate patients guidelines suggest two possible approaches to screen out at risk for Lynch syndrome. Cancer-free individuals whose Lynch syndrome: a universal one, that is, to test every patient family history indicates suspicion for a hereditary cancer with CRC, and a selective one (Jerusalem guidelines), which syndrome should undertake clinical genetic evaluation and broadens the indications for MSI or IHC testing to every receive genetic counseling. Even if a mutation is not detected, individual with CRC diagnosed prior to age 70 plus patients people may benefit from the genetic evaluation in other diagnosed at older ages who meet the Bethesda criteria , interventions to reduce future cancer risk. with the latter approach missing more than a quarter of This paper provides a comprehensive literature review patients with Lynch syndrome (Figure 2). This justification on the most common HNPCC and HNPCC-associated also supports the universal testing for endometrial cancer cancer syndromes (including Lynch syndrome, Lynch-like . Universal testing followed by germline testing oer ff s syndrome, and familial colorectal cancer type X) that present the highest sensitivity (and somewhat lower specicfi ity) distinguishing molecular phenotypes, histopathologic fea- than alternative screening strategies, although the increase tures, and clinical presentations among dieff rent subtypes in the diagnostic yield is modest compared with criteria- (Figure 1). based screening techniques . Cost-effectiveness analyses demonstrate varying results [19, 20]. In this review, HNPCC generally refers to any family that meets the Amsterdam I/II 2. Diagnosis of Hereditary Nonpolyposis or Revised Bethesda guidelines. Colorectal Cancer The Amsterdam I clinical criteria for HNPCC, which focus 3. Lynch Syndrome on the number and ages of family members with colorectal cancer, were published in 1990 to standardize the inclusion 3.1. Overview. One of the first hereditary nonpolyposis can- criteria for clinical research studies . For kindred families cer-associated syndromes to be identified, Lynch syndrome, fulfilling the Amsterdam criteria, the chance of identifying isalso themostrelevanttoHNPCC.Itisestimatedthat a germline mutation is 40% to 50% . Similarly, 40% of LS accounts for approximately 3% of all CRC cases, and its patients with an identified genetic mutation fail to meet Ams- prevalence in the general population is one in 440 . Lynch terdam criteria . er Th efore, Amsterdam I criteria were syndrome also increases the risk for extracolonic cancers believed to be insucffi iently sensitive and to be missing clear such as that of the endometrium (50–60%), ovaries (9–14%), familial clustering of extracolonic malignancies, which led to stomach (13–19%), small intestine, urinary tract, and central establishment of the Amsterdam II criteria in 1999, which nervous system [22, 23] (Table 1). Lynch syndrome is now Journal of Oncology 3 CRC < 70, or CRC > 70 and revised Bethesda guidelines/Amsterdam I or II Abnormal (loss of IHC ± MSI based on Normal (IHC and non-MSI) protein expression ± MSI tumor Loss of MLH1 Loss of MSH2, MSH6 or PMS2 FCCX Somatic BRAF mutation ± MLH1 promoter methylation analysis Germline testing of the Positive Negative corresponding gene Positive Negative Lynch-like syndrome Sporadic CRC Lynch syndrome Figure 2: The diagnostic algorithm for HNPCC-associated cancer syndrome. Amsterdam criteria I (1) At least three relatives with CRC (2) One of which is a first-degree relative of the other two (3) Colorectal cancer aec ff ting at least two successive generations (4) At least one patient with colorectal cancer diagnosed<50 years (5) Familial adenomatous polyposis should be excluded (6) Tumors should be verified by pathologic examination Amsterdam criteria II (1) There should be at least three relatives with an HNPCC-associated cancer (CRC, cancer of the endometrium, small bowel, ureter, or renal pelvis) (2) One patient must be a first-degree relative of the other two (3) Colorectal cancer aec ff ting at least two successive generations (4) As least one patient should be diagnosed<50 year (5) Familial adenomatous polyposis should be excluded (6) Tumors should be verified by pathologic examination Revised Bethesda criteria (1) CRC diagnosed in one patient<50 years (2) Presence of synchronous or metachronous, colorectal or other HNPCC-associated tumors (3) Pathologic features of a microsatellite instability-high cancer diagnosed in a patient<60 years (4)CRC diagnosedinapatientwithatleast onefirst-degree relativeswithanHNPCC-related tumor with one of the cancer diagnosed<50 years (including adenoma<40 years) (5) CRC diagnosed in a patient with at least two first-or second-degree relatives with HNPCC- related tumors Box 1: HNPCC clinical diagnostic criteria. well established as an inherited, autosomal dominant predis- 3.2. eTh Molecular Phenotype of Lynch Syndrome. Lynch syn- position to CRC, and certain extracolonic cancers are derived drome is an autosomal dominant condition caused by a from defective DNA mismatch repair (MMR) genes, which malfunctioning MMR system resulting from the pathological are a system for maintaining genome integrity. Accumulating mutation in at least one of the MMR genes. Germline genetic mutations of MMR genes lead to tracts of repetitive testing for germline mutations in the MMR genes—mutS DNA sequences called microsatellites, which typically mani- homologue 2 (MSH2), mutL homologue (MLH1), mutS fest microsatellite instability (MSI) . MSI facilitates tumor homologue 6 (MSH6), and postmeiotic segregation increased cell proliferation, invasion, and metastasis through activating 2 (PMS2)—can discriminate Lynch syndrome from Lynch oncogenes or suppressing tumor suppressors  and allows kindreds. During cellular proliferation and differentiation, detection of microsatellite instability (MSI) during tumor DNA randomly produces errors that may include single progression . base mismatch, insertions, misincorporation, and deletion of 4 Journal of Oncology Table 1: Genes associated and cancer risks for HNPCC. Syndrome Gene Percentage/syndrome Cancer risks 95% CI Lynch syndrome MLH1 60% Colorectum 52 (31–90) Endometrium 21 (9–82) Stomach 11–19 Ovary 38 (3–81) Hepatobiliary 2–7 Upper urinary tract 4-5 Pancreas 3-4 Small bowel 1–4 Glioblastoma 1–3 Lynch syndrome MSH2 20% Colorectum 49 (29–85) Lynch syndrome MSH6 6% Colorectum 18 (13–30) Endometrium 17 (8–47) Stomach ≤3 Ovary 1 (0-1) Urinary tract <1 Lynch syndrome PMS2 12% Colorectum 15–20 Endometrium 15 Lynch syndrome EPCAM <3% Endometrium 57 (22–82) Stomach 11–19 Ovary 20 (1–66) Hepatobiliary 2–7 Upper urinary tract 4-5 Pancreas 3-4 Glioblastoma 1–3 bases. The function of the MMR gene system is to recognize occurring in sporadic colorectal cancers . Additional and maintain the d fi elity of DNA by correcting the structure somaticmutations ofPOLEandMSH3,identiefi dinLS- of DNA replication errors . Approximately 70–90% of CRCs, are regarded to further accumulate somatic mutations Lynch syndrome tumors have germline MLH1 or MSH2 during tumor progression . Constitutional MMR defi- mutations. MLH1 and MSH2 mutations confer an elevated ciency (CMMRD), a very rare subtype of MMR deficiency, is lifetime cancer risk when compared to MSH6 and PMS2 a distinct childhood cancer predisposition syndrome charac- [28, 29]. MSH6 and PMS2 are detected in the remaining terized/caused by the presence of MMR homozygous muta- approximately 10–20% of LS cases, and up to 3% of LS is tions or inherited biallelic MMR protein inactivation . caused by deleterious mutations in epithelial cell adhesion The CMMRD harbors more somatic mutations compared molecule (EPACM). The deletion of the 3 end of EPCAM with Lynch syndrome individuals, especially in the DNA- immediatelyupstreamofMSH2onchromosome2,which binding domain of the TP53 gene. Some novel mutations causes allele-specific methylation of the MSH2 promoter, is such as POLE and POLD1 have also been identified in the a relatively rare cause for epigenetic silencing of MSH2 . CMMRD . Female POLD1 mutation carriers have a high SomaticBRAFmutations canbeusefultoruleoutLynch risk of endometrial cancer and a moderate risk of breast syndrome, because they frequently occur in sporadic MSI cancer  (Table 2). CRCs, caused by MLH1 promoter methylation. BRAF and promoter methylation are usually conducted in patients with 3.3. eTh Histopathologic Features and Clinical Presentation of a lack of MLH1 protein to eliminate the possibility of Lynch Lynch Syndrome. Since Lynch syndrome has been extensively syndrome. characterized, however, the incidence of Lynch syndrome Recent studieshavefocused on exploring thenovel varies by the endemicity of all diagnosed CRC patients in somatic mutations in the Lynch syndrome. For instance, different populations. Similar to the case of European indi- RNF43, one of the E3 ubiquitin ligases, acts as a negative- viduals with Lynch syndrome , recent clinic-based obser- regulatory factor of the WNT pathway via reducing mem- vations have reported deleterious mutations that disrupt the brane surface expression . RNF43 had been regarded as a function of the MMR gene product (MLH1 (61%), MSH2 pivotal mutational target of microsatellite instability (MSI) in (21%), PMS2 (12%), and MSH6 (6%)) in an African American 70–80% of sporadic colorectal carcinogenesis . Similarly, population with Lynch syndrome . eTh percentage of RNF43 mutations occurred in approximately 40% of LS- MMR gene mutations in the tumors was approximately CRCs, which was significantly lower than the percentage 13% in Latino individuals, which is similar to estimates in Journal of Oncology 5 Table 2: Germline and somatic genetic and epigenetic characteristics of HNPCC-associated cancer syndrome. Lynch syndrome Lynch-like syndrome FCCX Tumor MMR MSI MSI MSS MSH2, MLH1, MSH6, PMS2, Germline mutation ERBB2, MCM9 RPS20, SEMA4A, EPCAM RASSF9, NTS, SETD6, NDUFA9, Somatic mutation Second allele of MMR Both alleles of a MMR AXIN2, MYC, H2AFZ Epigenetic phenotype MSH2 promoter methylation None RASL10B MSS: microsatellite stable; MSI: microsatellite instability; FCCX: familial colorectal cancer X; MMR: mismatch repair. non-Hispanic white individuals. Furthermore, approximately frequently occur in MLH1 mutation carriers, whereas ovarian 61.9% of deficient MMR tumors were indeed attributable cancer occurs mainly in younger women, which is contrary to germline MMR gene mutations by in-depth molecular to ovarian cancers in BRCA1/2 mutation carriers and in the analysis, and Latino patients with Lynch syndrome develop general population . cancer at a younger age and have a higher percentage of For treatment, MSI in a tumor usually causes frameshift rectal cancers and advanced disease, which is consistent mutations in the DNA, resulting in immunogenic neoanti- with observations in other studies . eTh incidence of gens that induce an immune reaction against the tumor. Lynch syndrome among diagnosed CRC patients in Japan is eTh approval of pembrolizumab use for solid tumors with 0.7%, which is slightly lower than that reported previously high-level microsatellite instability or mismatch repair defi- but within the same range (0.7–3.7%) as that in recent ciency by the US Food and Drug Administration highlights investigations . eTh CRC incidence in Finnish MLH1 the promise of precision immuno-oncology. Immunother- mutation carriers was lower than that in non-Finnish carriers, apy strategies are based on immunopathology. Hence, but not significantly . patients would benefit from tumor immunopathology, espe- Very few studies have compared the epidemiological cially for some immune checkpoints, such as PD1 (pro- characteristics and clinicopathological differences between grammed cell death 1) and PDL1 (programmed cell death 1 Lynch syndrome patients with other disease and those with ligand 1). Lynch syndrome only. The MSH6 and PMS2 mutations indi- cate a decreased risk of cancer incidence when compared with 4. Lynch-Like Syndrome MLH1 and MSH2 mutations ; however, when comparing individualswithbreastcanceronlytothose with CRConly, 4.1. Overview. As many as 60–70% patients who fulfill the MSH6 and PMS2 mutations were more frequent than MLH1 AC criteria in the clinical and MMR deficiency in the tumor and MSH2 mutations . Inflammatory bowel disease but for whom germline testing lacks a detectable germline (IBD) is associated with a 1.7-fold greater CRC risk (95% mutation are defined as having “Lynch-like syndrome” . cond fi ence interval, 1.2–2.2) due to inflammatory factors Due to an early-onset age and abnormal MMR protein . In patients with both Lynch syndrome and IBD, there similar to those of Lynch syndrome patients, Lynch-like is an increased CRC risk at a younger onset compared to syndrome patients are nearly impossible to differentiate from those with Lynch syndrome only, especially in patients with Lynch syndrome patients. They all manifest MSI within their ulcerative colitis [45, 46]. cancers, and immunohistochemistry detects abnormal DNA Screening by colonoscopy enables the early detection and MMR protein—not only for MLH1 but also for the main removal of preinvasive neoplasia or adenomas before the DNA MMR proteins, including MSH2, MSH6, and PMS2, presence of symptoms and is the main strategy of secondary as with true Lynch syndrome cancers . Additionally, prevention in Lynch syndrome patients [47, 48]. Although Lynch-like syndrome patients have a slightly higher but the removal of adenomas is regarded as an effective way to insignificant mean age of onset than that of Lynch syn- prevent CRC and death, CRC still occurs frequently. How- drome patients (53.7 versus 48.5 years of onset). The only ever,theoverallsurvivalisgoodforpatientswithCRCandfor differentiating clinicopathological features between these two patients with first endometrial and ovarian cancer . The cancer syndromes are as follows. (1) eTh majority of those outcomes for Lynch syndrome patients who have survived with Lynch-like syndrome tend to have CRC in the right a first cancer attack are of great interest. In patients who colon (93%) when compared to those with Lynch syndrome have their rfi st cancer before the age of 40, the cumulative (45%) . (2) Epidemiologic studies to date have described incidences for any subsequent cancer are high, specifically, lower standardized incidence ratios for colorectal cancer 73% for MLH1 mutations, 76% for MSH2 mutations, and (2.12 versus 6.04) and noncolorectal cancer Lynch syndrome- 52% for MSH6 mutations . Of note, the relative incidence associated cancers (1.69 versus 2.81) in Lynch-like syndrome of subsequent cancer compared with the incidence of first compared with Lynch syndrome. Lynch-like syndrome is cancer is slightly but insignificantly higher than the cancer estimated to account for as many as 70% of clinical Lynch incidence in patients with Lynch syndrome without previous syndrome patients suspected to have a high MSI condition cancer. MSH2 mutation patients tend to have prostate and andtheabsenceofMMR proteins.Consequently, clinicians urinary tract cancers. Upper gastrointestinal tract cancers are limited in their knowledge of the genetic diagnosis of 6 Journal of Oncology these patients and are unconfident regarding which screening remote. eTh DNA MMR apparatus is well studied, and most should be recommended . associated components are known, with no other reports of germline mutations outside of these genes, other than 4.2.TheMolecularPhenotypeofLynch-LikeSyndrome. The EPCAM as described. Mensenkamp et al. made significant mechanism between Lynch syndrome and Lynch-like syn- headway in identifying that somatic mutations in MLH1 and MSH2 are a frequent cause for inactivating DNA MMR drome for causing the generation of MSI within Lynch-like syndrome patients is appealing and elusive. Three hypotheses function and subsequent MSI generation within Lynch-like have been proposed to explain why Lynch-like syndrome syndrome cancers . patients show MSI in the tumors but no DNA MMR germline 4.3. eTh Histopathologic Features and Clinical Presentation mutation: (1) there exist unknown gene mutations other than of Lynch-Like Syndrome. MUTYH encodes a base excision the DNA MMR genes in the germline that can drive MSI. repair DNA glycosylase. Mutations in this gene are found in Lynch syndrome and Lynch-like syndrome CRC frequently MUTYH-associated polyposis (MAP) syndrome, an autoso- harbor not only activating ERBB2 mutations but also specific mutational patterns in PIK3CA and KRAS. Furthermore, mal inherited condition commonly featured by the presence of a few to hundreds of colonic adenomatous polyps and an ERBB2-mutated MSI CRC is susceptible to irreversible pan- increased CRC risk at a young age . Biallelic MUTYH HER blockade . Recently, MCM9 was identified as the mutations also account for a proportion of LLS cases . DNAhelicaseintheMMRcomplex,andlossofhelicase Patients with Lynch-like syndrome and Lynch syndrome activity results in MSI. MCM9 recruitment and loading caused by EPCAM deletion share common clinical features into chromatin are MSH2-dependent and strengthens the that dieff r from patients with Lynch syndrome caused by recruitment of MLH1 to chromatin binding sites, and cells MMR, including a preference for the right colon, a lower lacking the MMR protein lose the maintenance of genome stability  Liu et al. reported that MCM9 unknown sig- degree of fulfillment of the revised Bethesda guidelines, and an older mean age at CRC diagnosis . Patients nicfi ance variants were only observed in a small proportion with Lynch-like syndrome more frequently have colorectal of Lynch-like syndrome patients and that MCM9 mutations carcinoma on the right side and are less likely to have are unable to explain the MSI in most Lynch-like syndrome synchronous or metachronous carcinoma. However, there cases . (2) Limited methods failed to detect germline are no significant differences in clinicopathological variables mutations in the DNA MMR genes . A new method of between patients with Lynch-like syndrome and Lynch syn- allelic dropout in long PCR was performed to seek potential drome with endometrial carcinoma . regionsofrearrangement intheMSH2gene. Sixof10 (60%) patients with previously unexplained MSH2-deficient Lynch syndrome were detected as harboring an inversion 5. Familial Colorectal Cancer Type X (FCCX) alteration from exon 1 to 7 in the MSH2 gene . Traditional 5.1. Overview. HNPCC is a clinically heterogeneous disease germline testing screens exons and splice sites for deleterious of which approximately 4% of cases are associated with Lynch mutations but does not review introns or RNA transcripts syndrome, which may not conform to AC,<1% of cases are for harmful alterations. cDNA screening to identify patients correlated to a Lynch-like syndrome, and 2–4% of cases are suspected to have cryptic MMR gene rearrangements is rec- diagnosed as FCCX . Familial colorectal cancer type X is ommended . (3) An unrevealed biological process within a collective designation by Lindor  and refers to families the tumors, not involving a germline mutation, for instance, who fulfill AC I but exhibit no evidence of a deficient DNA a double somatic mutation in the MMR gene, mostly occurs MMR gene (no deleterious germline mutations in the MMR in sporadic CRCs . For instance, approximately 60% of genes, no microsatellite instability, or no absence of immune- Lynch-like CRCs manifest biallelic somatic inactivation of histochemical staining of MMR protein), wherein “X” is used MMR genes within the tumor. A somatic mutation in one to describe the unknown nature of the etiology. As is the allele of an MMR gene along with loss of heterozygosity of the case for other familial cancer syndromes, the identification of other allele is the most commonly described pattern. These the genes associated with FCCX will facilitate the molecular somatic MMR gene mutations are likely sporadic events, diagnosis of the disease and the development of appropriate suggesting that such tumors are most likely cancers with surveillance guidelines and clinical management protocols sporadic DNA MMR decfi iency. Somatic mutation of POLE for these patients. was identified as a rare possibly underlying cause for MMR deficiency in Lynch-like syndrome . Other possible causes of Lynch-like syndrome-associated 5.2. eTh Molecular Phenotype of FCCX. The genomic pro- cancers could include false-positive results showing MSI. files of FCCX cancers show similarities to sporadic Each of these possibilities may be part of the reason for MMR-proficient CRC since the clinical performance and Lynch-like syndrome because they are not mechanisms that histopathological features resemble sporadic CRC. Chro- conflict with each other, and given the standardized inci- mosomal instability (CIN) is a type of genomic instability; as dence ratios of Lynch-like syndrome between the ratios for a result, the chromosomal structures are unstable and hence Lynch syndrome and sporadic colorectal cancer, Lynch-like facilitate carcinogenesis. Recently, high-resolution genomic syndrome may be a heterogeneous condition between these profiling elaborated a CIN-like profile that discriminated two extremes. In exploring the three hypotheses, the first 65% of colorectal cancers associated with FCCX from LS regarding an unknown germline gene driving MSI is the most based on the gain of chromosomal region 20q and loss of Journal of Oncology 7 18 . eTh genomic profiles of FCCX cancers are very Functional enrichment pathways were involved in G-protein- similar to those of stable early tumors but highly different coupled receptor signaling, proliferation and migration, from that of LS. Genome-wide linkage analysis suggests that cell cycle transition, DNA replication, and mitosis. Several linkage at four chromosomal regions, 2p24.3, 4q13.1, 4q31.21, candidate target genes such as NDUFA9, AXIN2, MYC, and 12q21.2–q21.31, are responsible for FCCX cancers, and and H2AFZ have been specifically linked to FCCX tumors RASSF9 and NTS are considered good candidates because . of their possible involvement in colorectal epithelium carcinogenesis . Except for the linkage to certain 5.3. The Histopathologic Features and Clinical Presentation of chromosomal regions, genomic insertion/deletion (INDEL) FCCX. FXXC presents a special clinically different pheno- and copy number variation (CNV) also locate parts or the type compared to that of Lynch syndrome families as follows entire sequences of genes and hence may regulate gene : (1) lower incidence of CRC; (2) developing CRC at a expression or function . Some mutations in several later age; (3) greater frequency in the distal colon; (4) poor cancer-related genes such as BMPR1a are also detected in differentiation and more mucinous characteristics; (5) dis- FCCX, but an independent cohort of 22 probands from tinctive morphological features, including tumor-infiltrating FCCX families have revealed that BMPR1a mutations are not lymphocytes; and (6) fewer multiple tumors. amajorcontributorofFCCXincidence . Obviously,FCCX isclearlyeasilydieff rentiated from Moreover, previous studies suggest that mutations of the Lynch syndrome . The identification of differences that GALNT12 gene might elucidate the unknown etiology of distinguish patients with FCCX from those with sporadic familial CRC. However, investigators found that GALNT12 is CRC could reinforce the characteristics of the syndrome, but not a major gene modulator in the predisposition to FCCX, only the identification of the gene expression associated with when delineating the relevance of GALNT12 mutations in the FCCX will assist in the early diagnosis of the disease. Age at etiology of FCCX . BRCA2 is a putative tumor suppressor the diagnosis of cancer is significantly lower in FCCX than gene and plays a pivotal part in repairing DNA. Pathogenic in sporadic CRC. Patients with FCCX have an approximately mutations in germline DNA are predominantly responsible larger number of synchronous tumors, but this number does for hereditary breast and ovarian cancer. Four BRCA2 vari- not reach the level of statistical significance. Recurrence is ants containing c.502C>A p. (Pro168Thr), c.927A>G p. (=), noticeably higher in FCCX than in sporadic CRC . FCCX c.5744C>Tp.(Thr1915Met),and c.7759C >Tp.(Leu2587Phe) hasalowerproportionofperitumoral lymphocytesand showcosegregationwithFCCXandmayexert afunction Crohn-like reactions. It is noteworthy that venous invasion as susceptibility alleles in FCCX families . A truncating is most commonly seen in FCCX . dominant negative mutation in SETD6 also provides a possi- ble explanation for the cancer predisposition of one FCCX 6. Conclusions and Future Perspectives family . Germline variants in the semaphorin 4A gene increase the predisposition to colorectal cancers in families To our limited knowledge, hereditary CRC syndromes are a with FCCX . A single truncating germline mutation of few causes of CRC in the general population. Different cancer RPS20, a ribosomal protein gene, was investigated in four syndromes encompass a spectrum of similar clinical presen- generations of an FCCX family. This variant was associated tations and genetic profiles. es Th e overlapping concepts and with a fault in preribosomal RNA maturation and was terms make early diagnosis in hereditary CRC cases clinically considered a new colon cancer predisposition gene . challenging. eTh refore, an awareness and understanding of RASL10B encodes a small GTPase with antitumor proper- these unique syndromes may help early diagnosis and pre- ties, and epigenetic silencing of this gene has been attributed ventative interventions in individual patients and their family to hepatocellular carcinoma cells and breast cancer [78, 79]. members. On the other hand, patients with cancer syndromes RASL10B has been reported to be differentially hypomethy- and their high-risk family members also expect early detec- lated in FXXC cancers compared to Lynch syndrome can- tion and intense surveillance to prevent and manage several cers . RASL10B is one member of Ras superfamily life-threatening malignancies. Moreover, screening, genetic with antitumor potential. Of note, segregation of deranged testing, and counseling of at-risk kindred can translate into methylation of RASL10B was revealed in relation to the a significant benefit across multiple generations, demonstrat- progression of sessile serrated adenomas/polyps5, which are ing the tremendous importance of understanding the genetic regarded as a putative prelude of colon cancer. A number profile and clinicopathological features of each syndrome. We of studies have mainly focused attention on different genes have herein provided a comprehensive overview of several between MMR-deficient and MMR-proficient nonpolyposis common hereditary colorectal nonpolyposis and cancer syn- tumors. es Th e two groups show various gene expression dromes for clinicians to successfully handle while engaged profiles of blood telomere length. Many studies support that in a busy clinical practice. Physicians should therefore stay long telomeres are associated with increased cancer risk: abreast of these discoveries. long telomeres may decrease cell apoptosis, accumulating eTh re still remain some problems. Interactions with deranged genomic aberrations. FCCX cancer patients had environmental factors make the identification and validation longer telomeres than healthy individuals of the same type of genetic deleterious mutations or genes complicated. First, X families and LS cancer families . 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