Preventive strategies in familial and hereditary colorectal cancer.

Colorectal cancer is a leading cause of cancer-related deaths worldwide. While most cases are sporadic, a significant proportion of cases are associated with familial and hereditary syndromes. Individuals with a family history of colorectal cancer have an increased risk of developing the disease, and those with hereditary syndromes such as Lynch syndrome or familial adenomatous polyposis have a significantly higher risk. In these populations, preventive strategies are critical for reducing the incidence and mortality of colorectal cancer. This review provides an overview of current preventive strategies for individuals at increased risk of colorectal cancer due to familial or hereditary factors. The manuscript includes a discussion of risk assessment and genetic testing, highlighting the importance of identifying at-risk individuals and families. This review describes various preventive measures, including surveillance colonoscopy, chemoprevention, and prophylactic surgery, and their respective benefits and limitations. Together, this work highlights the importance of preventive strategies in familial and hereditary colorectal cancer.

Colorectal Cancer in Younger Adults.

Contrary to decreasing incidence rate of colorectal cancer (CRC) in older adults, incidence rates have nearly doubled in younger adults (age <50 years) in the United States since the early 1990s. A similar increase has been observed across the globe. Despite overall population trends in aging, about 15% of CRCs will be diagnosed in younger adults by 2030. The mechanisms and factors contributing to early-onset CRC (EOCRC) remain puzzling, especially because most young adults diagnosed with CRC have no known risk factors or predisposing conditions, such as family history of CRC or polyps or a hereditary syndrome (eg, Lynch syndrome, polyposis). In this up-to-date review, we discuss the current knowledge of EOCRC, including epidemiology, risk factors, clinical and molecular features, treatment and survival, and recognition and screening strategies.

Racial and Ethnic Disparities in Germline Genetic Testing of Patients With Young-Onset Colorectal Cancer.

BACKGROUND & AIMS: Up to 20% of younger patients (age <50 years) diagnosed with colorectal cancer (CRC) have germline mutations in cancer susceptibility genes. Germline genetic testing may guide clinical management and facilitate earlier intervention in affected relatives. Few studies have characterized differences in genetic testing by race/ethnicity. METHODS: We identified young adults (age 18-49 years) diagnosed with CRC between 2009 and 2017 in 2 health systems in Dallas, TX. We evaluated referral to genetic counseling, attendance at genetic counseling appointments, and receipt of germline genetic testing by race/ethnicity. RESULTS: Of 385 patients with young-onset CRC (median age at diagnosis 44.4 years), 176 (45.7%) were Hispanic, 98 (25.4%) non-Hispanic Black, and 111 (28.8%) non-Hispanic White. Most patients (76.9%) received immunohistochemistry (IHC) for mismatch repair proteins, and there was no difference in receipt of IHC by race/ethnicity. However, a lower proportion of Black patients were referred to genetic counseling (50.0% vs White patients 54.1% vs Hispanic patients 65.9%; P = .02) and attended genetic counseling appointments (61.2% vs 81.7% White patients vs 86.2% Hispanic patients; P < .01). Of 141 patients receiving genetic testing, 38 (27.0%) had a pathogenic or likely pathogenic variant in a cancer susceptibility gene. An additional 33 patients (23.4%) had variants of uncertain significance, of which 84.8% occurred in racial/ethnic minorities. CONCLUSIONS: In a diverse population of patients diagnosed with young-onset CRC, we observed racial/ethnic differences in referral to and receipt of germline genetic testing. Our findings underscore the importance of universal genetic testing to address racial/ethnic disparities in young-onset CRC.

Is Colorectal Cancer in Patients Younger Than 50 Years of Age the Same Disease as in Older Patients?

The incidence of colorectal cancer (CRC) has declined steadily in persons over age 50 years of age, largely due to screening. In contrast, incidence rates have increased rapidly in younger adults (<50 years of age),1 raising the question of whether young-onset CRC is a distinct disease with unique biologic features or if it is the same disease occurring at a younger age. Studies comparing younger and older patients diagnosed with CRC have reported differences in clinical and molecular features, including tumor location, stage, and histology.2-6 However, increasing use of screening colonoscopy in the population has changed characteristics of CRC diagnosed over 50 years of age (eg, higher proportion now diagnosed with proximal tumors and/or at an earlier stage),7 so it is challenging to draw conclusions about the importance of these findings. To address this challenge, we compared characteristics of younger and older CRC patients in a predominantly unscreened population.

Exome sequencing links mutations in PARN and RTEL1 with familial pulmonary fibrosis and telomere shortening.

Idiopathic pulmonary fibrosis (IPF) is an age-related disease featuring progressive lung scarring. To elucidate the molecular basis of IPF, we performed exome sequencing of familial kindreds with pulmonary fibrosis. Gene burden analysis comparing 78 European cases and 2,816 controls implicated PARN, an exoribonuclease with no previous connection to telomere biology or disease, with five new heterozygous damaging mutations in unrelated cases and none in controls (P = 1.3 × 10(-8)); mutations were shared by all affected relatives (odds in favor of linkage = 4,096:1). RTEL1, an established locus for dyskeratosis congenita, harbored significantly more new damaging and missense variants at conserved residues in cases than in controls (P = 1.6 × 10(-6)). PARN and RTEL1 mutation carriers had shortened leukocyte telomere lengths, and we observed epigenetic inheritance of short telomeres in family members. Together, these genes explain ~7% of familial pulmonary fibrosis and strengthen the link between lung fibrosis and telomere dysfunction.