Familial colorectal cancer Type X (ORPHA:440437)
A rare inherited cancer-predisposing syndrome characterized by the fulfilment of the Amsterdam criteria for hereditary nonpolyposis colorectal cancer (HNPCC) but without alterations, either somatic or germline, in the DNA mismatch repair (MMR) genes.
Epidemiology
Cummulative evidence suggests that 40% of families with hereditary non-polyposis colorectal cancer (meeting Amsterdam criteria) do not show defects in the MMR machinery. A US population-based study finds that 2.6% of all colorectal cancer patients diagnosed meet the Amsterdam criteria for HNPCC, placing the estimated incidence of Familial Colorectal Cancer Type X (FCCTX) at approximately 1% of all CRC cases. There is no male or female predominance.
Clinical description
FCCTX includes a heterogeneous group of patients with familial aggregation of colorectal cancer (CRC), without gastrointestinal polyposis, and without evidence or molecular suspicion of Lynch syndrome. FCCTX is characterized by a strong aggregation of CRC cases in the family (fulfilment of Amsterdam criteria for hereditary nonpolyposis CRC) and absence of MMR deficiency, either germline or somatic. FCCTX tumors have normal expression of MMR proteins and no microsatellite instability, and no germline pathogenic variants in MMR genes are identified. FCCTX tumors are heterogeneous, likely due to their different etiologies. Compared to Lynch syndrome, FCCTX is not associated with extracolonic cancers, has a later mean age at CRC diagnosis (50-60 years vs 40 years), is more likely left-sided, and less likely associated with synchronous or metachronous cancers. FCCTX tumors have a more heterogeneous architecture, a predominant tubular growth pattern, less frequent mucinous histology, and less frequent peritumoral or tumor-infiltrating lymphocytes.
Etiology
The search for FCCTX causal genes has been large unsuccessful. Despite the identification of multiple candidate genes, only RSP20 has been unequivocally linked to the disease, explaining approximatively 0.07% of MMR-proficient familial/early-onset CRC cases.
Diagnostic methods
By definition, the diagnosis of FCCTX is based on the fulfilment of the clinical Amsterdam criteria for hereditary non-polyposis CRC and absence of an MMR defect. Amsterdam criteria include: having at least three relatives affected with histologically confirmed CRC or another HNPCC-associated cancer (endometrial, small bowel, ureter, renal pelvis), with at least one patient being a first-degree relative of the other two; at least two successive generations affected; at least one cancer diagnosed before age 50 (adenomatous polyposis excluded). MMR proficiency is evaluated under these criteria: Absence of microsatellite instability (MSI) in the tumors; normal expression of MLH1, MSH2, MSH6 and PMS2 proteins in the tumors; no germline pathogenic variants in the MMR genes. Multigene panel testing must be considered for CRC patients and/or families suspected of having a hereditary colorectal cancer syndrome and may reveal, although unfrequently, an RPS20 mutation in the case of FCCTX.
Differential diagnosis
Differential diagnosis includes Lynch syndrome and other forms of MMR-deficient hereditary nonpolyposis colon cancer. In rare cases, nonpolyposis CRC can occur in some forms of intestinal polyposis syndromes, caused by germline pathogenic variants in polyposis genes with a particularly broad polyposis expressivity—e.g. BMPR1A, MUTYH (biallelic), POLE, POLD1, or NTHL1. Other hereditary cancer syndromes may predispose to MMR-proficient CRC (and may be caused by mutations in BRCA1, BRCA2, ATM, CHEK2, or TP53).
Genetic counseling
A germline pathogenic variant in a hereditary cancer gene is hardly ever identified in FCCTX cases. Due to the increased risk of CRC, genetic counseling should be offered to family members based on the family history of cancer and ages at diagnosis following country-specific guidelines. RPS20-associated hereditary nonpolyposis CRC is an autosomal dominant disease. There is a 50% risk of transmitting the pathogenic allele at each pregnancy. The scarce data available suggests that this form of CRC occurs in the adulthood and that its penetrance is likely high.
Management and treatment
In the absence of a pathogenic variant in a cancer predisposition gene, cancer surveillance and clinical management of FCCTX families should be based on the personal and family history of cancer and the ages at cancer onset, as recommended by country-specific guidelines for colorectal cancer.
Prognosis
FCCTX cases show an excess of cancer-related mortality compared to Lynch syndrome, and an overall worse prognosis, both in terms of disease-free and overall survival.

                            Last update: 
                            December 2022


                            - Expert reviewer(s): 
                            Pr Stefan ARETZ | ERN GENTURIS* - Dr Marta PINEDA RÍU | ERN GENTURIS* - Dr Laura VALLE | ERN GENTURIS*


                                * European Reference Network