Xavier Llor, MD, PhD

Dr. Llor obtained his MD degree at the Autonomous University of Barcelona and his PhD in molecular biology at the University of Barcelona. He completed his Internal Medicine Residency at the University of Chicago-Lutheran General Hospital Program and his GI fellowship at the University of Illinois at Chicago. In 2014, Dr. Llor joined Yale University as co-Director of the Cancer Genetics and Prevention Program, Medical Director of the Colorectal Cancer Prevention Program, and more recently Associate Director of Cancer Screening at Yale's Cancer Center.

A clinically active gastroenterologist, Dr. Llor's research and clinical interests relate to GI cancer, mostly colorectal and stomach, with an emphasis on genetics and disparities. He spearheaded and carried out three large prospective cohorts of colorectal cancer patients and controls that produced a wealth of information. Some important contributions from Dr. Llor's lab include the description of the best diagnostic approaches to Lynch syndrome diagnosis; clinical and molecular characterization of mismatch repair proficient hereditary non-polyposis colorectal cancer (type X); identification of distinct clinical and molecular features of colorectal cancers in young African Americans, phenotypic features of hereditary gastric cancer.

Some of the themes of my research include:

1. Lynch syndrome (LS) is the most common inherited CRC syndrome and it is characterized by cancer development at a young age and very high risk of different extra-colonic malignancies. Affected family members require intensive cancer surveillance. LS is caused by mutations in the mismatch repair genes that result in tumor microsatellite instability (MSI) and loss of expression of the corresponding protein. A tremendous challenge is still diagnosing individuals with LS as patients do not have an obvious pre-morbid phenotype (development of multiple polyps) that could suggest the presence of this syndrome. Thus, establishing the best diagnostic approaches has been an important priority over the last few years. I have performed several studies that have become seminal in the diagnostic process of LS.

a. Pinol, Castells A, Andreu M, Castellví-Bel S, Alenda C, et al. Accuracy of revised Bethesda guidelines, microsatellite instability, and immunohistochemistry for the identification of patients with hereditary nonpolyposis colorectal cancer. JAMA. 2005 Apr 27;293(16):1986-94.

b. Xicola RM, Llor X*, Pons E, Castells A, Alenda C, et al. Performance of different microsatellite marker panels for detection of mismatch repair-deficient colorectal tumors. J Natl Cancer Inst. 2007 Feb 7;99(3):244-52. *Corresponding author.

c. Balaguer F, Balmaña J, Castellví-Bel S, Steyerberg EW, Andreu M, et al. Validation and extension of the PREMM1,2 model in a population-based cohort of colorectal cancer patients. Gastroenterology. 2008 Jan;134(1):39-46. PMCID: PMC2542581.

d. Bessa X, Ballesté B, Andreu M, Castells A, Bellosillo B, et al. A prospective, multicenter, population-based study of BRAF mutational analysis for Lynch syndrome screening. Clin Gastroenterol Hepatol. 2008 Feb;6(2):206-14.

2. African Americans have the highest incidence and mortality from colorectal cancer and several studies have suggested some clear biological differences. In order to better understand these differences while taking into account social and environmental factors, I established and lead the Chicago Colorectal Cancer Consortium (CCCC), a multiethnic cohort that recruited over 600 patients with CRC of which over 60% are African Americans. The CCCC established a strong team of collaborators working towards the identification of genetic-environmental interactions and socio-economic aspects. Some important findings have already been published and other manuscripts are under preparation. As these is a rich repository of clinical data and biological samples, we expect many more studies will be published in the future based on this cohort

a. RM Xicola, Z Manojlovic, GJ. Augustus, SS Kupfer, R Emmadi, et al. Lack of APC somatic mutation is associated with early-onset colorectal cancer in African Americans. Carcinogenesis. 2018 Dec 13;39(11):1331-1341. PMCID: PMC6292413

b. Pibiri F, Kittles RA, Sandler RS, Keku TO, Kupfer SS, et al. Genetic variation in vitamin D-related genes and risk of colorectal cancer in African Americans. Cancer Causes Control. 2014 May;25(5):561-70. PMCID: PMC3978221.

c. Xicola RM, Gagnon M, Clark JR, Carroll T, Gao W, et al. Excess of proximal microsatellite-stable colorectal cancer in African Americans from a multiethnic study. Clin Cancer Res. 2014 Sep 15;20(18):4962-70. PMCID: PMC4167473.

d. Guindalini RS, Win AK, Gulden C, Lindor NM, Newcomb PA, et al. Mutation spectrum and risk of colorectal cancer in African American families with Lynch syndrome. Gastroenterology. 2015 Nov;149(6):1446-53. PMCID: PMC4648287.

3. Colorectal cancer is among all common malignancies one with the highest percentage of familial clustering. In fact, several hereditary colorectal cancer syndromes have already been well characterized, which has allowed the implementation of genetic screening and prophylactic and preventive measures. Nevertheless, about half of the families showing a pedigree strongly suggestive of an autosomal dominant inheritance pattern with no polyposis phenotype do not have known genetic predisposing mutations identified so far. I have carried out different studies to characterize these patients, investigating germline associations as well as distinctive carcinogenic processes in order to identify their potential biological cause. Several key features have been identified and these describe this group as a different colorectal cancer entity.

a. Llor X, Pons E, Xicola RM, Castells A, Alenda C, et al. Differential features of colorectal cancers fulfilling Amsterdam criteria without involvement of the mutator pathway. Clin Cancer Res. 2005 Oct 15;11(20):7304-10.

b. Goel A, Xicola RM, Nguyen TP, Doyle BJ, Sohn VR, et al. Aberrant DNA methylation in hereditary nonpolyposis colorectal cancer without mismatch repair deficiency. Gastroenterology. 2010 May;138(5):1854-62. PMCID: PMC2859993.

c. Rodríguez-Soler M, Pérez-Carbonell L, Guarinos C, Zapater P, Castillejo A, et al. Risk of cancer in cases of suspected lynch syndrome without germline mutation. Gastroenterology. 2013 May;144(5):926-932.e1; quiz e13-4.

b. Xicola RM, Bontu S, Doyle BJ, Rawson J, Garre P, et al. Association of a let-7 miRNA binding region of TGFBR1 with hereditary mismatch repair proficient colorectal cancer (MSS HNPCC). Carcinogenesis. 2016 Aug;37(8):751-8. PMCID: PMC4967215.